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Current Publications Count: 653
| Title | Author | Year | Journal | Volume | Issue | Pages | DOI | Accession number | Keywords | Abstract | All authors/Notes | Link | Epub date |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Plasma proteomic profiles of pain subtypes in adolescents and young adults with endometriosis | Naoko Sasamoto | 2023 | Human Reproduction | What are the similarities and differences in the systemic proteomic profiles by endometriosis-associated pain subtypes among adolescents and young adults with endometriosis? | Naoko Sasamoto, Long Ngo, Allison F Vitonis, Simon T Dillon, Christine B Sieberg, Stacey A Missmer, Towia A Libermann, Kathryn L Terry | 05/17/2023 | |||||||
| Analytical validation of the PROphet computational model for clinical benefit prediction and decision-making tool in metastatic NSCLC | Itamar Sela | 2023 | bioRxiv | https://doi.org/10.1101/2023.04.20.537648 | Itamar Sela, Coren Lahav, Ben Yellin, Yehonatan Elon, Michal Harel | 04/24/2023 | |||||||
| Circulating proteins to predict COVID-19 severity | Chen-Yang Su | 2023 | Scientific Reports | 13 | 6236 | https://doi.org/10.1038/s41598-023-31850-y | Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict COVID-19 severity in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different COVID-19 severity were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of COVID-19 severity. Further research is needed to understand how to incorporate protein measurement into clinical care. | Chen-Yang Su, Sirui Zhou, Edgar Gonzalez-Kozlova, Guillaume Butler-Laporte, Elsa Brunet-Ratnasingham, Tomoko Nakanishi, Wonseok Jeon, David R. Morrison, Laetitia Laurent, Jonathan Afilalo, Marc Afilalo, Danielle Henry, Yiheng Chen, Julia Carrasco-Zanini, Yossi Farjoun, Maik Pietzner, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk, Meriem Bouab, Louis Petitjean, Charlotte Guzman, Xiaoqing Xue, Chris Tselios, Branka Vulesevic, Olumide Adeleye, Tala Abdullah, Noor Almamlouk, Yara Moussa, Chantal DeLuca, Naomi Duggan, Erwin Schurr, Nathalie Brassard, Madeleine Durand, Diane Marie Del Valle, Ryan Thompson, Mario A. Cedillo, Eric Schadt, Kai Nie, Nicole W. Simons, Konstantinos Mouskas, Nicolas Zaki, Manishkumar Patel, Hui Xie, Jocelyn Harris, Robert Marvin, Esther Cheng, Kevin Tuballes, Kimberly Argueta, Ieisha Scott, The Mount Sinai COVID-19 Biobank Team, Celia M. T. Greenwood, Clare Paterson, Michael A. Hinterberg, Claudia Langenberg, Vincenzo Forgetta, Joelle Pineau, Vincent Mooser, Thomas Marron, Noam D. Beckmann, Seunghee Kim-schulze, Alexander W. Charney, Sacha Gnjatic, Daniel E. Kaufmann, Miriam Merad & J. Brent Richards | 04/17/2023 | ||||
| Multi-omics identify falling LRRC15 as a COVID-19 severity marker and persistent pro-thrombotic signals in convalescence | Gisby J S, et al. | 2022 | Nature Communications | Patients with end-stage kidney disease (ESKD) are at high risk of severe COVID19. Here, we perform longitudinal blood sampling of ESKD haemodialysis patients with COVID-19, collecting samples pre-infection, serially during infection, and after clinical recovery. Using plasma proteomics, and RNAsequencing and flow cytometry of immune cells, we identify transcriptomic and proteomic signatures of COVID-19 severity, and find distinct temporal molecular profiles in patients with severe disease. | Jack S. Gisby, Norzawani B. Buiang, Artemis Papadaki, Candice L. Clarke, Talat H. Malik, Nicholas Medjeral-Thomas, Damiola Pinheiro, Page M. Mortimer, Shanice Lewis, Eleanor Sandhu, Stephen P McAdoo, Maria F. Prendecki, Michelle Willicombe, Matthew C. Pickering, Marina Botto, David C Thomas, James E. Peters | 12/15/2022 | |||||||
| Siglec-7 is a predictive biomarker for the efficacy of cancer vaccination against metastatic colorectal cancer | Yamada K, et al. | 2021 | Oncol Lett | 21 | 1 | 10 | https://doi.org/10.3892/ol.2020.12271 | biomarker; colorectal cancer; peptide vaccine; protein expression analysis; sialic acid-binding immunoglobulin type lectin-7. | Cancer immunotherapy, including vaccination, is considered a major scientific and medical breakthrough. However, cancer immunotherapy does not result in durable objective responses against colorectal cancer (CRC). To improve the efficacy of immunotherapy, the present study investigated several biomarkers for selecting patients who were expected to respond well to immunotherapy. Firstly, a comprehensive proteomic analysis was performed using tumor tissue lysates from patients enrolled in a phase II study, in which five human leukocyte antigen (HLA)-A*24:02-restricted peptides were administered. Sialic acid-binding immunoglobulin type lectin (Siglec)-7 was identified as a potential predictive biomarker. Subsequently, this biomarker was validated using western blot analysis, and immunofluorescence using tissue samples from the patients enrolled in the phase II study. The expression levels of Siglec-7 detected by immunofluorescence were quantified and their association with overall survival (OS) in patients treated with the peptide vaccine was examined. Furthermore, considering the important role of tumor-infiltrating lymphocytes (TILs) for CRC prognosis, the densities of CD3+, CD4+, CD8+ and forkhead box P3 (FOXP3)+ T cells in CRC tissues were examined and compared with Siglec-7 expression. The mean expression levels of Siglec-7 were significantly higher in patients with poor prognosis, with an OS of ≤2 years, as shown in comprehensive proteomic analysis (P=0.016) and western blot analysis (P=0.025). Immunofluorescence analysis demonstrated that Siglec-7 was expressed in intratumoral macrophages. The OS in patients with high Siglec-7 expression was significantly shorter than in that in patients with low Siglec-7 expression (P=0.017) in the HLA-A*24:02-matched patients. However, this difference was not observed in the HLA-unmatched patients. There was no significant difference in OS between patients according to the numbers of TILs, nor significant correlation between TILs and Siglec-7 expression. In conclusion, Siglec-7 expression in macrophages in tumor tissue may be a novel predictive biomarker for the efficacy of immunotherapy against metastatic CRC. | Yamada K, Hazama S, Suzuki N, Xu M, Nakagami Y, Fujiwara N, Tsunedomi R, Yoshida S, Tomochika S, Matsukuma S, Matsui H, Tokumitsu Y, Kanekiyo S, Shindo Y, Watanabe Y, Iida M, Takeda S, Ioka T, Ueno T, Ogihara H, Hamamoto Y, Hoshii Y, Kawano H, Fujita T, Kawakami Y, Nagano H. | 11/03/2021 | ||
| Proteome-Wide Analysis Using SOMAscan Identifies and Validates Epidermal Growth Factor as a Disease Marker of Collagenous Gastritis | Curci D, et al. | 2022 | Gastro Hep Advances | 1 | 5 | 689-702 | https://doi.org/10.1016/j.gastha.2022.04.016 | Collagenous Gastritis; Proteomics; Biomarker; Epidermal Growth Factor | Collagenous gastritis (CG) is a rare disorder characterized by increased subepithelial collagen deposition and inflammatory infiltrates. The mechanisms involved in CG pathogenesis are poorly understood, and no CG-associated biomarkers have been identified. This proteomics study identified serum biomarkers and pathogenic pathways to provide new knowledge about the pathobiology of CG, a disease reported in less than 100 patients. | Debora Curci, Simon T. Dillon, Xuesong Gu, Harland Winter, Towia A. Libermann | 04/08/2022 | ||
| High-Multiplex Aptamer-Based Serum Proteomics to Identify Candidate Serum Biomarkers of Oral Squamous Cell Carcinoma | Blatt S, et al. | 2023 | Cancers | 15 | 7 | 2071 | https://doi.org/10.3390/cancers15072071 | oral cancer; SOMAscan; proteomics; liquid biopsy; biomarker; serum; prognosis; therapy | Improved serological biomarkers are needed for the early detection, risk stratification and treatment surveillance of patients with oral squamous cell carcinoma (OSCC). We performed an exploratory study using advanced, highly specific, DNA-aptamer-based serum proteomics (SOMAscan, 1305-plex) to identify distinct proteomic changes in patients with OSCC pre- vs. post-resection and compared to healthy controls. A total of 63 significantly differentially expressed serum proteins (each p < 0.05) were found that could discriminate between OSCC and healthy controls with 100% accuracy. Furthermore, 121 proteins were detected that were significantly altered between pre- and post-resection sera, and 12 OSCC-associated proteins reversed to levels equivalent to healthy controls after resection. Of these, 6 were increased and 6 were decreased relative to healthy controls, highlighting the potential relevance of these proteins as OSCC tumor markers. Pathway analyses revealed potential pathophysiological mechanisms associated with OSCC. Hence, quantitative proteome analysis using SOMAscan technology is promising and may aid in the development of defined serum marker assays to predict tumor occurrence, progression and recurrence in OSCC, and to guide personalized therapies. | Blatt, S.; Kämmerer, P.W.; Krüger, M.; Surabattula, R.; Thiem, D.G.E.; Dillon, S.T.; Al-Nawas, B.; Libermann, T.A.; Schuppan, D. | 03/30/2023 | ||
| CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease | Pierson SK, et al. | 2022 | Nat Commun | 13 | 1 | 7236 | https://www.doi.org/10.1038/s41467-022-34873-7 | 36,433,996 | Humans, *Castleman Disease/drug therapy, Biomarkers, Healthy Volunteers, Immunotherapy, Chemokine CXCL13 | Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly-understood cytokine storm-driven inflammatory disorder. Interleukin-6 (IL-6) is a known disease driver in some patients, but anti-IL-6 therapy with siltuximab is not effective in all patients, and biomarkers indicating success at an early time point following treatment initiation are lacking. Here we show, by comparison of levels of 1,178 proteins in sera of healthy participants (N = 42), patients with iMCD (N = 88), and with related diseases (N = 60), a comprehensive landscape of candidate disease mediators and predictors of siltuximab response. C-X-C Motif Chemokine Ligand-13 (CXCL13) is identified and validated as the protein most prominently up-regulated in iMCD. Early and significant decrease in CXCL13 levels clearly distinguishes siltuximab responders from non-responders; a 17% reduction by day 8 following siltuximab therapy initiation is predictive of response at later time points. Our study thus suggests that CXCL13 is a predictive biomarker of response to siltuximab in iMCD. | Pierson, Sheila K, Katz, Laura, Williams, Reece, Mumau, Melanie, Gonzalez, Michael, Guzman, Stacy, Rubenstein, Ayelet, Oromendia, Ana B, Beineke, Philip, Fossa, Alexander, van Rhee, Frits, Fajgenbaum, David C | 11/27/2022 | |
| Effect of pegbelfermin on NASH and fibrosis-related biomarkers and correlation with histological response in the FALCON 1 trial | Elizabeth A. Brown, et al. | 2023 | JHEP Reports | FALCON 1 was a phase IIb study of pegbelfermin in patients with non-alcoholic steatohepatitis (NASH) and stage 3 fibrosis. This FALCON 1 post hoc analysis aimed to further assess the effect of pegbelfermin on NASH-related biomarkers, correlations between histological assessments and non-invasive biomarkers, and concordance between the week 24 histologically assessed primary endpoint response and biomarkers. | EA Brown, A Minnich, AJ Sanyal, R Loomba | 04/01/2023 | |||||||
| A proteomic approach for investigating the pleiotropic effects of statins in the atherosclerosis risk in communities (ARIC) study | Bruno Bohn, et al. | 2023 | Journal of Proteomics | Statins are prescribed to reduce LDL-c and risk of CVD. Statins have pleiotropic effects, affecting pathophysiological functions beyond LDL-c reduction. We compared the proteome of statin users and nonusers (controls). We hypothesized that statin use is associated with proteins unrelated to lipid metabolism. | B Bohn, PL Lutsey, W Tang, JS Pankow, FL Norby | 02/10/2023 | |||||||
| Circulatory proteins relate cardiovascular disease to cognitive performance: A mendelian randomisation study | Jian Huang, et al. | 2023 | Front Genet | Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. Interventions targeting proteins relevant to shared mechanisms underlying CVD and dementia could also be used for the prevention of cognitive impairment. | J Huang, D Gill, V Zuber, PM Matthews, P Elliott | 02/17/2023 | |||||||
| High dimensional proteomics identifies organ injury patterns associated with outcomes in human trauma | Héléne T. Cronjé, et al. | 2023 | Diabetes | High-throughput proteomics allow researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. | Héléne T. Cronjé; Michael Y. Mi; Thomas R. Austin; Mary L. Biggs; David S. Siscovick; Rozenn N. Lemaitre; Bruce M. Psaty; Russell P. Tracy; Luc Djoussé; Jorge R. Kizer; Joachim H. Ix; Prashant Rao; Jeremy M. Robbins; Jacob L. Barber; Mark A. Sarzynski; Clary B. Clish; Claude Bouchard; Kenneth J. Mukamal; Robert E. Gerszten; Majken K. Jensen | 02/07/2023 | |||||||
| Human influenza virus infection elicits distinct patterns of monocyte and dendritic cell mobilization in blood and the nasopharynx | Sindhu Vangeti, et al. | 2023 | Elife | uring respiratory viral infections, the precise roles of monocytes and dendritic cells (DCs) in the nasopharynx in limiting infection and influencing disease severity are incompletely described. We studied circulating and nasopharyngeal monocytes and DCs in healthy controls (HCs) and in patients with mild to moderate infections (primarily influenza A virus [IAV]). | Sindhu Vangeti, Sara Falck-Jones, Meng Yu, Björn Österberg, Sang Liu, Muhammad Asghar, Klara Sondén, Clare Paterson, Penn Whitley, Jan Albert, Niclas Johansson, Anna Färnert, Anna Smed-Sörensen | 02/08/2023 | |||||||
| Preclinical Serological Signatures are Associated with Complicated Crohn's Disease Phenotype at Diagnosis | Rok Seon Choung, et al. | 2023 | Clinical Gastroenterology and Hepatology | At diagnosis, up to one-third of patients with Crohn’s disease (CD) have a complicated phenotype with stricturing (B2) or penetrating (B3) behavior or require early surgery. We evaluated protein biomarkers and antimicrobial antibodies in serum archived years before CD diagnosis to assess whether complicated diagnoses were associated with a specific serological signature. | 02/11/2023 | ||||||||
| PSMA2 knockdown impacts expression of proteins involved in immune and cellular stress responses in human lung cells | Rashid MU, et al. | 2023 | Biochim Biophys Acta Mol Basis | No study yet has reported PSMA2 knockdown (KD) effects on the cellular proteome. METHODS: We used SOMAScan, an aptamer-based multiplexed technique, to measure >1300 human proteins to determine the impact of PSMA2 KD on A549 human lung epithelial cells. ... | Meng Yu, | 12/01/2022 | |||||||
| Cross-sectional proteomic expression in Parkinson's disease-related proteins in drug-naïve patients vs healthy controls with longitudinal clinical follow-up | Abdi IY, et al. | 2023 | Neurobiol Dis | There is an urgent need to find reliable and accessible blood-based biomarkers for early diagnosis of Parkinson's disease (PD) correlating with clinical symptoms and displaying predictive potential to improve future clinical trials. This led us to a conduct large-scale proteomics approach using an advanced high-throughput proteomics technology to create a proteomic profile for PD. Over 1300 proteins were measured in serum samples from a de novo Parkinson's (DeNoPa) cohort made up of 85 deep clinically phenotyped drug-naïve de novo PD patients and 93 matched healthy controls (HC) with longitudinal clinical follow-up available of up to 8 years. | Björn Österberg, | 01/10/2023 | |||||||
| Human influenza virus infection elicits distinct patterns of monocyte and dendritic cell mobilization in blood and the nasopharynx | Vangeti S, et al. | 2023 | Elife | In patients with other respiratory virus infections, we observed changes in monocyte and DC frequencies in the nasopharynx distinct from IAV patients, while differences in blood were more similar across infection groups. Using SomaScan, a high-throughput aptamer-based assa … | Sang Liu, | 02/01/2023 | |||||||
| Adjudicated myocarditis and multisystem illness trajectory in healthcare workers post-COVID-19. | Sykes R, et al. | 2023 | Open Heart | We investigated the associations of healthcare worker status with multisystem illness trajectory in hospitalised post-COVID-19 individuals. | Muhammad Asghar, | 02/10/2023 | |||||||
| Human influenza virus infection elicits distinct patterns of monocyte and dendritic cell mobilization in blood and the nasopharynx. | Sindhu Vangeti, et al. | 2023 | Elife | During respiratory viral infections, the precise roles of monocytes and dendritic cells (DCs) in the nasopharynx in limiting infection and influencing disease severity are incompletely described. We studied circulating and nasopharyngeal monocytes and DCs in healthy controls (HCs) and in patients with mild to moderate infections (primarily influenza A virus [IAV]). As compared to HCs, patients with acute IAV infection displayed reduced DC but increased intermediate monocytes frequencies in blood, and an accumulation of most monocyte and DC subsets in the nasopharynx. | Klara Sondén, | 02/08/2023 | |||||||
| A proteomic approach for investigating the pleiotropic effects of statins in the atherosclerosis risk in communities (ARIC) study | Bruno Bohn | 2022 | J Proteomics | Statins are prescribed to reduce LDL-c and risk of CVD. Statins have pleiotropic effects, affecting pathophysiological functions beyond LDL-c reduction. We compared the proteome of statin users and nonusers (controls). We hypothesized that statin use is associated with proteins unrelated to lipid metabolism. | Clare Paterson, | 12/08/2022 | |||||||
| PSMA2 knockdown impacts expression of proteins involved in immune and cellular stress responses in human lung cells | Rashid MU, et al. | 2022 | Biochim Biophys Acta Mol Basis | Proteasome subunit alpha type-2 (PSMA2) is a critical component of the 20S proteasome, which is the core particle of the 26S proteasome complex and is involved in cellular protein quality control by recognizing and recycling defective proteins. PSMA2 expression dysregulation has been detected in different human diseases and viral infections. No study yet has reported PSMA2 knockdown (KD) effects on the cellular proteome. | Penn Whitley, | 12/05/2022 | |||||||
| Multi-omics studies in historically excluded populations: the road to equity | G Yang, et al. | 2022 | Clinical Pharmacology & Therapeutics | Over the past few decades, genomewide association studies (GWASs) have identified the specific genetics variants contributing to many complex diseases by testing millions of genetic variations across the human genome against a variety of phenotypes. However, GWASs are limited in their ability to uncover mechanistic insight given that most significant associations are found in non-coding region of the genome. | Jan Albert, | 12/10/2022 | |||||||
| Proteomic profiling of serum identifies a molecular signature that correlates with clinical outcomes in COPD | R Dagher, et al. | 2022 | Plos One | Novel biomarkers related to main clinical hallmarks of Chronic obstructive pulmonary disease (COPD), a heterogeneous disorder with pulmonary and extra-pulmonary manifestations, were investigated by profiling the serum levels of 1305 proteins using Slow Off-rate Modified Aptamers (SOMA)scan technology. | Niclas Johansson, | 12/08/2022 | |||||||
| Radiation therapy induces innate immune responses in patients treated for prostate cancers | AK Cheema, et al. | 2022 | Clinical Cancer Research | Radiation therapy (RT) is a curative therapeutic modality used to treat cancers as a single agent or in combination with surgery and chemotherapy. Advanced RT technologies enable treatment with large fractions and highly conformal radiation doses to effect free-radical damage to cellular DNA leading to cell cycle arrest, cell death, and innate immune response (IIR) stimulation. | Anna Färnert, | 12/01/2022 | |||||||
| Molecular models of multiple sclerosis severity identify heterogeneity of pathogenic mechanisms | P Kosa, et al. | 2022 | Nature Communication | While autopsy studies identify many abnormalities in the central nervous system (CNS) of subjects dying with neurological diseases, without their quantification in living subjects across the lifespan, pathogenic processes cannot be differentiated from epiphenomena. Using machine learning (ML), we searched for likely pathogenic mechanisms of multiple sclerosis (MS). | Anna Smed-Sörensen | 12/12/2022 | |||||||
| Mendelian randomization and genetic colocalization infer the effects of the multi-tissue proteome on 211 complex disease-related phenotypes | C Yang, et al. | 2022 | Genome Medicine | Human proteins are widely used as drug targets. Integration of large-scale protein-level genome-wide association studies (GWAS) and disease-related GWAS has thus connected genetic variation to disease mechanisms via protein. Previous proteome-by-phenome-wide Mendelian randomization (MR) studies have been mainly focused on plasma proteomes. | C Yang, AM Fagan, RJ Perrin, H Rhinn, O Harari | 12/12/2022 | |||||||
| Comparison of Proteomic Measurements Across Platforms in the Atherosclerosis Risk in Communities (ARIC) Study. | Rooney Mary, et al. | 2022 | Clin Chem | The plasma proteome can be quantified using different types of highly multiplexed technologies, including aptamer-based and proximity-extension immunoassay methods. There has been limited characterization of how these protein measurements correlate across platforms and with absolute measures from targeted immunoassays. | Rooney MR, Chen J, Ballantyne CM, Hoogeveen RC, Tang O, Grams ME, Tin A, Ndumele CE, Zannad F, Couper DJ, Tang W, Selvin E, Coresh J. | 12/12/2022 | |||||||
| Predicting AT(N) pathologies in Alzheimer's disease from blood-based proteomic data using neural networks. | Zhang Y, et al. | 2022 | Front Aging Neurosci | Blood-based biomarkers represent a promising approach to help identify early Alzheimer's disease (AD). Previous research has applied traditional machine learning (ML) to analyze plasma omics data and search for potential biomarkers, but the most modern ML methods based on deep learning has however been scarcely explored. In the current study, we aim to harness the power of state-of-the-art deep learning neural networks (NNs) to identify plasma proteins that predict amyloid, tau, and neurodegeneration (AT[N]) pathologies in AD. | Zhang Y, Ghose U, Buckley NJ, Engelborghs S, Sleegers K, Frisoni GB, Wallin A, Lleó A, Popp J, Martinez-Lage P, Legido-Quigley C, Barkhof F, Zetterberg H, Visser PJ, Bertram L, Lovestone S, Nevado-Holgado AJ, Shi L. | 11/29/2022 | |||||||
| Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in nonalcoholic fatty liver disease. | Sanyal AJ, et al. | 2022 | J Hepatol | Despite recent progress, non-invasive tests for the diagnostic assessment and monitoring of non-alcoholic fatty liver disease (NAFLD) remain an unmet need. Herein, we aimed to identify diagnostic signatures of the key histological features of NAFLD. | Sanyal AJ, Williams SA, Lavine JE, Tetri B, Alexander L, Ostroff R, Biegel H, Kowdley K, Chalasani N, Dasarathy S, Diehl AM, Loomba R, Hameed B, Behling C, Kleiner DE, Karpen SJ, Williams J, Jia Y, Yates KP, Tonascia J. | 12/14/2022 | |||||||
| Plasma proteomics reveals early, broad release of chemokine, cytokine, TNF, and interferon mediators following trauma with delayed increases in a subset of chemokines and cytokines in patients that remain critically ill. | Bonaroti J, et al. | 2022 | Front Immunol | Severe injury is known to cause a systemic cytokine storm that is associated with adverse outcomes. However, a comprehensive assessment of the time-dependent changes in circulating levels of a broad spectrum of protein immune mediators and soluble immune mediator receptors in severely injured trauma patients remains uncharacterized. | Bonaroti J, Billiar I, Moheimani H, Wu J, Namas R, Li S, Kar UK, Vodovotz Y, Neal MD, Sperry JL, Billiar TR. | 11/30/2022 | |||||||
| Aptamer proteomics of serum exosomes from patients with Primary Raynaud's and patients with Raynaud's at risk of evolving into Systemic Sclerosis. | Piera-Velazquez S, et al. | 2022 | PLoS One | A major unmet need for Systemic Sclerosis (SSc) clinical management is the lack of biomarkers for the early diagnosis of patients with Raynaud's Phenomenon at high risk of evolving into SSc. | Piera-Velazquez S, Dillon ST, Gu X, Libermann TA, Jimenez SA. | 12/22/2022 | |||||||
| Biomarkers of haemodynamic severity of systemic sclerosis-associated pulmonary arterial hypertension by serum proteome analysis. | Sanges S, et al. | 2022 | Ann Rheum Dis | To mine the serum proteome of patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) and to detect biomarkers that may assist in earlier and more effective diagnosis and treatment. | Sanges S, Rice L, Tu L, Valenzi E, Cracowski JL, Montani D, Mantero JC, Ternynck C, Marot G, Bujor AM, Hachulla E, Launay D, Humbert M, Guignabert C, Lafyatis R. | 12/05/2022 | |||||||
| Classical and alternate complement factor overexpression in non-obese weight matched women with polycystic ovary syndrome does not correlate with vitamin D. | Abu Saleh Md Moin, et al. | 2022 | Front Endocrinol (Lausanne) | Women with polycystic ovary syndrome (PCOS) exhibit complement factor expression changes that may be obesity-driven rather than an intrinsic facet of PCOS; furthermore, complement changes have been associated with vitamin D deficiency, a common feature of PCOS. Therefore, complement pathway proteins and vitamin D levels may be linked in PCOS. | Abu Saleh Md Moin 1, Thozhukat Sathyapalan 2, Alexandra E Butler 1, Stephen L Atkin 1 | 12/31/2022 | |||||||
| Cross-sectional proteomic expression in Parkinson's disease-related proteins in drug-naive patients vs healthy controls with longitudinal clinical follow-up | Abdi IY, et al. | 2023 | Neurobiol Dis | There is an urgent need to find reliable and accessible blood-based biomarkers for early diagnosis of Parkinson's disease (PD) correlating with clinical symptoms and displaying predictive potential to improve future clinical trials. This led us to a conduct large-scale proteomics approach using an advanced high-throughput proteomics technology to create a proteomic profile for PD. | Abdi IY, Bartl M, Dakna M, Abdesselem H, Majbour N, Trenkwalder C, El-Agnaf O, Mollenhauer B. | 01/10/2023 | |||||||
| Differential Proteins Expression Distinguished Between Patients With Infectious and Noninfectious Uveitis. | Pesutti CL, et al. | 2023 | Ocul Immunol Inflamm | We investigated the aqueous humor proteome and associated plasma proteome in patients with infectious or noninfectious uveitis. | Pessuti CL, Medley QG, Li N, Huang CL, Loureiro J, Banks A, Zhang Q, Costa DF, Ribeiro KS, Nascimento H, Muccioli C, Commodaro AG, Huang Q, Belfort R Jr. | 01/13/2023 | |||||||
| Abstract A022: Proteomic age acceleration associated with all-cause mortality in cancer survivors in the Atherosclerosis Risk in Communities (ARIC) Study.[R] | Shuo Wang, et al. | 2023 | Cancer Research | Longer lifespan and improved cancer treatment led to a rapid rise in the number of cancer survivors. However, many cancer survivors have physiological dysregulations at earlier chronological ages than those without cancer, suggesting that cancer survivors’ biological age is higher than their chronological age, i.e., they have accelerated aging. Cancer survivors’ biological age may be estimated by a novel proteomic aging clock (PAC). | Shuo Wang | 01/15/2023 | |||||||
| Perinatal Mood and Anxiety Disorders: biomarker discovery using plasma proteomics. | Accortt E, et al. | 2023 | Am J Obstet Gynecol | Perinatal mood and anxiety disorders encompass a range of mental health disorders that occur during pregnancy and up to 1 year postpartum, affecting approximately 20% of women. Traditional risk factors, such as a history of depression and pregnancy complications including preeclampsia, are known. Their predictive utility, however, is not specific or sensitive enough to inform clinical decision-making or prevention strategies for perinatal mood and anxiety disorders. Better diagnostic and prognostic models are needed for early identification and referral to treatment. | Accortt E, Mirocha J, Zhang D, Kilpatrick SJ, Libermann T, Karumanchi SA. | 01/14/2023 | |||||||
| Proteomic Predictors of Incident Diabetes: Results From the Atherosclerosis Risk in Communities (ARIC) Study | Rooney Mary, et al. | 2023 | Diabetes Care | The plasma proteome preceding diabetes can improve our understanding of diabetes pathogenesis. | 01/27/2023 | ||||||||
| Identification of a possible proteomic biomarker in Parkinson's disease: discovery and replication in blood, brain and cerebrospinal fluid. | Winchester L, et al. | 2022 | Brain Commun | Biomarkers to aid diagnosis and delineate the progression of Parkinson's disease are vital for targeting treatment in the early phases of the disease. Here, we aim to discover a multi-protein panel representative of Parkinson's and make mechanistic inferences from protein expression profiles within the broader objective of finding novel biomarkers. | Winchester L, Barber I, Lawton M, Ash J, Liu B, Evetts S, Hopkins-Jones L, Lewis S, Bresner C, Malpartida AB, Williams N, Gentlemen S, Wade-Martins R, Ryan B, Holgado-Nevado A, Hu M, Ben-Shlomo Y, Grosset D, Lovestone S. | 12/28/2022 | |||||||
| Exocrine Proteins Including Trypsin(ogen) as a Key Biomarker in Type 1 Diabetes. | Bakinowska L, et al. | 2023 | Diabetes Care | Diabetes | Proteomic profiling can identify useful biomarkers. Monozygotic (MZ) twins discordant for a condition represent an ideal test population. We aimed to investigate and validate proteomic profiling in twins with type 1 diabetes and in other well-characterized cohorts. | Bakinowska L, Vartak T, Phuthego T, Taylor M, Chandler K, Jerram ST, Williams S, Feldmann M, Johnson DG, Patel KA, Williams AJK, Long AE, Leslie RD, Gillespie KM; Action LADA Consortium and BOX Study Group. | 01/26/2023 | ||||||
| Analytical and Biological Variability of a Commercial Modified Aptamer Assay in Plasma Samples of Patients with Chronic Kidney Disease. | Dubin RF, et al. | 2023 | J Appl Lab Med | We carried out a study of the aptamer proteomic assay, SomaScan V4, to evaluate the analytical and biological variability of the assay in plasma samples of patients with moderate to severe chronic kidney disease (CKD). | Dubin RF, Deo R, Ren Y, Lee H, Shou H, Feldman H, Kimmel P, Waikar SS, Rhee EP, Tin A, Chen J, Coresh J, Go AS, Kelly T, Rao PS, Chen TK, Segal MR, Ganz P. | 01/27/2023 | |||||||
| Proteomic aptamer analysis reveals serum markers that characterize preclinical systemic sclerosis (SSc) patients at risk for progression toward definite SSc. | Bellocchi C et al. | 2023 | Arthritis Res Ther. | Bellocchi C, Assassi S, Lyons M, Marchini M, Mohan C, Santaniello A, Beretta L. | |||||||||
| Abstract WMP101: Plasma Proteomic Determinants Of White Matter Hyperintensities And Covert Brain Infarction In The Cardiovascular Health Study | Bellocchi C et al. | 2023 | Stroke | Identification of novel biomarkers of cerebral small vessel disease is critical to elucidate pathophysiology and guide therapeutic development for prevention. We evaluated plasma proteomic associations of clinically asymptomatic … | M Sharma, WT Longstreth, R Kalani, B Psaty, M Elkind | ||||||||
| Aptamer-Based Plasma Proteomics Nominates Biomarkers Of Neurological Severity, Stroke Diagnosis And Age | A Natu | 2023 | Stroke | Plasma protein biomarkers measured in the hyperacute setting that are associated with stroke diagnosis or with clinical neurological severity, can be diagnostically and prognostically meaningful in patient care. We hypothesized that … | A Natu, P Kumar, MR Frankel, S RANGARAJU | ||||||||
| Proteomic Mediators of Overall Cardiovascular Health on All-Cause Mortality | T Tanaka | 2023 | Nutrients | … The hybridization controls, viral proteins, and flagged SOMAmer Reagents were removed, resulting in a total of 1301 SOMAmer Reagents that were used in the final analysis. Some of the SOMAmer Reagents are designed to capture multiplex … | T Tanaka, SA Talegawkar, Y Jin, J Candia, G Fantoni… - Nutrients, 2023 | ||||||||
| Broadly neutralizing aptamers to SARS-CoV-2: a diverse panel of modified DNA antiviral agents. | Gelinas AD | 2023 | Mol Ther Nucleic Acids | Gelinas AD, Tan TK, Liu S, Jaramillo JG, Chadwick J, Harding AC, Zhang C, Ream BE, Chase CN, Otis MR, Lee T, Schneider DJ, James WS, Janjic N. | |||||||||
| Novel biomarkers and emerging tools to identify causal molecular pathways in hypertension and associated cardiovascular diseases. | Jozefczuk E, et al. | 2023 | Kardiol Pol | Józefczuk E, Guzik TJ, Siedlinski M. | |||||||||
| CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease | Pierson SK, et al. | 2022 | Nat Commun | 13 | 1 | 7236 | https://www.doi.org/10.1038/s41467-022-34873-7 | 36,433,996 | Humans *Castleman Disease/drug therapy Biomarkers Healthy Volunteers Immunotherapy Chemokine CXCL13 | Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly-understood cytokine storm-driven inflammatory disorder. Interleukin-6 (IL-6) is a known disease driver in some patients, but anti-IL-6 therapy with siltuximab is not effective in all patients, and biomarkers indicating success at an early time point following treatment initiation are lacking. Here we show, by comparison of levels of 1,178 proteins in sera of healthy participants (N = 42), patients with iMCD (N = 88), and with related diseases (N = 60), a comprehensive landscape of candidate disease mediators and predictors of siltuximab response. C-X-C Motif Chemokine Ligand-13 (CXCL13) is identified and validated as the protein most prominently up-regulated in iMCD. Early and significant decrease in CXCL13 levels clearly distinguishes siltuximab responders from non-responders; a 17% reduction by day 8 following siltuximab therapy initiation is predictive of response at later time points. Our study thus suggests that CXCL13 is a predictive biomarker of response to siltuximab in iMCD. | Pierson, Sheila K Katz, Laura Williams, Reece Mumau, Melanie Gonzalez, Michael Guzman, Stacy Rubenstein, Ayelet Oromendia, Ana B Beineke, Philip Fossa, Alexander van Rhee, Frits Fajgenbaum, David C eng R01HL141408/U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ England Nat Commun. 2022 Nov 24;13(1):7236. doi: 10.1038/s41467-022-34873-7.I | 11/27/2022 | |
| The Childhood Acute Illness and Nutrition (CHAIN) network nested case-cohort study protocol: a multi-omics approach to understanding mortality among children in sub-Saharan Africa and South Asia | Njunge JM, et al. | 2022 | Gates Open Res | 6 | 77 | https://www.doi.org/10.12688/gatesopenres.13635.2 | 36,415,883 | Case-Cohort Children Lmic Mortality Omics Systems Biology | Introduction: Many acutely ill children in low- and middle-income settings have a high risk of mortality both during and after hospitalisation despite guideline-based care. Understanding the biological mechanisms underpinning mortality may suggest optimal pathways to target for interventions to further reduce mortality. The Childhood Acute Illness and Nutrition (CHAIN) Network ( www.chainnnetwork.org) Nested Case-Cohort Study (CNCC) aims to investigate biological mechanisms leading to inpatient and post-discharge mortality through an integrated multi-omic approach. Methods and analysis; The CNCC comprises a subset of participants from the CHAIN cohort (1278/3101 hospitalised participants, including 350 children who died and 658 survivors, and 270/1140 well community children of similar age and household location) from nine sites in six countries across sub-Saharan Africa and South Asia. Systemic proteome, metabolome, lipidome, lipopolysaccharides, haemoglobin variants, toxins, pathogens, intestinal microbiome and biomarkers of enteropathy will be determined. Computational systems biology analysis will include machine learning and multivariate predictive modelling with stacked generalization approaches accounting for the different characteristics of each biological modality. This systems approach is anticipated to yield mechanistic insights, show interactions and behaviours of the components of biological entities, and help develop interventions to reduce mortality among acutely ill children. Ethics and dissemination. The CHAIN Network cohort and CNCC was approved by institutional review boards of all partner sites. Results will be published in open access, peer reviewed scientific journals and presented to academic and policy stakeholders. Data will be made publicly available, including uploading to recognised omics databases. Trial registration NCT03208725. | Njunge, James M Tickell, Kirkby Diallo, Abdoulaye Hama Sayeem Bin Shahid, Abu Sadat Mohammad Gazi, Md Amran Saleem, Ali Kazi, Zaubina Ali, Syed Tigoi, Caroline Mupere, Ezekiel Lancioni, Christina L Yoshioka, Emily Chisti, Mohammod Jobayer Mburu, Moses Ngari, Moses Ngao, Narshion Gichuki, Bonface Omer, Elisha Gumbi, Wilson Singa, Benson Bandsma, Robert Ahmed, Tahmeed Voskuijl, Wieger Williams, Thomas N Macharia, Alex Makale, Johnstone Mitchel, Anna Williams, Jessica Gogain, Joe Janjic, Nebojsa Mandal, Rupasri Wishart, David S Wu, Hang Xia, Lei Routledge, Michael Gong, Yun Yun Espinosa, Camilo Aghaeepour, Nima Liu, Jie Houpt, Eric Lawley, Trevor D Browne, Hilary Shao, Yan Rwigi, Doreen Kariuki, Kevin Kaburu, Timothy Uhlig, Holm H Gartner, Lisa Jones, Kelsey Koulman, Albert Walson, Judd Berkley, James eng Gates Open Res. 2022 Nov 3;6:77. doi: 10.12688/gatesopenres.13635.2. eCollection 2022.I | 11/25/2022 | ||
| Thirty novel sequence variants impacting human intracranial volume | Nawaz MS, et al. | 2022 | Brain Commun | 4 | 6 | fcac271 | https://www.doi.org/10.1093/braincomms/fcac271 | 36,415,660 | Mendelian randomization brain structure genetic correlation genome-wide association study intracranial volume | Intracranial volume, measured through magnetic resonance imaging and/or estimated from head circumference, is heritable and correlates with cognitive traits and several neurological disorders. We performed a genome-wide association study meta-analysis of intracranial volume (n = 79 174) and found 64 associating sequence variants explaining 5.0% of its variance. We used coding variation, transcript and protein levels, to uncover 12 genes likely mediating the effect of these variants, including GLI3 and CDK6 that affect cranial synostosis and microcephaly, respectively. Intracranial volume correlates genetically with volumes of cortical and sub-cortical regions, cognition, learning, neonatal and neurological traits. Parkinson's disease cases have greater and attention deficit hyperactivity disorder cases smaller intracranial volume than controls. Our Mendelian randomization studies indicate that intracranial volume associated variants either increase the risk of Parkinson's disease and decrease the risk of attention deficit hyperactivity disorder and neuroticism or correlate closely with a confounder. | Nawaz, Muhammad Sulaman Einarsson, Gudmundur Bustamante, Mariana Gisladottir, Rosa S Walters, G Bragi Jonsdottir, Gudrun A Skuladottir, Astros Th Bjornsdottir, Gyda Magnusson, Sigurdur H Asbjornsdottir, Bergrun Unnsteinsdottir, Unnur Sigurdsson, Engilbert Jonsson, Palmi V Palmadottir, Vala Kolbrun Gudjonsson, Sigurjon A Halldorsson, Gisli H Ferkingstad, Egil Jonsdottir, Ingileif Thorleifsson, Gudmar Holm, Hilma Thorsteinsdottir, Unnur Sulem, Patrick Gudbjartsson, Daniel F Stefansson, Hreinn Thorgeirsson, Thorgeir E Ulfarsson, Magnus O Stefansson, Kari eng England Brain Commun. 2022 Oct 25;4(6):fcac271. doi: 10.1093/braincomms/fcac271. eCollection 2022.I | 11/24/2022 | |
| Are EPB41 and alpha-synuclein diagnostic biomarkers of sport-related concussion?Findings from the NCAA and Department of Defense CARE Consortium | Vorn R, et al. | 2022 | J Sport Health Sci | epub ahead of print | https://www.doi.org/10.1016/j.jshs.2022.11.007 | 36,403,906 | Biomarkers College athletes Concussion Mild traumatic brain injury Sport injury | BACKGROUND: Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion. Therefore, more accurate diagnostic markers are needed for sport-related concussion (SRC). METHODS: This was a multicenter, prospective, case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the NCAA-DoD Concussion Assessment, Research, and Education (CARE) Consortium conducted between 2015 and 2019. The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints. Athletes with concussion were divided into 6 h post-injury (0-6 h post-injury) and after 6 h post-injury (7-48 hours post-injury) groups. We applied a highly multiplexed proteomic technique that used a DNA aptamers assay to target 1305 proteins in plasma samples from athletes with and without SRC. RESULTS: A total of 140 athletes with concussion (79.3% male; aged 18.71 +/- 1.10 years, mean +/- SD) and 21 non-concussed athletes (76.2% male; 19.14 +/- 1.10 years) were included in this study. We identified 338 plasma proteins that significantly differed in abundance (319 upregulated and 19 downregulated) in concussed athletes compared to non-concussed athletes. The top 20 most differentially abundant proteins discriminated concussed athletes from non-concussed athletes with an area under the curve (AUC) of 0.954 (95% confidence interval: 0.922_0.986). Specifically, after 6 h of injury, the individual AUC of plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein (SNCA) were 0.956 and 0.875, respectively. The combination of EPB41 and SNCA provided the best AUC (1.000), which suggests this combination of candidate plasma biomarkers is best for diagnosing concussion in athletes after 6 h of injury. CONCLUSION: Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and SNCA is the most predictive biomarker of concussion after 6 h of injury. | Vorn, Rany Devoto, Christina Meier, Timothy B Lai, Chen Yun, Sijung Broglio, Steven P Mithani, Sara McAllister, Thomas W Giza, Christopher C Kim, Hyung-Suk Huber, Daniel Harezlak, Jaroslaw Cameron, Kenneth L McGinty, Gerald Jackson, Jonathan Guskiewicz, Kevin M Mihalik, Jason P Brooks, Alison Duma, Stefan Rowson, Steven Nelson, Lindsay D Pasquina, Paul McCrea, Michael A Gill, Jessica M eng China J Sport Health Sci. 2022 Nov 17:S2095-2546(22)00114-4. doi: 10.1016/j.jshs.2022.11.007.I | 11/21/2022 | |||
| Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population | Zaghlool SB, et al. | 2022 | Nat Commun | 13 | 1 | 7121 | https://www.doi.org/10.1038/s41467-022-34754-z | 36,402,758 | Humans *Diabetes Mellitus, Type 2/genetics/metabolism Proteomics Arabs *Diabetes Mellitus, Type 1 Insulin | Type 2 diabetes (T2D) has a heterogeneous etiology influencing its progression, treatment, and complications. A data driven cluster analysis in European individuals with T2D previously identified four subtypes: severe insulin deficient (SIDD), severe insulin resistant (SIRD), mild obesity-related (MOD), and mild age-related (MARD) diabetes. Here, the clustering approach was applied to individuals with T2D from the Qatar Biobank and validated in an independent set. Cluster-specific signatures of circulating metabolites and proteins were established, revealing subtype-specific molecular mechanisms, including activation of the complement system with features of autoimmune diabetes and reduced 1,5-anhydroglucitol in SIDD, impaired insulin signaling in SIRD, and elevated leptin and fatty acid binding protein levels in MOD. The MARD cluster was the healthiest with metabolomic and proteomic profiles most similar to the controls. We have translated the T2D subtypes to an Arab population and identified distinct molecular signatures to further our understanding of the etiology of these subtypes. | Zaghlool, Shaza B Halama, Anna Stephan, Nisha Gudmundsdottir, Valborg Gudnason, Vilmundur Jennings, Lori L Thangam, Manonanthini Ahlqvist, Emma Malik, Rayaz A Albagha, Omar M E Abou-Samra, Abdul Badi Suhre, Karsten eng NPRP11C-0115-180010/Qatar Foundation (Qatar Foundation for Education, Science and Community Development)/ England Nat Commun. 2022 Nov 19;13(1):7121. doi: 10.1038/s41467-022-34754-z.I | 11/20/2022 | |
| Multi-platform proteomic analysis of Alzheimer's disease cerebrospinal fluid and plasma reveals network biomarkers associated with proteostasis and the matrisome | Dammer EB, et al. | 2022 | Alzheimers Res Ther | 14 | 1 | 174 | https://www.doi.org/10.1186/s13195-022-01113-5 | 36,384,809 | Humans *Alzheimer Disease/cerebrospinal fluid Proteomics Proteostasis Amyloid beta-Peptides/cerebrospinal fluid Biomarkers/cerebrospinal fluid | Robust and accessible biomarkers that can capture the heterogeneity of Alzheimer's disease and its diverse pathological processes are urgently needed. Here, we undertook an investigation of Alzheimer's disease cerebrospinal fluid (CSF) and plasma from the same subjects (n=18 control, n=18 AD) using three different proteomic platforms-SomaLogic SomaScan, Olink proximity extension assay, and tandem mass tag-based mass spectrometry-to assess which protein markers in these two biofluids may serve as reliable biomarkers of AD pathophysiology observed from unbiased brain proteomics studies. Median correlation of overlapping protein measurements across platforms in CSF (r~0.7) and plasma (r~0.6) was good, with more variability in plasma. The SomaScan technology provided the most measurements in plasma. Surprisingly, many proteins altered in AD CSF were found to be altered in the opposite direction in plasma, including important members of AD brain co-expression modules. An exception was SMOC1, a key member of the brain matrisome module associated with amyloid-beta deposition in AD, which was found to be elevated in both CSF and plasma. Protein co-expression analysis on greater than 7000 protein measurements in CSF and 9500 protein measurements in plasma across all proteomic platforms revealed strong changes in modules related to autophagy, ubiquitination, and sugar metabolism in CSF, and endocytosis and the matrisome in plasma. Cross-platform and cross-biofluid proteomics represents a promising approach for AD biomarker development. | Dammer, Eric B Ping, Lingyan Duong, Duc M Modeste, Erica S Seyfried, Nicholas T Lah, James J Levey, Allan I Johnson, Erik C B eng K08 AG068604/AG/NIA NIH HHS/ P30 AG066511/AG/NIA NIH HHS/ U54 AG065187/AG/NIA NIH HHS/ England Alzheimers Res Ther. 2022 Nov 17;14(1):174. doi: 10.1186/s13195-022-01113-5.I | 11/18/2022 | |
| Proteomic signatures for identification of impaired glucose tolerance | Carrasco-Zanini J, et al. | 2022 | Nat Med | 28 | 11 | 2293-2300 | https://www.doi.org/10.1038/s41591-022-02055-z | 36,357,677 | Humans *Glucose Intolerance/diagnosis *Diabetes Mellitus, Type 2/diagnosis Blood Glucose/metabolism Proteomics Glucose Tolerance Test Fasting | The implementation of recommendations for type 2 diabetes (T2D) screening and diagnosis focuses on the measurement of glycated hemoglobin (HbA1c) and fasting glucose. This approach leaves a large number of individuals with isolated impaired glucose tolerance (iIGT), who are only detectable through oral glucose tolerance tests (OGTTs), at risk of diabetes and its severe complications. We applied machine learning to the proteomic profiles of a single fasted sample from 11,546 participants of the Fenland study to test discrimination of iIGT defined using the gold-standard OGTTs. We observed significantly improved discriminative performance by adding only three proteins (RTN4R, CBPM and GHR) to the best clinical model (AUROC = 0.80 (95% confidence interval: 0.79-0.86), P = 0.004), which we validated in an external cohort. Increased plasma levels of these candidate proteins were associated with an increased risk for future T2D in an independent cohort and were also increased in individuals genetically susceptible to impaired glucose homeostasis and T2D. Assessment of a limited number of proteins can identify individuals likely to be missed by current diagnostic strategies and at high risk of T2D and its complications. | Carrasco-Zanini, Julia Pietzner, Maik Lindbohm, Joni V Wheeler, Eleanor Oerton, Erin Kerrison, Nicola Simpson, Missy Westacott, Matthew Drolet, Dan Kivimaki, Mika Ostroff, Rachel Williams, Stephen A Wareham, Nicholas J Langenberg, Claudia eng MC_UU_12015/1/RCUK | Medical Research Council (MRC)/ R024227/RCUK | Medical Research Council (MRC)/ MC_PC_13046/RCUK | Medical Research Council (MRC)/ 220044/Z/19/Z/Wellcome Trust (Wellcome)/ 221854/Z/20/Z/Wellcome Trust (Wellcome)/ 311492/Academy of Finland (Suomen Akatemia)/ 339568/Academy of Finland (Suomen Akatemia)/ Nat Med. 2022 Nov;28(11):2293-2300. doi: 10.1038/s41591-022-02055-z. Epub 2022 Nov 10.I | 11/11/2022 | |
| Identifying causal serum protein-cardiometabolic trait relationships using whole genome sequencing | Png G, et al. | 2022 | Hum Mol Genet | epub ahead of print | https://www.doi.org/10.1093/hmg/ddac275 | 36,349,687 | Cardiometabolic diseases, such as type 2 diabetes and cardiovascular disease, have a high public health burden. Understanding the genetically-determined regulation of proteins that are dysregulated in disease can help to dissect the complex biology underpinning them. Here, we perform a protein quantitative trait locus (pQTL) analysis of 255 serum proteins relevant to cardiometabolic processes in 2893 individuals. Meta-analysing whole-genome sequencing (WGS) data from two Greek cohorts, MANOLIS (n = 1356; 22.5x WGS) and Pomak (n = 1537; 18.4x WGS), we detect 302 independently-associated pQTL variants for 171 proteins, including 12 rare variants (minor allele frequency [MAF] < 1%). We additionally find 15 pQTL variants that are rare in non-Finnish European populations, but have drifted up in frequency in the discovery cohorts here. We identify proteins causally associated with cardiometabolic traits, including MEP1B for high-density lipoprotein levels; and describe a knock-out Mep1b mouse model. Our findings furnish insights into the genetic architecture of the serum proteome, identify new protein-disease relationships, and demonstrate the importance of isolated populations in pQTL analysis. | Png, Grace Gerlini, Raffaele Hatzikotoulas, Konstantinos Barysenka, Andrei Rayner, N William Klaric, Lucija Rathkolb, Birgit Aguilar-Pimentel, Juan A Rozman, Jan Fuchs, Helmut Gailus-Durner, Valerie Tsafantakis, Emmanouil Karaleftheri, Maria Dedoussis, George Pietrzik, Claus Wilson, James F Angelis, Martin Hrabe Becker-Pauly, Christoph Gilly, Arthur Zeggini, Eleftheria eng England Hum Mol Genet. 2022 Nov 9:ddac275. doi: 10.1093/hmg/ddac275.I | 11/10/2022 | ||||
| Omics-based biomarkers discovery for Alzheimer's disease | Aerqin Q, et al. | 2022 | Cell Mol Life Sci | 79 | 12 | 585 | https://www.doi.org/10.1007/s00018-022-04614-6 | 36,348,101 | Humans *Alzheimer Disease/diagnosis/genetics/pathology Metabolomics Biomarkers Proteomics Genomics Alzheimer's disease Epigenomics Transcriptomics | Alzheimer's disease (AD) is the most common neurodegenerative disorders presenting with the pathological hallmarks of amyloid plaques and tau tangles. Over the past few years, great efforts have been made to explore reliable biomarkers of AD. High-throughput omics are a technology driven by multiple levels of unbiased data to detect the complex etiology of AD, and it provides us with new opportunities to better understand the pathophysiology of AD and thereby identify potential biomarkers. Through revealing the interaction networks between different molecular levels, the ultimate goal of multi-omics is to improve the diagnosis and treatment of AD. In this review, based on the current AD pathology and the current status of AD diagnostic biomarkers, we summarize how genomics, transcriptomics, proteomics and metabolomics are all conducing to the discovery of reliable AD biomarkers that could be developed and used in clinical AD management. | Aerqin, Qiaolifan Wang, Zuo-Teng Wu, Kai-Min He, Xiao-Yu Dong, Qiang Yu, Jin-Tai eng 82071201/National Natural Science Foundation of China/ 81971032/National Natural Science Foundation of China/ No.2018SHZDZX01/Shanghai Municipal Science and Technology Major Project/ 2022QD002/Doctoral Scientific Research Start-up Foundation from Henan University of Technology/ 3030277001/Excellence 2025 Talent Cultivation Program at Fudan University/ Review Switzerland Cell Mol Life Sci. 2022 Nov 8;79(12):585. doi: 10.1007/s00018-022-04614-6.I | 11/09/2022 | |
| Novel plasma and brain proteins that are implicated in multiple sclerosis | Lin X, et al. | 2022 | Brain | epub ahead of print | https://www.doi.org/10.1093/brain/awac420 | 36,346,149 | Multiple sclerosis biomarkers proteomics transcriptomics | Understanding how variations in the plasma and brain proteome contribute to multiple sclerosis susceptibility can provide important insights to guide drug repurposing and therapeutic development for multiple sclerosis. However, the role of genetically predicted protein abundance in multiple sclerosis remains largely unknown. Integrating plasma proteomics (n = 3,301) and brain proteomics (n = 376 discovery; n = 152 replication) into multiple sclerosis genome-wide association studies (n = 14,802 cases and 26,703 controls), we employed summary-based methods to identify candidate proteins involved in multiple sclerosis susceptibility. Next, we evaluated associations of the corresponding genes with multiple sclerosis at tissue-level using large gene expression quantitative trait data from whole-blood (n = 31,684) and brain (n = 1,194) tissue. Further, to assess transcriptional profiles for candidate proteins at cell-level, we examined gene expression patterns in immune cell types (dataset 1: n = 73 cases and 97 controls; dataset 2: n = 31 cases and 31 controls) for identified plasma proteins, and in brain cell types (dataset 1: n = 4 cases and 5 controls; dataset 2: n = 5 cases and 3 controls) for identified brain proteins. In a longitudinal multiple sclerosis cohort (n = 203 cases followed up to 15 years), we also assessed the corresponding gene-level associations with the outcome of disability worsening. We identified 39 novel proteins associated with multiple sclerosis risk. Based on five identified plasma proteins, four available corresponding gene candidates showed consistent associations with multiple sclerosis risk in whole-blood, and we found TAPBPL upregulation in multiple sclerosis B cells, CD8+ T cells and natural killer cells compared to controls. Among the 34 candidate brain proteins, 18 were replicated in a smaller cohort and 14 of 21 available corresponding gene candidates also showed consistent associations with multiple sclerosis risk in brain tissue. In cell-specific analysis, six identified brain candidates showed consistent differential gene expression in neuron and oligodendrocyte cell clusters. Based on the 39 protein-coding genes, we found 23 genes that were associated with disability worsening in multiple sclerosis cases. The findings present a set of candidate protein biomarkers for multiple sclerosis, reinforced by high concordance in downstream transcriptomics findings at tissue-level. This study also highlights the heterogeneity of cell-specific transcriptional profiles for the identified proteins, and that numerous candidates were also implicated in disease progression. Together, these findings can serve as an important anchor for future studies of disease mechanisms and therapeutic development. | Lin, Xin Yang, Yuanhao Gresle, Melissa Cuellar-Partida, Gabriel Han, Xikun Stankovich, Jim Fuh-Ngwa, Valery Charlesworth, Jac Burdon, Kathryn P Butzkueven, Helmut Taylor, Bruce V Zhou, Yuan eng England Brain. 2022 Nov 8:awac420. doi: 10.1093/brain/awac420.I | 11/09/2022 | |||
| Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma | Allam V, et al. | 2022 | Thorax | epub ahead of print | https://www.doi.org/10.1136/thorax-2021-218555 | 36,344,253 | asthma asthma mechanisms cytokine biology have nothing to disclose. EFM reports grants from Janssen, Bristol Myers Squibb, UCB, Merck Serono and Eli Lilly outside the submitted work. In addition, EFM has patents 7,709,514 and 7,863,313 issued. KFC has received honoraria for participating in advisory board meetings of GlaxoSmithKline, AstraZeneca, Novartis, Merck, Boehringer Ingelheim and TEVA regarding treatments for asthma and chronic obstructive pulmonary disease and has also been renumerated for speaking engagements. IA and PS report grants from the public private European Union Innovative Medicines Initiative during the conduct of the study. RD reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and TEVA consultation for TEVA and Novartis as member of advisory boards and participation in a scientific discussion about asthma organised by GlaxoSmithKline. RD is a cofounder and current consultant and has shares in Synairgen, a University of Southampton spin-out company. | BACKGROUND: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma. METHODS: We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo. RESULTS: MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity. CONCLUSION: Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophilic asthma. | Allam, Venkata Sita Rama Raju Pavlidis, Stelios Liu, Gang Kermani, Nazanin Zounemat Simpson, Jennifer To, Joyce Donnelly, Sheila Guo, Yi-Ke Hansbro, Philip M Phipps, Simon Morand, Eric F Djukanovic, Ratko Sterk, Peter Chung, Kian Fan Adcock, Ian Harris, James Sukkar, Maria B eng England Thorax. 2022 Nov 7:thoraxjnl-2021-218555. doi: 10.1136/thorax-2021-218555.I | 11/08/2022 | |||
| Vascular endothelial-cadherin as a marker of endothelial injury in preclinical Alzheimer disease | Tarawneh R, et al. | 2022 | Ann Clin Transl Neurol | epub ahead of print | https://www.doi.org/10.1002/acn3.51685 | 36,342,663 | OBJECTIVE: Endothelial dysfunction is an early and prevalent pathology in Alzheimer disease (AD). We here investigate the value of vascular endothelial-cadherin (VEC) as a cerebrospinal fluid (CSF) marker of endothelial injury in preclinical AD. METHODS: Cognitively normal participants (Clinical Dementia Rating [CDR] 0) from the Knight Washington University-ADRC were included in this study (n = 700). Preclinical Alzheimer's Cognitive Composite (PACC) scores, CSF VEC, tau, p-tau181, Abeta42/Abeta40, neurofilament light-chain (NFL) levels, and magnetic resonance imaging (MRI) assessments of white matter injury (WMI) were obtained from all participants. A subset of participants underwent brain amyloid imaging using positron emission tomography (amyloid-PET) (n = 534). Linear regression examined associations of CSF VEC with PACC and individual cognitive scores in preclinical AD. Mediation analyses examined whether CSF VEC mediated effects of CSF amyloid and tau markers on cognition in preclinical AD. RESULTS: CSF VEC levels significantly correlated with PACC and individual cognitive scores in participants with amyloid (A+T+/-N+/-; n = 558) or those with amyloid and tau pathologies (A+T+N+/-; n = 259), after adjusting for covariates. CSF VEC also correlated with CSF measures of amyloid, tau, and neurodegeneration and global amyloid burden on amyloid-PET scans in our cohort. Importantly, our findings suggest that CSF VEC mediates associations of CSF Abeta42/Abeta40, p-tau181, and global amyloid burden with cognitive outcomes in preclinical AD. INTERPRETATION: Our results support the utility of CSF VEC as a marker of endothelial injury in AD and highlight the importance of endothelial injury as an early pathology that contributes to cognitive impairment in even the earliest preclinical stages. | Tarawneh, Rawan Kasper, Rachel S Sanford, Jessie Phuah, Chia-Ling Hassenstab, Jason Cruchaga, Carlos eng 3962/The Foundation for Barnes-Jewish Hospital/ P50AG05681/National Institutes of Health and National Institute of Aging/ RF1AG053303/National Institutes of Health and National Institute of Aging/ Neuro-Genomics and Informatics Center/ P30AG066444/National Institutes of Health and National Institute of Aging/ Charleston Conference on Alzheimer's Disease/ P01AG03991/National Institutes of Health and National Institute of Aging/ RF1AG058501/National Institutes of Health and National Institute of Aging/ Hope Center for Neurological Disorders/ U01AG058922/National Institutes of Health and National Institute of Aging/ Chan Zuckerberg Initiative/ P19-00559/Centene Corporation/ R21 AG067755/AG/NIA NIH HHS/ K23 NS110927/NS/NINDS NIH HHS/ Washington University-Centene ARCH Personalized Medicine Initiative/ P30NS048056/National Institutes of Health and National Institute of Aging/ P30 AG066444/AG/NIA NIH HHS/ P20AG068077/National Institutes of Health and National Institute of Aging/ P01AG026276/National Institutes of Health and National Institute of Aging/ R01AG044546/National Institutes of Health and National Institute of Aging/ P01 AG003991/AG/NIA NIH HHS/ P50 AG005681/AG/NIA NIH HHS/ P01 AG026276/AG/NIA NIH HHS/ University of New Mexico Grand Challenges Initiative/ Washington University School of Medicine/ R21-AG067755-01A1/National Institutes of Health and National Institute of Aging/ Ann Clin Transl Neurol. 2022 Nov 7. doi: 10.1002/acn3.51685.I | 11/08/2022 | ||||
| Plasma proteomic signature of decline in gait speed and grip strength | Liu X, et al. | 2022 | Aging Cell | epub ahead of print | e13736 | https://www.doi.org/10.1111/acel.13736 | 36,333,824 | aging gait speed grip strength physical function proteomics | The biological mechanisms underlying decline in physical function with age remain unclear. We examined the plasma proteomic profile associated with longitudinal changes in physical function measured by gait speed and grip strength in community-dwelling adults. We applied an aptamer-based platform to assay 1154 plasma proteins on 2854 participants (60% women, aged 76 years) in the Cardiovascular Health Study (CHS) in 1992-1993 and 1130 participants (55% women, aged 54 years) in the Framingham Offspring Study (FOS) in 1991-1995. Gait speed and grip strength were measured annually for 7 years in CHS and at cycles 7 (1998-2001) and 8 (2005-2008) in FOS. The associations of individual protein levels (log-transformed and standardized) with longitudinal changes in gait speed and grip strength in two populations were examined separately by linear mixed-effects models. Meta-analyses were implemented using random-effects models and corrected for multiple testing. We found that plasma levels of 14 and 18 proteins were associated with changes in gait speed and grip strength, respectively (corrected p < 0.05). The proteins most strongly associated with gait speed decline were GDF-15 (Meta-analytic p = 1.58 x 10(-15) ), pleiotrophin (1.23 x 10(-9) ), and TIMP-1 (5.97 x 10(-8) ). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 x 10(-7) ), CDON (2.38 x 10(-7) ), and SMOC1 (7.47 x 10(-7) ). Several statistically significant proteins are involved in the inflammatory responses or antagonism of activin by follistatin pathway. These novel proteomic biomarkers and pathways should be further explored as future mechanisms and targets for age-related functional decline. | Liu, Xiaojuan Pan, Stephanie Xanthakis, Vanessa Vasan, Ramachandran S Psaty, Bruce M Austin, Thomas R Newman, Anne B Sanders, Jason L Wu, Chenkai Tracy, Russell P Gerszten, Robert E Odden, Michelle C eng 75N92019D00031/HL/NHLBI NIH HHS/ 75N92021D00006/HL/NHLBI NIH HHS/ HHSN268200800007C/HL/NHLBI NIH HHS/ HHSN268201200036C/HL/NHLBI NIH HHS/ HHSN268201500001I/HL/NHLBI NIH HHS/ HHSN268201800001C/HL/NHLBI NIH HHS/ N01HC55222/HL/NHLBI NIH HHS/ N01HC85079/HL/NHLBI NIH HHS/ N01HC85080/HL/NHLBI NIH HHS/ N01HC85081/HL/NHLBI NIH HHS/ N01HC85082/HL/NHLBI NIH HHS/ N01HC85083/HL/NHLBI NIH HHS/ N01HC85086/HL/NHLBI NIH HHS/ NO1-HC-25195/HL/NHLBI NIH HHS/ R01HL144483/HL/NHLBI NIH HHS/ U01HL080295/HL/NHLBI NIH HHS/ U01HL130114/HL/NHLBI NIH HHS/ R01AG023629/AG/NIA NIH HHS/ England Aging Cell. 2022 Nov 4:e13736. doi: 10.1111/acel.13736.I | 11/06/2022 | ||
| Integrated proteomic and metabolomic modules identified as biomarkers of mortality in the Atherosclerosis Risk in Communities study and the African American Study of Kidney Disease and Hypertension | Zhou L, et al. | 2022 | Hum Genomics | 16 | 1 | 53 | https://www.doi.org/10.1186/s40246-022-00425-9 | 36,329,547 | Humans Aged Middle Aged African Americans/genetics *Cardiovascular Diseases Cross-Sectional Studies Proteomics Risk Factors Biomarkers *Hypertension/epidemiology/genetics Metabolomics *Kidney Diseases *Atherosclerosis/genetics *Diabetes Mellitus Chronic kidney disease Cluster analysis Dimensionality reduction Mortality | BACKGROUND: Proteins and metabolites are essential for many biological functions and often linked through enzymatic or transport reactions. Individual molecules have been associated with all-cause mortality. Many of these are correlated and might jointly represent pathways or endophenotypes involved in diseases. RESULTS: We present an integrated analysis of proteomics and metabolomics via a local dimensionality reduction clustering method. We identified 224 modules of correlated proteins and metabolites in the Atherosclerosis Risk in Communities (ARIC) study, a general population cohort of older adults (N = 4046, mean age 75.7, mean eGFR 65). Many of the modules displayed strong cross-sectional associations with demographic and clinical characteristics. In comprehensively adjusted analyses, including fasting plasma glucose, history of cardiovascular disease, systolic blood pressure and kidney function among others, 60 modules were associated with mortality. We transferred the network structure to the African American Study of Kidney Disease and Hypertension (AASK) (N = 694, mean age 54.5, mean mGFR 46) and identified mortality associated modules relevant in this disease specific cohort. The four mortality modules relevant in both the general population and CKD were all a combination of proteins and metabolites and were related to diabetes / insulin secretion, cardiovascular disease and kidney function. Key components of these modules included N-terminal (NT)-pro hormone BNP (NT-proBNP), Sushi, Von Willebrand Factor Type A, EGF And Pentraxin (SVEP1), and several kallikrein proteases. CONCLUSION: Through integrated biomarkers of the proteome and metabolome we identified functions of (patho-) physiologic importance related to diabetes, cardiovascular disease and kidney function. | Zhou, Linda Surapaneni, Aditya Rhee, Eugene P Yu, Bing Boerwinkle, Eric Coresh, Josef Grams, Morgan E Schlosser, Pascal eng K24 HL155861/HL/NHLBI NIH HHS/ R01 DK124399/DK/NIDDK NIH HHS/ R01 DK108803/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Hum Genomics. 2022 Nov 3;16(1):53. doi: 10.1186/s40246-022-00425-9.I | 11/05/2022 | |
| The 2022 Report on the Human Proteome from the HUPO Human Proteome Project | Omenn GS, et al. | 2022 | J Proteome Res | epub ahead of print | https://www.doi.org/10.1021/acs.jproteome.2c00498 | 36,318,223 | Biology and Disease-HPP (B/D-HPP) Grand Challenge Project Human Protein Atlas Human Proteome Project (HPP) Mass Spectrometry Interactive Virtual Environment (MassIVE) PeptideAtlas Ribo-Seq chromosome-centric HPP (C-HPP) missing proteins (MP) neXtProt protein existence (PE metrics) non-MS PE1 proteins small open reading frames (smORFs) uncharacterized protein existence 1 (uPE1) | The 2022 Metrics of the Human Proteome from the HUPO Human Proteome Project (HPP) show that protein expression has now been credibly detected (neXtProt PE1 level) for 18_407 (93.2%) of the 19_750 predicted proteins coded in the human genome, a net gain of 50 since 2021 from data sets generated around the world and reanalyzed by the HPP. Conversely, the number of neXtProt PE2, PE3, and PE4 missing proteins has been reduced by 78 from 1421 to 1343. This represents continuing experimental progress on the human proteome parts list across all the chromosomes, as well as significant reclassifications. Meanwhile, applying proteomics in a vast array of biological and clinical studies continues to yield significant findings and growing integration with other omics platforms. We present highlights from the Chromosome-Centric HPP, Biology and Disease-driven HPP, and HPP Resource Pillars, compare features of mass spectrometry and Olink and Somalogic platforms, note the emergence of translation products from ribosome profiling of small open reading frames, and discuss the launch of the initial HPP Grand Challenge Project, A Function for Each Protein"." | Omenn, Gilbert S Lane, Lydie Overall, Christopher M Pineau, Charles Packer, Nicolle H Cristea, Ileana M Lindskog, Cecilia Weintraub, Susan T Orchard, Sandra Roehrl, Michael H A Nice, Edouard Liu, Siqi Bandeira, Nuno Chen, Yu-Ju Guo, Tiannan Aebersold, Ruedi Moritz, Robert L Deutsch, Eric W eng Review J Proteome Res. 2022 Nov 1. doi: 10.1021/acs.jproteome.2c00498.I | 11/02/2022 | |||
| Evaluating the Utility of Proteomics for the Identification of Circulating Pharmacodynamic Biomarkers of IFNbeta-1a Biologics | Hyland PL, et al. | 2022 | Clin Pharmacol Ther | epub ahead of print | https://www.doi.org/10.1002/cpt.2778 | 36,308,070 | Proteomics has the potential to identify pharmacodynamic (PD) biomarkers for similarity assessment of proposed biosimilars without relying on clinical efficacy end points. In this study, with 36 healthy participants randomized to therapeutic doses of interferon-beta 1a products (IFNbeta-1a) or pegylated-IFNbeta-1a (pegIFNbeta-1a) approved to treat multiple sclerosis or placebo, we evaluated the utility of a proteomic assay that profiles > 7,000 plasma proteins. IFNbeta-1a and pegIFNbeta-1a resulted in 248 and 528 differentially expressed protein analytes, respectively, between treatment and placebo groups over the time course. Thirty-one proteins were prioritized based on a maximal fold change >/= 2 from baseline, baseline adjusted area under the effect curve (AUEC) and overlap between the 2 products. Of these, the majority had a significant AUEC compared with placebo in response to either product; 8 proteins showed > 4-fold maximal change from baseline. We identified previously reported candidates, beta-2microglobulin and interferon-induced GTP-binding protein (Mx1) with ~ 50% coefficient of variation (CV) for AUEC, and many new candidates (including I-TAC, C1QC, and IP-10) with CVs ranging from 26%-129%. Upstream regulator analysis of differentially expressed proteins predicted activation of IFNbeta1 signaling as well as other cytokine, enzyme, and transcription signaling networks by both products. Although independent replication is required to confirm present results, our study demonstrates the utility of proteomics for the identification of individual and composite candidate PD biomarkers that may be leveraged to support clinical pharmacology studies for biosimilar approvals, especially when biologics have complex mechanisms of action or do not have previously characterized PD biomarkers. | Hyland, Paula L Chekka, Lakshmi Manasa S Samarth, Deepti P Rosenzweig, Barry A Decker, Erica Mohamed, Esraa G Guo, Yan Matta, Murali K Sun, Qin Wheeler, William Sanabria, Carlos Weaver, James L Schrieber, Sarah J Florian, Jeffry Wang, Yow-Ming Strauss, David G eng Clin Pharmacol Ther. 2022 Oct 29. doi: 10.1002/cpt.2778.I | 10/30/2022 | ||||
| Components of the Complement Cascade Differ in Polycystic Ovary Syndrome | Butler AE, et al. | 2022 | Int J Mol Sci | 23 | 20 | https://www.doi.org/10.3390/ijms232012232 | 36,293,087 | Female Humans Properdin/metabolism Complement Factor H Complement Factor B/metabolism *Mannose-Binding Lectin CD55 Antigens *Polycystic Ovary Syndrome Complement Factor D *Insulin Resistance Cohort Studies Proteomics Complement C1q Complement C3b Fibrinogen Cytokines C3 complement factors factor B polycystic ovary syndrome properdin | Complement pathway proteins are reported to be increased in polycystic ovary syndrome (PCOS) and may be affected by obesity and insulin resistance. To investigate this, a proteomic analysis of the complement system was undertaken, including inhibitory proteins. In this cohort study, plasma was collected from 234 women (137 with PCOS and 97 controls). SOMALogic proteomic analysis was undertaken for the following complement system proteins: C1q, C1r, C2, C3, C3a, iC3b, C3b, C3d, C3adesArg, C4, C4a, C4b, C5, C5a, C5b-6 complex, C8, properdin, factor B, factor D, factor H, factor I, mannose-binding protein C (MBL), complement decay-accelerating factor (DAF) and complement factor H-related protein 5 (CFHR5). The alternative pathway of the complement system was primarily overexpressed in PCOS, with increased C3 (p < 0.05), properdin and factor B (p < 0.01). In addition, inhibition of this pathway was also seen in PCOS, with an increase in CFHR5, factor H and factor I (p < 0.01). Downstream complement factors iC3b and C3d, associated with an enhanced B cell response, and C5a, associated with an inflammatory cytokine release, were increased (p < 0.01). Hyperandrogenemia correlated positively with properdin and iC3b, whilst insulin resistance (HOMA-IR) correlated with iC3b and factor H (p < 0.05) in PCOS. BMI correlated positively with C3d, factor B, factor D, factor I, CFHR5 and C5a (p < 0.05). This comprehensive evaluation of the complement system in PCOS revealed the upregulation of components of the complement system, which appears to be offset by the concurrent upregulation of its inhibitors, with these changes accounted for in part by BMI, hyperandrogenemia and insulin resistance. | Butler, Alexandra E Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L eng Switzerland Int J Mol Sci. 2022 Oct 13;23(20):12232. doi: 10.3390/ijms232012232.I | 10/28/2022 | ||
| Testican-2 is Associated with Reduced Risk of Incident ESKD | Wen D, et al. | 2022 | J Am Soc Nephrol | epub ahead of print | https://www.doi.org/10.1681/ASN.2022020216 | 36,288,905 | Background: Testican-2 was recently identified as a podocyte-derived protein that is released into circulation by the kidneys and is positively correlated with estimated glomerular filtration rate (eGFR) and eGFR slope. However, whether higher testican-2 levels are associated with lower risk of end stage kidney disease (ESKD) is unknown. Methods: Aptamer-based proteomics assessed blood testican-2 levels among participants in the African American Study of Kidney Disease and Hypertension (AASK, n=703), the Chronic Renal Insufficiency Cohort (CRIC) study (n=3,196), and the Atherosclerosis Risk in Communities (ARIC) study (n=4,378). We compared baseline characteristics by testican-2 tertile and used Cox proportional hazards models to study the association of testican-2 with incident ESKD. Results: Higher testican-2 levels were associated with higher measured GFR (mGFR) in AASK, higher eGFR in the CRIC and ARIC studies, and lower albuminuria in all cohorts. Baseline testican-2 levels were significantly associated with incident ESKD in Cox proportional hazards models adjusted for age, sex, and race (Model 1) and Model 1 + mGFR or eGFR + comorbidities (Model 2). In Model 3 (Model 2 + proteinuria), the associations between testican-2 (per SD increase) and incident ESKD were: AASK (HR = 0.84 [0.72, 0.98], P = 0.023), CRIC (HR = 0.95 [0.89, 1.02], P = 0.14), ARIC (HR = 0.54 [0.36, 0.83], P = 0.0044), and meta-analysis (HR = 0.92 [0.86, 0.98], P = 0.0073). Conclusions: Across three cohorts spanning >8,000 individuals, testican-2 is associated with kidney health and prognosis, with higher levels associated with reduced risk of ESKD. | Wen, Donghai Zhou, Linda Zheng, Zihe Surapaneni, Aditya Ballantyne, Christie Hoogeveen, Ron Shlipak, Michael Waikar, Sushrut Vasan, Ramachandra Kimmel, Paul Dubin, Ruth Deo, Rajat Feldman, Harold Ganz, Peter Coresh, Josef Grams, Morgan Rhee, Eugene eng J Am Soc Nephrol. 2022 Oct 26:ASN.2022020216. doi: 10.1681/ASN.2022020216.I | 10/27/2022 | ||||
| Multiomics study of nonalcoholic fatty liver disease | Sveinbjornsson G, et al. | 2022 | Nat Genet | 54 | 11 | 1652-1663 | https://www.doi.org/10.1038/s41588-022-01199-5 | 36,280,732 | Humans *Non-alcoholic Fatty Liver Disease/genetics Proteomics Genome-Wide Association Study Liver/metabolism Liver Cirrhosis/genetics/metabolism/pathology *Liver Neoplasms/genetics/metabolism | Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis and hepatocellular carcinoma, and integrated the findings with expression and proteomic data. For NAFL, we utilized 9,491 clinical cases and proton density fat fraction extracted from 36,116 liver magnetic resonance images. We identified 18 sequence variants associated with NAFL and 4 with cirrhosis, and found rare, protective, predicted loss-of-function variants in MTARC1 and GPAM, underscoring them as potential drug targets. We leveraged messenger RNA expression, splicing and predicted coding effects to identify 16 putative causal genes, of which many are implicated in lipid metabolism. We analyzed levels of 4,907 plasma proteins in 35,559 Icelanders and 1,459 proteins in 47,151 UK Biobank participants, identifying multiple proteins involved in disease pathogenesis. We show that proteomics can discriminate between NAFL and cirrhosis. The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options. | Sveinbjornsson, Gardar Ulfarsson, Magnus O Thorolfsdottir, Rosa B Jonsson, Benedikt A Einarsson, Eythor Gunnlaugsson, Gylfi Rognvaldsson, Solvi Arnar, David O Baldvinsson, Magnus Bjarnason, Ragnar G Eiriksdottir, Thjodbjorg Erikstrup, Christian Ferkingstad, Egil Halldorsson, Gisli H Helgason, Hannes Helgadottir, Anna Hindhede, Lotte Hjorleifsson, Grimur Jones, David Knowlton, Kirk U Lund, Sigrun H Melsted, Pall Norland, Kristjan Olafsson, Isleifur Olafsson, Sigurdur Oskarsson, Gudjon R Ostrowski, Sisse Rye Pedersen, Ole Birger Snaebjarnarson, Auethunn S Sigurdsson, Emil Steinthorsdottir, Valgerdur Schwinn, Michael Thorgeirsson, Gudmundur Thorleifsson, Gudmar Jonsdottir, Ingileif Bundgaard, Henning Nadauld, Lincoln Bjornsson, Einar S Rulifson, Ingrid C Rafnar, Thorunn Norddahl, Gudmundur L Thorsteinsdottir, Unnur Sulem, Patrick Gudbjartsson, Daniel F Holm, Hilma Stefansson, Kari eng Nat Genet. 2022 Nov;54(11):1652-1663. doi: 10.1038/s41588-022-01199-5. Epub 2022 Oct 24.I | 10/26/2022 | |
| Circulating Proteins Influencing Psychiatric Disease: A Mendelian Randomization Study | Lu T, et al. | 2022 | Biol Psychiatry | epub ahead of print | https://www.doi.org/10.1016/j.biopsych.2022.08.015 | 36,280,454 | Blood-brain barrier Circulating proteins Genome-wide association studies Mendelian randomization Psychiatric diseases Quantitative trait loci | BACKGROUND: There is a pressing need for novel drug targets for psychiatric disorders. Circulating proteins are potential candidates because they are relatively easy to measure and modulate and play important roles in signaling. METHODS: We performed two-sample Mendelian randomization analyses to estimate the associations between circulating protein abundances and risk of 10 psychiatric disorders. Genetic variants associated with 1611 circulating protein abundances identified in 6 large-scale proteomic studies were used as genetic instruments. Effects of the circulating proteins on psychiatric disorders were estimated by Wald ratio or inverse variance-weighted ratio tests. Horizontal pleiotropy, colocalization, and protein-altering effects were examined to validate the assumptions of Mendelian randomization. RESULTS: Nine circulating protein-to-disease associations withstood multiple sensitivity analyses. Among them, 2 circulating proteins had associations replicated in 3 proteomic studies. A 1 standard deviation increase in the genetically predicted circulating TIMP4 level was associated with a reduced risk of anorexia nervosa (minimum odds ratio [OR] = 0.83; 95% CI, 0.76-0.91) and bipolar disorder (minimum OR = 0.88; 95% CI, 0.82-0.94). A 1 standard deviation increase in the genetically predicted circulating ESAM level was associated with an increased risk of schizophrenia (maximum OR = 1.32; 95% CI, 1.22-1.43). In addition, 58 suggestive protein-to-disease associations warrant validation with observational or experimental evidence. For instance, a 1 standard deviation increase in the ERLEC1-201-to-ERLEC1-202 splice variant ratio was associated with a reduced risk of schizophrenia (OR = 0.94; 95% CI, 0.90-0.97). CONCLUSIONS: Prioritized circulating proteins appear to influence the risk of psychiatric disease and may be explored as intervention targets. | Lu, Tianyuan Forgetta, Vincenzo Greenwood, Celia M T Zhou, Sirui Richards, J Brent eng Biol Psychiatry. 2022 Aug 22:S0006-3223(22)01524-4. doi: 10.1016/j.biopsych.2022.08.015.I | 10/25/2022 | |||
| Plasma proteome profiling identifies changes associated to AD but not to FTD | Mofrad RB, et al. | 2022 | Acta Neuropathol Commun | 10 | 1 | 148 | https://www.doi.org/10.1186/s40478-022-01458-w | 36,273,219 | Humans Female Middle Aged Aged Male *Frontotemporal Dementia/diagnosis/genetics Proteome Proteomics *Frontotemporal Lobar Degeneration/diagnosis/pathology *Pick Disease of the Brain Biomarkers Ad Alzheimer's disease Ftd Frontotemporal dementia Plasma biomarkers Somascan | BACKGROUND: Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process. METHODS: Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 +/- 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 +/- 7.9; 45% female), AD patients (n = 57; age = 65.5 +/- 8.0; 39% female), and non-demented controls (n = 148; 61.3 +/- 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 +/- 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 +/- 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 +/- 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis. RESULTS: Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified. CONCLUSIONS: We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts. | Mofrad, R Babapour Del Campo, M Peeters, C F W Meeter, L H H Seelaar, H Koel-Simmelink, M Ramakers, I H G B Middelkoop, H A M De Deyn, P P Claassen, J A H R van Swieten, J C Bridel, C Hoozemans, J J M Scheltens, P van der Flier, W M Pijnenburg, Y A L Teunissen, Charlotte E eng 733050206/ZONMW_/ZonMw/Netherlands ToBike4Alzheimer/Alzheimer Nederland/ England Acta Neuropathol Commun. 2022 Oct 22;10(1):148. doi: 10.1186/s40478-022-01458-w.I | 10/24/2022 | |
| Association of mTORC1_dependent circulating protein levels with cataract formation: a mendelian randomization study | Cai Y, et al. | 2022 | BMC Genomics | 23 | 1 | 719 | https://www.doi.org/10.1186/s12864-022-08925-7 | 36,271,348 | Humans *Cataract/genetics Eukaryotic Initiation Factor-4A Eukaryotic Initiation Factor-4E/genetics *Eukaryotic Initiation Factor-4G Genome-Wide Association Study Mechanistic Target of Rapamycin Complex 1/genetics Mendelian Randomization Analysis Polymorphism, Single Nucleotide Sirolimus TOR Serine-Threonine Kinases/genetics Cataract Circulating Eif4ebp Mendelian randomization mTOR | BACKGROUND: The mechanistic target of rapamycin (mTOR) signal pathway plays a critical regulating role in the occurrence and development of cataract. However, the role of mTORC1 downstream proteins, including ribosomal protein S6K (RP-S6K), eukaryotic initiation factor 4E-binding protein (EIF4EBP), eukaryotic initiation factor 4G (EIF-4G), eukaryotic initiation factor 4E (EIF-4E), and eukaryotic initiation factor 4A (EIF-4A), in regulating cataract development is still unknown. Herein, we conducted a mendelian randomization (MR) study to understand the function of mTORC1 signaling in the process of cataract development. RESULTS: The causal estimate was evaluated with inverse-variance weighted (IVW) estimate, weighted median estimator, MR-Egger and MR robust adjusted profile score (MR. RAPS). The single-nucleotide polymorphisms (SNPs), P<5 x 10(- 6) and r(2)<0.05, were selected to genetically predict the RP-S6K, EIF4EBP, EIF-4E, EIF-4A, and EIF-4G. We included a total of 26,758 cases and 189,604 controls in this MR study. The study revealed causal association between circulating EIF4EBP (OR 1.09, 95% confidence interval 1.03,1.16, P = 0.004), RP-S6K (OR 1.04, 95% confidence interval 1.01, 1.08, P = 0.02) and cataract formation with IVW estimate. Whereas after correcting outliers, MR robust adjusted profile score (MR. RAPS) shows consistent result with IVW for EIF4EBP (OR = 1.08, 95%CI:1.05-1.11, P = 0.007). The observation strengthened the confidence in the true causal associations. However, no association was found for circulating EIF-4E (OR 1.03, 95% confidence interval 0.97, 1.09, P = 0.31), EIF-4A (OR 1.02, 95% confidence interval 0.98, 1.07, P = 0.34), and EIF-4G (OR 1.02, 95% confidence interval 0.94, 1.01, P = 0.64) levels with cataract formation. No evidence of heterogeneity and unbalanced horizontal pleiotropy was detected. CONCLUSION: The MR study suggests that EIF4EBP is a high-risk factor for cataract development. There may be a potential causal association between the mTORC1/EIF4EBP axis and cataract. This research highlights the potential mechanism for cataract development and a genetic target to prevent as well as treat cataracts. | Cai, Yingjun Liu, Kangcheng Wu, Pengfei Yuan, Ruolan He, Fei Zou, Jing eng NO. 2022JJ40855/Jing Zou/ England BMC Genomics. 2022 Oct 21;23(1):719. doi: 10.1186/s12864-022-08925-7.I | 10/23/2022 | |
| Molecular subclasses of preeclampsia characterized by a longitudinal maternal proteomics study: distinct biomarkers, disease pathways and options for prevention | Than NG, et al. | 2022 | J Perinat Med | epub ahead of print | https://www.doi.org/10.1515/jpm-2022-0433 | 36,253,935 | great obstetrical syndromes liquid biopsy omics personalized medicine prenatal diagnosis screening | OBJECTIVES: The heterogeneous nature of preeclampsia is a major obstacle to early screening and prevention, and a molecular taxonomy of disease is needed. We have previously identified four subclasses of preeclampsia based on first-trimester plasma proteomic profiles. Herein, we expanded this approach by using a more comprehensive panel of proteins profiled in longitudinal samples. METHODS: Proteomic data collected longitudinally from plasma samples of women who developed preeclampsia (n=109) and of controls (n=90) were available from our previous report on 1,125 proteins. Consensus clustering was performed to identify subgroups of patients with preeclampsia based on data from five gestational-age intervals by using select interval-specific features. Demographic, clinical, and proteomic differences among clusters were determined. Differentially abundant proteins were used to identify cluster-specific perturbed KEGG pathways. RESULTS: Four molecular clusters with different clinical phenotypes were discovered by longitudinal proteomic profiling. Cluster 1 involves metabolic and prothrombotic changes with high rates of early-onset preeclampsia and small-for-gestational-age neonates; Cluster 2 includes maternal anti-fetal rejection mechanisms and recurrent preeclampsia cases; Cluster 3 is associated with extracellular matrix regulation and comprises cases of mostly mild, late-onset preeclampsia; and Cluster 4 is characterized by angiogenic imbalance and a high prevalence of early-onset disease. CONCLUSIONS: This study is an independent validation and further refining of molecular subclasses of preeclampsia identified by a different proteomic platform and study population. The results lay the groundwork for novel diagnostic and personalized tools of prevention. | Than, Nandor Gabor Romero, Roberto Gyorffy, Daniel Posta, Mate Bhatti, Gaurav Done, Bogdan Chaemsaithong, Piya Jung, Eunjung Suksai, Manaphat Gotsch, Francesca Gallo, Dahiana M Bosco, Mariachiara Kim, Bomi Kim, Yeon Mee Chaiworapongsa, Tinnakorn Rossi, Simona W Szilagyi, Andras Erez, Offer Tarca, Adi L Papp, Zoltan eng Germany J Perinat Med. 2022 Oct 18. doi: 10.1515/jpm-2022-0433.I | 10/19/2022 | |||
| A Network of Serum Proteins Predict the Need for Systemic Immunomodulatory Therapy at Diagnosis in Noninfectious Uveitis | Kuiper JJW, et al. | 2022 | Ophthalmol Sci | 2 | 3 | 100175 | https://www.doi.org/10.1016/j.xops.2022.100175 | 36,245,752 | IMT, immunomodulatory therapy Network-based medicine Neutrophils Noninfectious uveitis Proteomics Systemic immunomodulatory therapy | PURPOSE: Early identification of patients with noninfectious uveitis requiring steroid-sparing immunomodulatory therapy (IMT) is currently lacking in objective molecular biomarkers. We evaluated the proteomic signature of patients at the onset of disease and associated proteomic clusters with the need for IMT during the course of the disease. DESIGN: Multicenter cohort study. PARTICIPANTS: Two hundred thirty treatment-free patients with active noninfectious uveitis. METHODS: We used aptamer-based proteomics (n = 1305 proteins) and a bioinformatic pipeline as a molecular stratification tool to define the serum protein network of a Dutch discovery cohort (n = 78) of patients and healthy control participants and independently validated our results in another Dutch cohort (n = 111) and a United States cohort (n = 67). Multivariate Cox analysis was used to assess the relationship between the protein network and IMT use. MAIN OUTCOME MEASURES: Serum protein levels and use of IMT. RESULTS: Network-based analyses revealed a tightly coexpressed serum cluster (n = 85 proteins) whose concentration was consistently low in healthy control participants (n = 26), but varied among patients with noninfectious uveitis (n = 52). Patients with high levels of the serum cluster at disease onset showed a significantly increased need for IMT during follow-up, independent of anatomic location of uveitis (hazard ratio, 3.42; 95% confidence interval, 1.22-9.5; P = 0.019). The enrichment of neutrophil-associated proteins in the protein cluster led to our finding that the neutrophil count could serve as a clinical proxy for this proteomic signature (correlation: r = 0.57, P = 0.006). In an independent Dutch cohort (n = 111), we confirmed that patients with relatively high neutrophil count at diagnosis (> 5.2 x 10(9)/L) had a significantly increased chance of requiring IMT during follow-up (hazard ratio, 3.2; 95% confidence interval, 1.5-6.8; P = 0.002). We validated these findings in a third cohort of 67 United States patients. CONCLUSIONS: A serum protein signature correlating with neutrophil levels was highly predictive for IMT use in noninfectious uveitis. We developed a routinely available tool that may serve as a novel objective biomarker to aid in clinical decision-making for noninfectious uveitis. | Kuiper, Jonas J W Verhagen, Fleurieke H Hiddingh, Sanne Wennink, Roos A W Hansen, Anna M Casey, Kerry A Hoefer, Imo E Haitjema, Saskia Drylewicz, Julia Yakin, Mehmet Sen, H Nida Radstake, Timothy R D J de Boer, Joke H eng Netherlands Ophthalmol Sci. 2022 May 31;2(3):100175. doi: 10.1016/j.xops.2022.100175. eCollection 2022 Sep.I | 10/18/2022 | |
| Assessment of variability in the plasma 7k SomaScan proteomics assay | Candia J, et al. | 2022 | Sci Rep | 12 | 1 | 17147 | https://www.doi.org/10.1038/s41598-022-22116-0 | 36,229,504 | Biomarkers/metabolism Humans *Proteomics/methods | SomaScan is a high-throughput, aptamer-based proteomics assay designed for the simultaneous measurement of thousands of proteins with a broad range of endogenous concentrations. In its most current version, the 7k SomaScan assay v4.1 is capable of measuring 7288 human proteins. In this work, we present an extensive technical assessment of this platform based on a study of 2050 samples across 22 plates. Included in the study design were inter-plate technical duplicates from 102 human subjects, which allowed us to characterize different normalization procedures, evaluate assay variability by multiple analytical approaches, present signal-over-background metrics, and discuss potential specificity issues. By providing detailed performance assessments on this wide range of technical aspects, we aim for this work to serve as a valuable resource for the growing community of SomaScan users. | Candia, Julian Daya, Gulzar N Tanaka, Toshiko Ferrucci, Luigi Walker, Keenan A eng ZIAAG000971-14/AG/NIA NIH HHS/ ZIAAG000349-01/AG/NIA NIH HHS/ England Sci Rep. 2022 Oct 13;12(1):17147. doi: 10.1038/s41598-022-22116-0.I | 10/14/2022 | |
| The severity and duration of Hypoglycemia affect platelet-derived protein responses in Caucasians | Moin ASM, et al. | 2022 | Cardiovasc Diabetol | 21 | 1 | 202 | https://www.doi.org/10.1186/s12933-022-01639-w | 36,203,210 | Blood Glucose/metabolism CD40 Ligand *Diabetes Mellitus, Type 2/diagnosis Humans *Hypoglycemia Plasminogen Plasminogen Activator Inhibitor 1 Thromboplastin von Willebrand Factor Hypoglycemia Inflammation Platelet-associated proteins Type 2 diabetes conflict of interest or competing interests to declare. | OBJECTIVE: Severe hypoglycemia is associated with increased cardiovascular death risk, and platelet responses to hypoglycemia (hypo) have been described. However, the impact of deep transient hypo (deep-hypo) versus prolonged milder hypo (mild-hypo) on platelet response is unclear. RESEARCH DESIGN AND METHODS: Two hypo studies were compared; firstly, mild-hypo in 18-subjects (10 type-2-diabetes (T2D), 8 controls), blood glucose to 2.8mmoL/L (50 mg/dL) for 1-hour; secondly deep-hypo in 46-subjects (23 T2D, 23 controls), blood glucose to < 2.2mmoL/L (< 40 mg/dL) transiently. Platelet-related protein (PRP) responses from baseline to after 1-hour of hypo (mild-hypo) or at deep-hypo were compared, and at 24-hours post-hypo. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was used to determine PRP changes for 13 PRPs. RESULTS: In controls, from baseline to hypo, differences were seen for four PRPs, three showing increased %change in deep-hypo (Plasminogen activator inhibitor-1(PAI-1), CD40 ligand (CD40LG) and Protein-S), one showing increased %change in mild-hypo (von Willebrand factor (vWF)); at 24-hours in controls, %change for Protein-S remained increased in deep-hypo, whilst % change for vWF and plasminogen were increased in mild-hypo. In T2D, from baseline to hypo, differences were seen for 4 PRPs, three showing increased %change in deep-hypo (PAI-1, platelet glycoprotein VI and Tissue factor), one showing increased %change in mild-hypo (CD40LG); at 24-hours in T2D, %change for CD40LG remained increased, together with vWF, in deep-hypo. CONCLUSION: Both mild-hypo and deep-hypo showed marked PRP changes that continued up to 24-hours, showing that both the severity and duration of hypoglycemia are likely important and that any degree of hypoglycemia may be detrimental for increased cardiovascular risk events through PRP changes. | Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng England Cardiovasc Diabetol. 2022 Oct 6;21(1):202. doi: 10.1186/s12933-022-01639-w.I | 10/07/2022 | |
| Comment on A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk"" | Kivimaki M, et al. | 2022 | Sci Transl Med | 14 | 665 | eabq4810 | https://www.doi.org/10.1126/scitranslmed.abq4810 | 36,197,964 | *Decision Making *Proteomics | A 27-protein signature has been proposed to predict cardiovascular disease, but its applicability in clinical decision-making remains unclear. | Kivimaki, Mika Hingorani, Aroon D Lindbohm, Joni V eng 221854/Z/20/Z/WT_/Wellcome Trust/United Kingdom MR/R024227/1/MRC_/Medical Research Council/United Kingdom DH_/Department of Health/United Kingdom Comment Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Sci Transl Med. 2022 Oct 5;14(665):eabq4810. doi: 10.1126/scitranslmed.abq4810. Epub 2022 Oct 5.I | 10/06/2022 | |
| Response to comment on A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk"" | Williams SA, et al. | 2022 | Sci Transl Med | 14 | 665 | eadd1355 | https://www.doi.org/10.1126/scitranslmed.add1355 | 36,197,965 | *Cardiovascular Diseases *Decision Making Humans Proteomics | A 27-protein signature has been proposed to predict cardiovascular disease, and its applicability in some clinical decision-making situations is discussed. | Williams, Stephen A Ganz, Peter eng Comment Sci Transl Med. 2022 Oct 5;14(665):eadd1355. doi: 10.1126/scitranslmed.add1355. Epub 2022 Oct 5.I | 10/06/2022 | |
| Proteomic analysis of diabetes genetic risk scores identifies complement C2 and neuropilin-2 as predictors of type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) Study | Steffen BT, et al. | 2022 | Diabetologia | epub ahead of print | https://www.doi.org/10.1007/s00125-022-05801-7 | 36,194,249 | Beta cell Diabetes Genetic risk score Insulin resistance Mendelian Proteomics | AIMS/HYPOTHESIS: Genetic predisposition to type 2 diabetes is well-established, and genetic risk scores (GRS) have been developed that capture heritable liabilities for type 2 diabetes phenotypes. However, the proteins through which these genetic variants influence risk have not been thoroughly investigated. This study aimed to identify proteins and pathways through which type 2 diabetes risk variants may influence pathophysiology. METHODS: Using a proteomics data-driven approach in a discovery sample of 7241 White participants in the Atherosclerosis Risk in Communities Study (ARIC) cohort and a replication sample of 1674 Black ARIC participants, we interrogated plasma levels of 4870 proteins and four GRS of specific type 2 diabetes phenotypes related to beta cell function, insulin resistance, lipodystrophy, BMI/blood lipid abnormalities and a composite score of all variants combined. RESULTS: Twenty-two plasma proteins were identified in White participants after Bonferroni correction. Of the 22 protein-GRS associations that were statistically significant, 10 were replicated in Black participants and all but one were directionally consistent. In a secondary analysis, 18 of the 22 proteins were found to be associated with prevalent type 2 diabetes and ten proteins were associated with incident type 2 diabetes. Two-sample Mendelian randomisation indicated that complement C2 may be causally related to greater type 2 diabetes risk (inverse variance weighted estimate: OR 1.65 per SD; p=7.0 x 10(-3)), while neuropilin-2 was inversely associated (OR 0.44 per SD; p=8.0 x 10(-3)). CONCLUSIONS/INTERPRETATION: Identified proteins may represent viable intervention or pharmacological targets to prevent, reverse or slow type 2 diabetes progression, and further research is needed to pursue these targets. | Steffen, Brian T Tang, Weihong Lutsey, Pamela L Demmer, Ryan T Selvin, Elizabeth Matsushita, Kunihiro Morrison, Alanna C Guan, Weihua Rooney, Mary R Norby, Faye L Pankratz, Nathan Couper, David Pankow, James S eng UL1RR025005/NH/NIH HHS/ R01 HL059367/HL/NHLBI NIH HHS/ R01HL134320/HL/NHLBI NIH HHS/ U01HG004402/HG/NHGRI NIH HHS/ T32 HL007779/HL/NHLBI NIH HHS/ Germany Diabetologia. 2022 Oct 4. doi: 10.1007/s00125-022-05801-7.I | 10/05/2022 | |||
| Renin: Measurements, Correlates, and Associations with Long-Term Adverse Kidney Outcomes | Blum MF, et al. | 2022 | Am J Hypertens | epub ahead of print | https://www.doi.org/10.1093/ajh/hpac112 | 36,190,914 | aptamer chronic kidney disease end stage kidney disease kidney mortality renin | BACKGROUND: The association of renin with adverse kidney outcomes is largely unknown, and renin measurement strategies vary. We aimed to measure the clinical correlates of different renin measurements and the association between renin and incident chronic kidney disease (CKD), end-stage kidney disease (ESKD), and mortality. METHODS: We performed a prospective cohort analysis 9420 participants in the Atherosclerosis Risk in Communities (ARIC) study followed from 1996-1998 through 2019. We estimated longitudinal associations of renin measured using SomaScan modified nucleotide aptamer assay with incident CKD, ESKD, and death using Cox proportional hazards models. Using samples from a subsequent study visit, we compared SomaScan renin with plasma renin activity (PRA) and renin level from Olink, and estimated associations with covariates using univariate and multivariable regression. RESULTS: Higher SomaScan renin levels were associated with higher risk of incident CKD (hazard ratio per two-fold higher [HR], 1.14; 95% confidence interval [CI], 1.09 to 1.20), ESKD (HR, 1.20; 95% CI, 1.03 to 1.41), and mortality (HR, 1.08; 95% CI, 1.04 to 1.13) in analyses adjusted for demographic, clinical, and socioeconomic covariates. SomaScan renin was moderately correlated with PRA (r=0.61) and highly correlated with Olink renin (r=0.94). SomaScan renin and PRA had similar clinical correlates except for divergent associations with age and beta blocker use, both of which correlated positively with SomaScan renin but negatively with PRA. CONCLUSIONS: SomaScan aptamer-based renin level was associated with higher risk of CKD, ESKD, and mortality. It was moderately correlated with PRA, sharing generally similar clinical covariate associations. | Blum, Matthew F Chen, Jingsha Surapaneni, Aditya Turner, Stephen T Ballantyne, Christie M Welling, Paul A Kottgen, Anna Coresh, Josef Crews, Deidra C Grams, Morgan E eng Am J Hypertens. 2022 Oct 3:hpac112. doi: 10.1093/ajh/hpac112.I | 10/04/2022 | |||
| Altered methylation pattern in EXOC4 is associated with stroke outcome: an epigenome-wide association study | Cullell N, et al. | 2022 | Clin Epigenetics | 14 | 1 | 124 | https://www.doi.org/10.1186/s13148-022-01340-5 | 36,180,927 | *Brain Ischemia/genetics CpG Islands DNA Methylation Epigenesis, Genetic Epigenome Genome-Wide Association Study Humans Rna *Stroke/genetics c-Mer Tyrosine Kinase/genetics | BACKGROUND AND PURPOSE: The neurological course after stroke is highly variable and is determined by demographic, clinical and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke. METHODS: We performed a three-stage epigenome-wide association study to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (DeltaNIHSS) in ischaemic stroke patients. DNA methylation data in the Discovery (n = 643) and Replication (n = 62) Cohorts were interrogated with the 450 K and EPIC BeadChip. Nominal CpG sites from the Discovery (p value < 10(-06)) were also evaluated in a meta-analysis of the Discovery and Replication cohorts, using a random-fixed effect model. Metabolic pathway enrichment was calculated with methylGSA. We integrated the methylation data with 1305 plasma protein expression levels measured by SOMAscan in 46 subjects and measured RNA expression with RT-PCR in a subgroup of 13 subjects. Specific cell-type methylation was assessed using EpiDISH. RESULTS: The meta-analysis revealed an epigenome-wide significant association in EXOC4 (p value = 8.4 x 10(-08)) and in MERTK (p value = 1.56 x 10(-07)). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication Cohorts (p value = 1.14 x 10(-06) and p value = 1.3 x 10(-02), respectively). EXOC4 methylation negatively correlated with the long-term outcome (coefficient = - 4.91) and showed a tendency towards a decrease in EXOC4 expression (rho = - 0.469, p value = 0.091). Pathway enrichment from the meta-analysis revealed significant associations related to the endocytosis and deubiquitination processes. Seventy-nine plasma proteins were differentially expressed in association with EXOC4 methylation. Pathway analysis of these proteins showed an enrichment in natural killer (NK) cell activation. The cell-type methylation analysis in blood also revealed a differential methylation in NK cells. CONCLUSIONS: DNA methylation of EXOC4 is associated with a worse neurological course after stroke. The results indicate a potential modulation of pathways involving endocytosis and NK cells regulation. | Cullell, Natalia Soriano-Tarraga, Carolina Gallego-Fabrega, Cristina Carcel-Marquez, Jara Muino, Elena Llucia-Carol, Laia Lledos, Miquel Esteller, Manel de Moura, Manuel Castro Montaner, Joan Rosell, Anna Delgado, Pilar Marti-Fabregas, Joan Krupinski, Jerzy Roquer, Jaume Jimenez-Conde, Jordi Fernandez-Cadenas, Israel eng Meta-Analysis Research Support, Non-U.S. Gov't Germany Clin Epigenetics. 2022 Sep 30;14(1):124. doi: 10.1186/s13148-022-01340-5.I | 10/01/2022 | |
| Proteomics of Coagulopathy Following Injury Reveals Limitations of Using Laboratory Assessment to Define Trauma-Induced Coagulopathy to Predict Massive Transfusion | Moore HB, et al. | 2022 | Ann Surg Open | 3 | 2 | e167 | https://www.doi.org/10.1097/as9.0000000000000167 | 36,177,090 | OBJECTIVE: Trauma-induced coagulopathy (TIC) is provoked by multiple mechanisms and is perceived to be one driver of massive transfusions (MT). Single laboratory values using prothrombin time (INR) or thrombelastography (TEG) are used to clinically define this complex process. We used a proteomics approach to test whether current definitions of TIC (INR, TEG, or clinical judgement) are sufficient to capture the majority of protein changes associated with MT. METHODS: Eight level-I trauma centers contributed blood samples from patients available early after injury. TIC was defined as INR >1.5 (INR-TIC), TEG maximum amplitude <50mm (TEG-TIC), or clinical judgement (Clin-TIC) by the trauma surgeon. MT was defined as > 10 units of red blood cells in 24 hours or > 4 units RBC/hour during the first 4 hr. SomaLogic proteomic analysis of 1,305 proteins was performed. Pathways associated with proteins dysregulated in patients with each TIC definition and MT were identified. RESULTS: Patients (n=211) had a mean injury severity score of 24, with a MT and mortality rate of 22% and 12%, respectively. We identified 578 SOMAscan analytes dysregulated among MT patients, of which INR-TIC, TEG-TIC, and Clin-TIC patients showed dysregulation only in 25%, 3%, and 4% of these, respectively. TIC definitions jointly failed to show changes in 73% of the protein levels associated with MT, and failed to identify 26% of patients that received a massive transfusion. INR-TIC and TEG-TIC patients showed dysregulation of proteins significantly associated with complement activity. Proteins dysregulated in Clin-TIC or massive transfusion patients were not significantly associated with any pathway. CONCLUSION: These data indicate there are unexplored opportunities to identify patients at risk for massive bleeding. Only a small subset of proteins that are dysregulated in patients receiving MT are statistically significantly dysregulated among patients whose TIC is defined based solely on laboratory measurements or clinical assessment. | Moore, Hunter B Neal, Matthew D Bertolet, Marnie Joughin, Brian A Yaffe, Michael B Barrett, Christopher D Bird, Molly A Tracy, Russell P Moore, Ernest E Sperry, Jason L Zuckerbraun, Brian S Park, Myung S Cohen, Mitchell J Wisniewski, Stephen R Morrissey, James H eng R00 HL151887/HL/NHLBI NIH HHS/ R35 GM119526/GM/NIGMS NIH HHS/ R35 HL135823/HL/NHLBI NIH HHS/ K99 HL151887/HL/NHLBI NIH HHS/ UM1 HL120877/HL/NHLBI NIH HHS/ Ann Surg Open. 2022 Jun;3(2):e167. doi: 10.1097/as9.0000000000000167. Epub 2022 May 25.I | 10/01/2022 | ||
| The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals | Butler-Laporte G, et al. | 2022 | Clin Proteomics | 19 | 1 | 34 | https://www.doi.org/10.1186/s12014-022-09371-z | 36,171,541 | Covid-19 Immunity Proteomics SOMAscan the Founder of 5 Prime Sciences. The Lady Davis Institute has previously received funding from GlaxoSmithKline, Eli Lilly, and Biogen for research programs at Dr. Richards' laboratory unrelated to this manuscript. C.P. and M.H. are employees of SomaLogic. | INTRODUCTION: Severe COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions. METHODS: We measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support. RESULTS: 580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p < 3.4 x 10(-4)). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex. CONCLUSIONS: Severe COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection. | Butler-Laporte, Guillaume Gonzalez-Kozlova, Edgar Su, Chen-Yang Zhou, Sirui Nakanishi, Tomoko Brunet-Ratnasingham, Elsa Morrison, David Laurent, Laetitia Afilalo, Jonathan Afilalo, Marc Henry, Danielle Chen, Yiheng Carrasco-Zanini, Julia Farjoun, Yossi Pietzner, Maik Kimchi, Nofar Afrasiabi, Zaman Rezk, Nardin Bouab, Meriem Petitjean, Louis Guzman, Charlotte Xue, Xiaoqing Tselios, Chris Vulesevic, Branka Adeleye, Olumide Abdullah, Tala Almamlouk, Noor Moussa, Yara DeLuca, Chantal Duggan, Naomi Schurr, Erwin Brassard, Nathalie Durand, Madeleine Del Valle, Diane Marie Thompson, Ryan Cedillo, Mario A Schadt, Eric Nie, Kai Simons, Nicole W Mouskas, Konstantinos Zaki, Nicolas Patel, Manishkumar Xie, Hui Harris, Jocelyn Marvin, Robert Cheng, Esther Tuballes, Kevin Argueta, Kimberly Scott, Ieisha Greenwood, Celia M T Paterson, Clare Hinterberg, Michael Langenberg, Claudia Forgetta, Vincenzo Mooser, Vincent Marron, Thomas Beckmann, Noam Kenigsberg, Ephraim Charney, Alexander W Kim-Schulze, Seunghee Merad, Miriam Kaufmann, Daniel E Gnjatic, Sacha Richards, J Brent eng England Clin Proteomics. 2022 Sep 28;19(1):34. doi: 10.1186/s12014-022-09371-z.I | 09/29/2022 | |
| Differences and commonalities in the genetic architecture of protein quantitative trait loci in European and Arab populations | Thareja G, et al. | 2022 | Hum Mol Genet | epub ahead of print | https://www.doi.org/10.1093/hmg/ddac243 | 36,168,886 | Polygenic scores (PGS) can identify individuals at risk of adverse health events and guide genetics-based personalized medicine. However, it is not clear how well PGS translate between different populations, limiting their application to well-studied ethnicities. Proteins are intermediate traits linking genetic predisposition and environmental factors to disease, with numerous blood circulating protein levels representing functional readouts of disease-related processes. We hypothesized that studying the genetic architecture of a comprehensive set of blood-circulating proteins between a European and an Arab population could shed fresh light on the translatability of PGS to understudied populations. We therefore conducted a genome-wide association study with whole-genome sequencing data using 1301 proteins measured on the SOMAscan aptamer-based affinity proteomics platform in 2935 samples of Qatar Biobank and evaluated the replication of protein quantitative traits (pQTLs) from European studies in an Arab population. Then, we investigated the colocalization of shared pQTL signals between the two populations. Finally, we compared the performance of protein PGS derived from a Caucasian population in a European and an Arab cohort. We found that the majority of shared pQTL signals (81.8%) colocalized between both populations. About one-third of the genetic protein heritability was explained by protein PGS derived from a European cohort, with protein PGS performing ~ 20% better in Europeans when compared to Arabs. Our results are relevant for the translation of PGS to non-Caucasian populations, as well as for future efforts to extend genetic research to understudied populations. | Thareja, Gaurav Belkadi, Aziz Arnold, Matthias Albagha, Omar M E Graumann, Johannes Schmidt, Frank Grallert, Harald Peters, Annette Gieger, Christian Consortium, The Qatar Genome Program Research Suhre, Karsten eng England Hum Mol Genet. 2022 Sep 28:ddac243. doi: 10.1093/hmg/ddac243.I | 09/29/2022 | ||||
| Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease | Serban KA, et al. | 2022 | EBioMedicine | 84 | 104262 | https://www.doi.org/10.1016/j.ebiom.2022.104262 | 36,155,958 | Biomarkers Humans Myosins Pharmaceutical Preparations *Pulmonary Disease, Chronic Obstructive/diagnosis/etiology *Pulmonary Emphysema/diagnosis/etiology *Somatomedins *alpha 1-Antitrypsin Deficiency/complications/diagnosis/genetics Alpha-1 antitrypsin deficiency Emphysema Plasma biomarker Protein score SomaScan Committee, Alpha-1 Foundation Medical Advisory and Scientific Committee, ATS - RCMB Website Committee, National Jewish Health IBC committee (all unpaid) KAP does not report any potential conflict of interest CS reports grants or contracts from Adverum, Arrowhead, AstraZeneca, CSA Medical, Grifols, Nuvaira, Takeda, Vertex consulting fees from AstraZenca, Dicerna, Glaxo Smith Kline, Inhibrx, Morair, UpToDate, Vertex has received honoraria for presentations from the American Thoracic Society has received support for travel from CSL Behring serves as the Medical Director for AlphaNet RAS reports grants or contracts from Vertex, NIH/NCATS, Alpha-1 Foundation, consulting fees from Grifols, CSL Behring, Vertex, Intellia, Inhibrx, Takeda, Evolve Biologics, has received travel support from CSL Behring has served on the Advisory Board of Arrowhead Pharmaceuticals, and serves as the Medical Director for AlphaNet and on the board of directors for Global Implementation Solutions, Osteogenesis Imperfecta Foundation, Alpha-1 Foundation, and AlphaNet AMT reports grants or contracts from Vertex, Grifols, and CSl Behring has received consulting fees from CSL Behring, Inhibrix, Z-factor, and Takeda, has received honoraria for lectures from Glaxo Smith Kline and AstraZeneca TB does not report any potential conflict of interest DAS does not report any potential conflict of interest LM does not report any potential conflict of interest NH does not report any potential conflict of interest EKS reports grants or contracts from Glaxo Smith Kline, Bayer BDH does not report any potential conflict of interest CPH reports grants or contracts from Alpha-1 Foundation, Bayer, Boehringer-Ingelheim, and Vertex, consulting fees from AstraZeneca and Takeda DLD has received honoraria for lectures from Novartis and financial support from Bayer towards the institution MHC reports grants or contracts from Glaxo Smith Kline, Bayer, consulting fees from AstraZeneca and Genentech, honoraria for presentations from Illumina, RPB does not report any potential conflict of interest. | BACKGROUND: Alpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity. METHODS: The plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis. FINDINGS: In PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes. INTERPRETATION: Using SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD. FUNDING: This work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL137995. GRADS was supported by Award U01HL112707, U01 HL112695 from the National Heart, Lung, and Blood Institute, and UL1TRR002535 to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR019498-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. | Serban, K A Pratte, K A Strange, C Sandhaus, R A Turner, A M Beiko, T Spittle, D A Maier, L Hamzeh, N Silverman, E K Hobbs, B D Hersh, C P DeMeo, D L Cho, M H Bowler, R P eng K08 HL141770/HL/NHLBI NIH HHS/ Meta-Analysis Netherlands EBioMedicine. 2022 Oct;84:104262. doi: 10.1016/j.ebiom.2022.104262. Epub 2022 Sep 22.I | 09/27/2022 | ||
| Human Plasma Proteome During Normal Pregnancy | Tarca AL, et al. | 2022 | J Proteome Res | 21 | 11 | 2687-2702 | https://www.doi.org/10.1021/acs.jproteome.2c00391 | 36,154,181 | Humans Pregnancy Female *Proteome/genetics/metabolism *Placenta/metabolism Longitudinal Studies Gestational Age aptamer biomarker machine learning proteomic standards single-cell RNA signature | The human plasma proteome is underexplored despite its potential value for monitoring health and disease. Herein, using a recently developed aptamer-based platform, we profiled 7288 proteins in 528 plasma samples from 91 normal pregnancies (Gene Expression Omnibus identifier GSE206454). The coefficient of variation was <20% for 93% of analytes (median 7%), and a cross-platform correlation for selected key angiogenic and anti-angiogenic proteins was significant. Gestational age was associated with changes in 953 proteins, including highly modulated placenta- and decidua-specific proteins, and they were enriched in biological processes including regulation of growth, angiogenesis, immunity, and inflammation. The abundance of proteins corresponding to RNAs specific to populations of cells previously described by single-cell RNA-Seq analysis of the placenta was highly modulated throughout gestation. Furthermore, machine learning-based prediction of gestational age and of time from sampling to term delivery compared favorably with transcriptomic models (mean absolute error of 2 weeks). These results suggested that the plasma proteome may provide a non-invasive readout of placental cellular dynamics and serve as a blueprint for investigating obstetrical disease. | Tarca, Adi L Romero, Roberto Bhatti, Gaurav Gotsch, Francesca Done, Bogdan Gudicha, Dereje W Gallo, Dahiana M Jung, Eunjung Pique-Regi, Roger Berry, Stanley M Chaiworapongsa, Tinnakorn Gomez-Lopez, Nardhy eng J Proteome Res. 2022 Nov 4;21(11):2687-2702. doi: 10.1021/acs.jproteome.2c00391. Epub 2022 Sep 26.I | 09/27/2022 | |
| Multi-Omic Admission-Based Prognostic Biomarkers Identified by Machine Learning Algorithms Predict Patient Recovery and 30-Day Survival in Trauma Patients | Abdelhamid SS, et al. | 2022 | Metabolites | 12 | 9 | 774 | https://www.doi.org/10.3390/metabo12090774 | 36,144,179 | biomarkers machine learning multi-omics prognostic proteomics trauma equity stake in Haima Therapeutics. He has received research support and/or honoraria from Haemonetics, Instrumentation Laboratories, Janssen Pharmaceuticals, and Meredian. T.R.B. is a stakeholder in Immunetrics. Other authors declare no conflict of interests. | Admission-based circulating biomarkers for the prediction of outcomes in trauma patients could be useful for clinical decision support. It is unknown which molecular classes of biomolecules can contribute biomarkers to predictive modeling. Here, we analyzed a large multi-omic database of over 8500 markers (proteomics, metabolomics, and lipidomics) to identify prognostic biomarkers in the circulating compartment for adverse outcomes, including mortality and slow recovery, in severely injured trauma patients. Admission plasma samples from patients (n = 129) enrolled in the Prehospital Air Medical Plasma (PAMPer) trial were analyzed using mass spectrometry (metabolomics and lipidomics) and aptamer-based (proteomics) assays. Biomarkers were selected via Least Absolute Shrinkage and Selection Operator (LASSO) regression modeling and machine learning analysis. A combination of five proteins from the proteomic layer was best at discriminating resolvers from non-resolvers from critical illness with an Area Under the Receiver Operating Characteristic curve (AUC) of 0.74, while 26 multi-omic features predicted 30-day survival with an AUC of 0.77. Patients with traumatic brain injury as part of their injury complex had a unique subset of features that predicted 30-day survival. Our findings indicate that multi-omic analyses can identify novel admission-based prognostic biomarkers for outcomes in trauma patients. Unique biomarker discovery also has the potential to provide biologic insights. | Abdelhamid, Sultan S Scioscia, Jacob Vodovotz, Yoram Wu, Junru Rosengart, Anna Sung, Eunseo Rahman, Syed Voinchet, Robert Bonaroti, Jillian Li, Shimena Darby, Jennifer L Kar, Upendra K Neal, Matthew D Sperry, Jason Das, Jishnu Billiar, Timothy R eng T32 HL098036/HL/NHLBI NIH HHS/ R38 HL150207/HL/NHLBI NIH HHS/ R35 GM127027/GM/NIGMS NIH HHS/ R35GM119526/NH/NIH HHS/ DP2AI164325/National Institute of Allergy and Infectious Diseases/ R35-GM-127027/NH/NIH HHS/ R35 GM119526/GM/NIGMS NIH HHS/ DP2 AI164325/AI/NIAID NIH HHS/ Switzerland Metabolites. 2022 Aug 23;12(9):774. doi: 10.3390/metabo12090774.I | 09/24/2022 | |
| Prediction of Total-Body and Partial-Body Exposures to Radiation Using Plasma Proteomic Expression Profiles | Sproull M, et al. | 2022 | Radiat Res | epub ahead of print | https://www.doi.org/10.1667/RADE-22-00074.1 | 36,136,739 | There is a need to identify new biomarkers of radiation exposure for not only systemic total-body irradiation (TBI) but also to characterize partial-body irradiation and organ specific radiation injury. In the current study, we sought to develop novel biodosimetry models of radiation exposure using TBI and organ specific partial-body irradiation to only the brain, lung or gut using a multivariate proteomics approach. Subset panels of significantly altered proteins were selected to build predictive models of radiation exposure in a variety of sample cohort configurations relevant to practical field application of biodosimetry diagnostics during future radiological or nuclear event scenarios. Female C57BL/6 mice, 8-15 weeks old, received a single total-body or partial-body dose of 2 or 8 Gy TBI or 2 or 8 Gy to only the lung or gut, or 2, 8 or 16 Gy to only the brain using a Pantak X-ray source. Plasma was collected by cardiac puncture at days 1, 3 and 7 postirradiation for total-body exposures and only the lung and brain exposures, and at days 3, 7 and 14 postirradiation for gut exposures. Plasma was then screened using the aptamer-based SOMAscan proteomic assay technology, for changes in expression of 1,310 protein analytes. A subset panel of protein biomarkers which demonstrated significant changes (P < 0.01) in expression after irradiation were used to build predictive models of radiation exposure using different sample cohorts. Model 1 compared controls vs. all pooled irradiated samples, which included TBI and all organ specific partial irradiation. Model 2 compared controls vs. TBI vs. partial irradiation (with all organ specific partial exposure pooled within the partial-irradiated group), and model 3 compared controls vs. each individual organ specific partial-body exposure separately (brain, gut and lung). Detectable values were obtained for all 1,310 proteins included in the SOMAscan assay for all samples. Each model algorithm built using a unique sample cohort was validated with a training set of samples and tested with a separate new sample series. Overall predictive accuracies of 89%, 78% and 55% resulted for models 1-3, respectively, representing novel predictive panels of radiation responsive proteomic biomarkers. Though relatively high overall predictive accuracies were achieved for models 1 and 2, all three models showed limited accuracy at differentiating between the controls and partial-irradiated body samples. In our study we were able to identify novel panels of radiation responsive proteins useful for predicting radiation exposure and to create predictive models of partial-body exposure including organ specific radiation exposures. This proof-of-concept study also illustrates the inherent physiological limitations of distinguishing between small-body exposures and the unirradiated using proteomic biomarkers of radiation exposure. As use of biodosimetry diagnostics in future mass casualty settings will be complicated by the heterogeneity of partial-body exposure received in the field, further work remains in adapting these diagnostic tools for practical use. | Sproull, M Kawai, T Krauze, A Shankavaram, U Camphausen, K eng Radiat Res. 2022 Sep 22. doi: 10.1667/RADE-22-00074.1.I | 09/23/2022 | ||||
| Proteomic Analysis of Effects of Spironolactone in Heart Failure With Preserved Ejection Fraction | Javaheri A, et al. | 2022 | Circ Heart Fail | 15 | 9 | e009693 | https://www.doi.org/10.1161/CIRCHEARTFAILURE.121.009693 | 36,126,144 | Apelin/pharmacology/therapeutic use *Biological Products/pharmacology/therapeutic use Caspases/pharmacology/therapeutic use *Heart Failure Humans *Insulins/therapeutic use Liver X Receptors Mineralocorticoid Receptor Antagonists/therapeutic use Phospholipid Transfer Proteins/pharmacology/therapeutic use Proteome Proteomics Spironolactone/adverse effects Stroke Volume/physiology Treatment Outcome Americas caspase glycoprotein heart failure spironolactone | BACKGROUND: The TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) suggested clinical benefits of spironolactone treatment among patients with heart failure with preserved ejection fraction enrolled in the Americas. However, a comprehensive assessment of biologic pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction has not been performed. METHODS: We conducted aptamer-based proteomic analysis utilizing 5284 modified aptamers to 4928 unique proteins on plasma samples from TOPCAT participants from the Americas (n=164 subjects with paired samples at baseline and 1 year) to identify proteins and pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction. Mean percentage change from baseline was calculated for each protein. Additionally, we conducted pathway analysis of proteins altered by spironolactone. RESULTS: Spironolactone therapy was associated with proteome-wide significant changes in 7 proteins. Among these, CARD18 (caspase recruitment domain-containing protein 18), PKD2 (polycystin 2), and PSG2 (pregnancy-specific glycoprotein 2) were upregulated, whereas HGF (hepatic growth factor), PLTP (phospholipid transfer protein), IGF2R (insulin growth factor 2 receptor), and SWP70 (switch-associated protein 70) were downregulated. CARD18, a caspase-1 inhibitor, was the most upregulated protein by spironolactone (-0.5% with placebo versus +66.5% with spironolactone, P<0.0001). The top canonical pathways that were significantly associated with spironolactone were apelin signaling, stellate cell activation, glycoprotein 6 signaling, atherosclerosis signaling, liver X receptor activation, and farnesoid X receptor activation. Among the top pathways, collagens were a consistent theme that increased in patients receiving placebo but decreased in patients randomized to spironolactone. CONCLUSIONS: Proteomic analysis in the TOPCAT trial revealed proteins and pathways altered by spironolactone, including the caspase inhibitor CARD18 and multiple pathways that involved collagens. In addition to effects on fibrosis, our studies suggest potential antiapoptotic effects of spironolactone in heart failure with preserved ejection fraction, a hypothesis that merits further exploration. | Javaheri, Ali Diab, Ahmed Zhao, Lei Qian, Chenao Cohen, Jordana B Zamani, Payman Kumar, Anupam Wang, Zhaoqing Ebert, Christina Maranville, Joseph Kvikstad, Erika Basso, Michael van Empel, Vanessa Richards, A Mark Doughty, Robert N Rietzschel, Ernst Kammerhoff, Karl Gogain, Joseph Schafer, Peter Seiffert, Dietmar A Gordon, David A Ramirez-Valle, Francisco Mann, Douglas L Cappola, Thomas P Chirinos, Julio A eng R01 HL155599/HL/NHLBI NIH HHS/ U01 TR003734/TR/NCATS NIH HHS/ R03 HL146874/HL/NHLBI NIH HHS/ K24 AG070459/AG/NIA NIH HHS/ R01 HL104106/HL/NHLBI NIH HHS/ R01 HL121510/HL/NHLBI NIH HHS/ R56 HL136730/HL/NHLBI NIH HHS/ R01 AG058969/AG/NIA NIH HHS/ R01 HL153646/HL/NHLBI NIH HHS/ U01 HL160277/HL/NHLBI NIH HHS/ K08 HL138262/HL/NHLBI NIH HHS/ R33 HL146390/HL/NHLBI NIH HHS/ P01 HL094307/HL/NHLBI NIH HHS/ R01 HL157264/HL/NHLBI NIH HHS/ R01 HL155344/HL/NHLBI NIH HHS/ Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circ Heart Fail. 2022 Sep;15(9):e009693. doi: 10.1161/CIRCHEARTFAILURE.121.009693. Epub 2022 Aug 9.I | 09/21/2022 | |
| Inflammatory Markers in Non-Obese Women with Polycystic Ovary Syndrome Are Not Elevated and Show No Correlation with Vitamin D Metabolites | Moin ASM, et al. | 2022 | Nutrients | 14 | 17 | https://www.doi.org/10.3390/nu14173540 | 36,079,796 | Aged Biomarkers Female Humans Inflammation/complications *Insulin Resistance Obesity *Polycystic Ovary Syndrome Vitamin D Vitamins inflammation matrix metalloproteinases polycystic ovary syndrome vitamin D3 | INTRODUCTION: Chronic low-grade inflammation is a characteristic of women with polycystic ovary syndrome (PCOS), although this may be obesity-driven rather than an intrinsic facet of PCOS; furthermore, vitamin D deficiency, another common feature of PCOS, is reported to have an association with increased inflammation. Therefore, circulating inflammatory protein levels and circulating levels of vitamin D may be linked in PCOS, though it is unclear which vitamin D metabolites may be important. METHODS: We measured plasma levels of 24 inflammatory proteins and 12 matrix metalloproteinases (proteins modulated by the inflammatory process) by slow off-rate modified aptamer (SOMA)-scan plasma protein measurement in weight and aged-matched non-obese non-insulin resistant PCOS (n = 24) and control (n = 24) women. Inflammatory proteins and matrix metalloproteinases were correlated to 25-hydroxy vitamin D(3) (25(OH)D(3)), its epimer 25-hydroxy-3epi-vitamin D (3epi25(OH)D) and the active 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) as measured by gold standard isotope-dilution liquid chromatography tandem mass spectrometry. RESULTS: PCOS women had both an elevated free androgen index and circulating anti-mullerian hormone, though insulin resistance was comparable to controls. C-reactive protein, as a standard circulatory marker of inflammation, was comparable between cohorts. Levels of circulating inflammatory proteins and matrix metalloproteinases were not different between the PCOS and control women, with no correlation of 25(OH)D(3,) 1,25(OH)(2)D(3) or 3epi25(OH)D with any of the inflammatory proteins. CONCLUSION: In a non-obese PCOS population matched for age and insulin resistance, circulating inflammatory proteins and matrix metalloproteinases were not elevated and did not correlate with 25(OH)D(3,) its epimer 3epi25(OH)D or 1,25(OH)(2)D(3) in either control or PCOS women, indicating that the inflammatory response is absent and the vitamin D-metabolite independent in non-obese women with PCOS. | Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Switzerland Nutrients. 2022 Aug 27;14(17):3540. doi: 10.3390/nu14173540.I | 09/10/2022 | ||
| The associations between plasma soluble Trem1 and neurological diseases: a Mendelian randomization study | Shi X, et al. | 2022 | J Neuroinflammation | 19 | 1 | 218 | https://www.doi.org/10.1186/s12974-022-02582-z | 36,068,612 | *Alzheimer Disease/genetics *Amyotrophic Lateral Sclerosis Genome-Wide Association Study Humans Mendelian Randomization Analysis/methods *Parkinson Disease/genetics Polymorphism, Single Nucleotide/genetics Triggering Receptor Expressed on Myeloid Cells-1/genetics Alzheimer's disease Epilepsy Mendelian randomization Neurological diseases sTrem1 | BACKGROUND: Triggering receptor expressed on myeloid cell 1 (Trem1) is an important regulator of cellular inflammatory responses. Neuroinflammation is a common thread across various neurological diseases. Soluble Trem1 (sTrem1) in plasma is associated with the development of central nervous system disorders. However, the extent of any causative effects of plasma sTrem1 on the risk of these disorders is still unclear. METHOD: Genetic variants for plasma sTrem1 levels were selected as instrumental variables. Summary-level statistics of neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), epilepsy, cerebrovascular diseases, and migraine were collected from genome-wide association studies (GWASs). Whether plasma sTrem1 was causally associated with neurological disorders was assessed using a two-sample Mendelian randomization (MR) analysis, with false discovery rate (FDR)-adjusted methods applied. RESULTS: We inferred suggestive association of higher plasma sTrem1 with the risk of AD (odds ratio [OR] per one standard deviation [SD] increase = 1.064, 95% CI 1.012-1.119, P = 0.014, P(FDR) = 0.056). Moreover, there was significant association between plasma sTrem1 level and the risk of epilepsy (OR per one SD increase = 1.044, 95% CI 1.016-1.072, P = 0.002, P(FDR) = 0.032), with a modest statistical power of 41%. Null associations were found for plasma sTrem1 with other neurological diseases and their subtypes. CONCLUSIONS: Taken together, this study indicates suggestive association between plasma sTrem1 and AD. Moreover, higher plasma sTrem1 was associated with the increased risk of epilepsy. The findings support the hypothesis that sTrem1 may be a vital element on the causal pathway to AD and epilepsy. | Shi, Xiaolei Wei, Tao Hu, Yachun Wang, Meng Tang, Yi eng 2021-2023/Guangzhou Municipal Key Discipline in Medicine/ 2019B030316001/Science and Technology Plan Project of Guangdong Province/ JQ19024/Beijing Natural Science Foundation/ 81970996/National Natural Science Foundation of China/ Z191100006619046/Beijing Municipal Science & Technology Commission/ DFL20220703/Beijing Hospitals Authority's Ascent Plan/ England J Neuroinflammation. 2022 Sep 6;19(1):218. doi: 10.1186/s12974-022-02582-z.I | 09/07/2022 | |
| Is an MRI-derived anatomical measure of dementia risk also a measure of brain aging? | Casanova R, et al. | 2022 | Geroscience | epub ahead of print | https://www.doi.org/10.1007/s11357-022-00650-z | 36,050,589 | Aging Alzheimer's disease Deficit accumulation index Machine learning Mortality Proteomics | Machine learning methods have been applied to estimate measures of brain aging from neuroimages. However, only rarely have these measures been examined in the context of biologic age. Here, we investigated associations of an MRI-based measure of dementia risk, the Alzheimer's disease pattern similarity (AD-PS) scores, with measures used to calculate biological age. Participants were those from visit 5 of the Atherosclerosis Risk in Communities Study with cognitive status adjudication, proteomic data, and AD-PS scores available. The AD-PS score estimation is based on previously reported machine learning methods. We evaluated associations of the AD-PS score with all-cause mortality. Sensitivity analyses using only cognitively normal (CN) individuals were performed treating CNS-related causes of death as competing risk. AD-PS score was examined in association with 32 proteins measured, using a Somalogic platform, previously reported to be associated with age. Finally, associations with a deficit accumulation index (DAI) based on a count of 38 health conditions were investigated. All analyses were adjusted for age, race, sex, education, smoking, hypertension, and diabetes. The AD-PS score was significantly associated with all-cause mortality and with levels of 9 of the 32 proteins. Growth/differentiation factor 15 (GDF-15) and pleiotrophin remained significant after accounting for multiple-testing and when restricting the analysis to CN participants. A linear regression model showed a significant association between DAI and AD-PS scores overall. While the AD-PS scores were created as a measure of dementia risk, our analyses suggest that they could also be capturing brain aging. | Casanova, Ramon Anderson, Andrea M Barnard, Ryan T Justice, Jamie N Kucharska-Newton, Anna Windham, Beverly Gwen Palta, Priya Gottesman, Rebecca F Mosley, Thomas H Hughes, Timothy M Wagenknecht, Lynne E Kritchevsky, Stephen B eng grant R01 HL134320/HL/NHLBI NIH HHS/ U01 AG024904/AG/NIA NIH HHS/ Switzerland Geroscience. 2022 Sep 2. doi: 10.1007/s11357-022-00650-z.I | 09/02/2022 | |||
| Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer's disease | Paranjpe MD, et al. | 2022 | PLoS Genet | 18 | 9 | e1010294 | https://www.doi.org/10.1371/journal.pgen.1010294 | 36,048,760 | Adult Aged *Alzheimer Disease/pathology Biomarkers Cross-Sectional Studies Genome-Wide Association Study Humans Middle Aged Proteomics | For Alzheimer's disease-a leading cause of dementia and global morbidity-improved identification of presymptomatic high-risk individuals and identification of new circulating biomarkers are key public health needs. Here, we tested the hypothesis that a polygenic predictor of risk for Alzheimer's disease would identify a subset of the population with increased risk of clinically diagnosed dementia, subclinical neurocognitive dysfunction, and a differing circulating proteomic profile. Using summary association statistics from a recent genome-wide association study, we first developed a polygenic predictor of Alzheimer's disease comprised of 7.1 million common DNA variants. We noted a 7.3-fold (95% CI 4.8 to 11.0; p < 0.001) gradient in risk across deciles of the score among 288,289 middle-aged participants of the UK Biobank study. In cross-sectional analyses stratified by age, minimal differences in risk of Alzheimer's disease and performance on a digit recall test were present according to polygenic score decile at age 50 years, but significant gradients emerged by age 65. Similarly, among 30,541 participants of the Mass General Brigham Biobank, we again noted no significant differences in Alzheimer's disease diagnosis at younger ages across deciles of the score, but for those over 65 years we noted an odds ratio of 2.0 (95% CI 1.3 to 3.2; p = 0.002) in the top versus bottom decile of the polygenic score. To understand the proteomic signature of inherited risk, we performed aptamer-based profiling in 636 blood donors (mean age 43 years) with very high or low polygenic scores. In addition to the well-known apolipoprotein E biomarker, this analysis identified 27 additional proteins, several of which have known roles related to disease pathogenesis. Differences in protein concentrations were consistent even among the youngest subset of blood donors (mean age 33 years). Of these 28 proteins, 7 of the 8 proteins with concentrations available were similarly associated with the polygenic score in participants of the Multi-Ethnic Study of Atherosclerosis. These data highlight the potential for a DNA-based score to identify high-risk individuals during the prolonged presymptomatic phase of Alzheimer's disease and to enable biomarker discovery based on profiling of young individuals in the extremes of the score distribution. | Paranjpe, Manish D Chaffin, Mark Zahid, Sohail Ritchie, Scott Rotter, Jerome I Rich, Stephen S Gerszten, Robert Guo, Xiuqing Heckbert, Susan Tracy, Russ Danesh, John Lander, Eric S Inouye, Michael Kathiresan, Sekar Butterworth, Adam S Khera, Amit V eng NIHR BTRU-2014- 10024/DH_/Department of Health/United Kingdom MR/L003120/1/MRC_/Medical Research Council/United Kingdom SP/09/002/BHF_/British Heart Foundation/United Kingdom RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom CSO_/Chief Scientist Office/United Kingdom 75N92020D00001/HL/NHLBI NIH HHS/ HHSN268201500003I/HL/NHLBI NIH HHS/ N01HC95159/HL/NHLBI NIH HHS/ N01HC95160/HL/NHLBI NIH HHS/ N01HC95161/HL/NHLBI NIH HHS/ N01HC95162/HL/NHLBI NIH HHS/ N01HC95163/HL/NHLBI NIH HHS/ N01HC95164/HL/NHLBI NIH HHS/ N01HC95165/HL/NHLBI NIH HHS/ N01HC95166/HL/NHLBI NIH HHS/ N01 HC095167/HC/NHLBI NIH HHS/ N01HC95168/HL/NHLBI NIH HHS/ N01HC95169/HL/NHLBI NIH HHS/ 75N92020D00005/HL/NHLBI NIH HHS/ 75N92020D00002/HL/NHLBI NIH HHS/ 75N92020D00003/HL/NHLBI NIH HHS/ 75N92020D00006/HL/NHLBI NIH HHS/ 75N92020D00004/HL/NHLBI NIH HHS/ 75N92020D00007/HL/NHLBI NIH HHS/ N02 HL64278/HL/NHLBI NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS Genet. 2022 Sep 1;18(9):e1010294. doi: 10.1371/journal.pgen.1010294. eCollection 2022 Sep.I | 09/02/2022 | |
| Highly sensitive protein detection by aptamer-based single-molecule kinetic fingerprinting | Chatterjee T, et al. | 2022 | Biosens Bioelectron | 216 | 114639 | https://www.doi.org/10.1016/j.bios.2022.114639 | 36,037,714 | Antibodies, Monoclonal *Aptamers, Nucleotide/chemistry Biomarkers *Biosensing Techniques Humans Interleukin-8 Ligands *Nucleic Acids Reproducibility of Results SELEX Aptamer Technique/methods Vascular Endothelial Growth Factor A Analyte detection Aptamer Kinetic fingerprinting Protein biomarkers Sensitivity Single molecule fluorescence microscopy interests/personal relationships which may be considered as potential competing interests: N.G.W and A.J.-B are cofounder of aLight Sciences, Inc., which seeks to commercialize the SiMREPS technology. A.J.-B is an employee of aLight Sciences, Inc. N.G.W and A.J.-B are co-inventors of patent applications related to the SiMREPS technology. | Sensitive assays of protein biomarkers play critical roles in clinical diagnostics and biomedical research. Such assays typically employ immunoreagents such as monoclonal antibodies that suffer from several drawbacks, including relatively tedious production, significant batch-to-batch variability, and challenges in site-specific, stoichiometric modification with fluorophores or other labels. One proposed alternative to such immunoreagents, nucleic acid aptamers generated by systematic evolution of ligand by exponential enrichment (SELEX), can be chemically synthesized with much greater ease, precision, and reproducibility than antibodies. However, most aptamers exhibit relatively poor affinity, yielding low sensitivity in the assays employing them. Recently, single molecule recognition through equilibrium Poisson sampling (SiMREPS) has emerged as a platform for detecting proteins and other biomarkers with high sensitivity without requiring high-affinity detection probes. In this manuscript, we demonstrate the applicability and advantages of aptamers as detection probes in SiMREPS as applied to two clinically relevant biomarkers, VEGF(165) and IL-8, using a wash-free protocol with limits of detection in the low femtomolar range (3-9 fM). We show that the kinetics of existing RNA aptamers can be rationally optimized for use as SiMREPS detection probes by mutating a single nucleotide in the conserved binding region or by shortening the aptamer sequence. Finally, we demonstrate the detection of endogenous IL-8 from human serum at a concentration below the detection limit of commercial ELISAs. | Chatterjee, Tanmay Johnson-Buck, Alexander Walter, Nils G eng England Biosens Bioelectron. 2022 Nov 15;216:114639. doi: 10.1016/j.bios.2022.114639. Epub 2022 Aug 22.I | 08/30/2022 | ||
| Markers of endothelial glycocalyx dysfunction in Clarkson disease | Xie Z, et al. | 2022 | J Transl Med | 20 | 1 | 380 | https://www.doi.org/10.1186/s12967-022-03587-1 | 36,038,904 | Biomarkers *Capillary Leak Syndrome/diagnosis/pathology/therapy Endothelial Cells/pathology Glycocalyx Humans Proteomics Capillary leak Endothelium Glyocalcyx | BACKGROUND: Clarkson disease (monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome, ISCLS) is a rare idiopathic condition marked by transient, relapsing-remitting episodes of systemic microvascular hyper-permeability, which liberates plasma fluid and macromolecules into the peripheral tissues. This pathology manifests clinically as the abrupt onset of hypotensive shock, hemoconcentration, and hypoalbuminemia. METHODS: We analysed endothelial glycocalyx (eGCX)-related markers in plasma from patients with ISCLS during acute disease flares and convalescence by ELISA and comprehensive proteomic profiling. We evaluated eGCX-related components and gene expression in cultured endothelial cells using RNA-sequencing, real-time PCR, and fluorescence staining. RESULTS: Serum levels of eGCX-related core components including hyaluronic acid (HA) and the core proteoglycan soluble syndecan-1 (sCD138) were elevated at baseline and during acute ISCLS flares. Serial measurements demonstrated that sCD138 levels peaked during the recovery (post-leak) phase of the illness. Proteomic analysis of matched acute and convalescent ISCLS plasma revealed increased abundance of eGCX-related proteins, including glypicans, thrombospondin-1 (TSP-1), and eGCX-degrading enzymes in acute compared to remission plasma. Abundance of endothelial cell damage markers did not differ in acute and baseline plasma. Expression of several eGCX-related genes and surface carbohydrate content in endothelial cells from patients with ISCLS did not differ significantly from that observed in healthy control cells. CONCLUSIONS: eGCX dysfunction, but not endothelial injury, may contribute to clinical symptoms of acute ISCLS. Serum levels of of eGCX components including sCD138 may be measured during acute episodes of ISCLS to monitor clinical status and therapeutic responses. | Xie, Zhihui Borset, Magne Sveen, Kjell Boe, Ole Wilhelm Chan, Eunice C Lack, Justin B Hornick, Katherine M Verlicchi, Franco Eisch, A Robin Melchio, Remo Dudek, Arkadiusz Z Druey, Kirk M eng Z01-AI-001083/Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ Research Support, N.I.H., Intramural England J Transl Med. 2022 Aug 29;20(1):380. doi: 10.1186/s12967-022-03587-1.I | 08/30/2022 | |
| Recent developments of aptamer-based lateral flow assays for point-of-care (POC) diagnostics | Jaisankar A, et al. | 2022 | Anal Biochem | 655 | 114874 | https://www.doi.org/10.1016/j.ab.2022.114874 | 36,027,971 | Antibodies *Aptamers, Nucleotide Biological Assay *Biosensing Techniques Humans Point-of-Care Systems SELEX Aptamer Technique Aptamer-based LFA Aptamers Lateral flow assay Selex Sensors of interest. | In the field of lateral flow assay (LFA), the application of aptamer as a bioreceptor has been implemented to overcome the limitations of antibodies, such as tedious in vivo processes, short shelf-life, and functionalization issues. To address these limitations aptamer-based LFA (ALFA) is preferred to antibody-based LFA that produces higher sensitivity and specificity. In principle, aptamers have a strong affinity towards their targets like small, large, and non-immunogenic molecules because of their high affinity, sensitivity, low dissociation constant, cost-effectiveness, and flexible nature. Thus, ALFA can be considered an efficient biosensor model for its superior portability, rapid detection with quick turnaround time, and usability by a non-technical person at any location with simple visual output. This review concisely overviews ALFA, its principles, formats, aptamer selection process, and biomedical applications. In addition, the critical components to design, develop, test, and amplify signals to create ALFA are discussed in brief. In addition, the aspects of conceptualization of ALFA product transforming from bench-side laboratory design and fabrication to commercial market are addressed in detail. | Jaisankar, Abinaya Krishnan, Sasirekha Rangasamy, Loganathan eng Research Support, Non-U.S. Gov't Review Anal Biochem. 2022 Oct 15;655:114874. doi: 10.1016/j.ab.2022.114874. Epub 2022 Aug 24.I | 08/27/2022 | ||
| Blood-biomarkers and devices for atrial fibrillation screening: Lessons learned from the AFRICAT (Atrial Fibrillation Research In CATalonia) study | Pala E, et al. | 2022 | PLoS One | 17 | 8 | e0273571 | https://www.doi.org/10.1371/journal.pone.0273571 | 35,998,199 | *Atrial Fibrillation Biomarkers Electrocardiography, Ambulatory Humans Prospective Studies Spain | BACKGROUND AND OBJECTIVE: AFRICAT is a prospective cohort study intending to develop an atrial fibrillation (AF) screening program through the combination of blood markers, rhythm detection devices, and long-term monitoring in our community. In particular, we aimed to validate the use of NT-proBNP, and identify new blood biomarkers associated with AF. Also, we aimed to compare AF detection using various wearables and long-term Holter monitoring. METHODS: 359 subjects aged 65-75 years with hypertension and diabetes were included in two phases: Phase I (n = 100) and Phase II (n = 259). AF diagnosis was performed by baseline 12-lead ECG, 4 weeks of Holter monitoring (NuuboTM), and/or medical history. An aptamer array including 1310 proteins was measured in the blood of 26 patients. Candidates were selected according to p-value, logFC and biological function to be tested in verification and validation phases. Several screening devices were tested and compared: AliveCor, Watch BP, MyDiagnostick and Fibricheck. RESULTS: AF was present in 34 subjects (9.47%). The aptamer array revealed 41 proteins with differential expression in AF individuals. TIMP-2 and ST-2 were the most promising candidates in the verification analysis, but none of them was further validated. NT-proBNP (log-transformed) (OR = 1.934; p<0.001) was the only independent biomarker to detect AF in the whole cohort. Compared to an ECG, WatchBP had the highest sensitivity (84.6%) and AUC (0.895 [0.780-1]), while MyDiagnostick showed the highest specificity (97.10%). CONCLUSION: The inclusion and monitoring of a cohort of primary care patients for AF detection, together with the testing of biomarkers and screening devices provided useful lessons about AF screening in our community. An AF screening strategy using rhythm detection devices and short monitoring periods among high-risk patients with high NT-proBNP levels could be feasible. | Pala, Elena Bustamante, Alejandro Clua-Espuny, Josep Lluis Acosta, Juan Gonzalez-Loyola, Felipe Santos, Sara Dos Ribas-Segui, Domingo Ballesta-Ors, Juan Penalba, Anna Giralt, Marina Lechuga-Duran, Inigo Gentille-Lorente, Delicia Pedrote, Alonso Munoz, Miguel Angel Montaner, Joan eng Research Support, Non-U.S. Gov't PLoS One. 2022 Aug 23;17(8):e0273571. doi: 10.1371/journal.pone.0273571. eCollection 2022.I | 08/24/2022 | |
| Proteomic profiling platforms head to head: Leveraging genetics and clinical traits to compare aptamer- and antibody-based methods | Katz DH, et al. | 2022 | Sci Adv | 8 | 33 | eabm5164 | https://www.doi.org/10.1126/sciadv.abm5164 | 35,984,888 | Adult Antibodies/chemistry Aptamers, Peptide/chemistry Humans Longitudinal Studies Phenotype *Proteome *Proteomics/methods | High-throughput proteomic profiling using antibody or aptamer-based affinity reagents is used increasingly in human studies. However, direct analyses to address the relative strengths and weaknesses of these platforms are lacking. We assessed findings from the SomaScan1.3K (N = 1301 reagents), the SomaScan5K platform (N = 4979 reagents), and the Olink Explore (N = 1472 reagents) profiling techniques in 568 adults from the Jackson Heart Study and 219 participants in the HERITAGE Family Study across four performance domains: precision, accuracy, analytic breadth, and phenotypic associations leveraging detailed clinical phenotyping and genetic data. Across these studies, we show evidence supporting more reliable protein target specificity and a higher number of phenotypic associations for the Olink platform, while the Soma platforms benefit from greater measurement precision and analytic breadth across the proteome. | Katz, Daniel H Robbins, Jeremy M Deng, Shuliang Tahir, Usman A Bick, Alexander G Pampana, Akhil Yu, Zhi Ngo, Debby Benson, Mark D Chen, Zsu-Zsu Cruz, Daniel E Shen, Dongxiao Gao, Yan Bouchard, Claude Sarzynski, Mark A Correa, Adolfo Natarajan, Pradeep Wilson, James G Gerszten, Robert E eng HHSN268201100037C/HL/NHLBI NIH HHS/ R01 NR019628/NR/NINR NIH HHS/ R01 HL127564/HL/NHLBI NIH HHS/ U24 DK112340/DK/NIDDK NIH HHS/ HHSN268201800014C/HL/NHLBI NIH HHS/ R01 HL142711/HL/NHLBI NIH HHS/ RF1 AG063507/AG/NIA NIH HHS/ R01 HL117626/HL/NHLBI NIH HHS/ HHSN268201800011I/HB/NHLBI NIH HHS/ R01 HL146462/HL/NHLBI NIH HHS/ P30 GM118430/GM/NIGMS NIH HHS/ HHSN268201800012I/HB/NHLBI NIH HHS/ HHSN268201800012C/HL/NHLBI NIH HHS/ DP5 OD029586/OD/NIH HHS/ R01 HL120393/HL/NHLBI NIH HHS/ R01 HL047327/HL/NHLBI NIH HHS/ KL2 TR002542/TR/NCATS NIH HHS/ R01 HL047323/HL/NHLBI NIH HHS/ HHSN268201800014I/HB/NHLBI NIH HHS/ U01 HL120393/HL/NHLBI NIH HHS/ R01 DK081572/DK/NIDDK NIH HHS/ HHSN268201800001C/HL/NHLBI NIH HHS/ HHSN268201800013I/MD/NIMHD NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ HHSN268201800011C/HL/NHLBI NIH HHS/ T32 HL007374/HL/NHLBI NIH HHS/ HHSN268201800015I/HB/NHLBI NIH HHS/ K23 HL150327/HL/NHLBI NIH HHS/ F32 HL150992/HL/NHLBI NIH HHS/ HHSN268201800010I/HB/NHLBI NIH HHS/ R01 HL047317/HL/NHLBI NIH HHS/ K08 HL145095/HL/NHLBI NIH HHS/ R01 HL045670/HL/NHLBI NIH HHS/ Sci Adv. 2022 Aug 19;8(33):eabm5164. doi: 10.1126/sciadv.abm5164. Epub 2022 Aug 19.I | 08/20/2022 | |
| Long-term changes in plasma proteomic profiles in premenopausal and postmenopausal Black and White women: the Atherosclerosis Risk in Communities study | Appiah D, et al. | 2022 | Menopause | 29 | 10 | 1150-1160 | https://www.doi.org/10.1097/GME.0000000000002031 | 35,969,495 | *Atherosclerosis Cholesterol Cross-Sectional Studies Female Humans Lipids Menopause Middle Aged *Postmenopause/physiology Premenopause/physiology Proteomics | OBJECTIVE: The activity, localization, and turnover of proteins within cells and plasma may contribute to physiologic changes during menopause and may influence disease occurrence. We examined cross-sectional differences and long-term changes in plasma proteins between premenopausal and naturally postmenopausal women. METHODS: We used data from 4,508 (19% Black) women enrolled in the Atherosclerosis Risk in Communities study. SOMAscan multiplexed aptamer technology was used to measure 4,697 plasma proteins. Linear regression models were used to compare differences in proteins at baseline (1993-1995) and 18-year change in proteins from baseline to 2011-2013. RESULTS: At baseline, 472 women reported being premenopausal and 4,036 women reported being postmenopausal, with average ages of 52.3 and 61.4 years, respectively. A greater proportion of postmenopausal women had diabetes (15 vs 9%), used hypertension (38 vs 27%) and lipid-lowering medications (10 vs 3%), and had elevated total cholesterol and waist girth. In multivariable adjusted models, 38 proteins differed significantly between premenopausal and postmenopausal women at baseline, with 29 of the proteins also showing significantly different changes between groups over the 18-year follow-up as the premenopausal women also reached menopause. These proteins were associated with various molecular/cellular functions (cellular development, growth, proliferation and maintenance), physiological system development (skeletal and muscular system development, and cardiovascular system development and function), and diseases/disorders (hematological and metabolic diseases and developmental disorders). CONCLUSIONS: We observed significantly different changes between premenopausal and postmenopausal women in several plasma proteins that reflect many biological processes. These processes may help to understand disease development during the postmenopausal period. | Appiah, Duke Schreiner, Pamela J Pankow, James S Brock, Guy Tang, Weihong Norby, Faye L Michos, Erin D Ballantyne, Christie M Folsom, Aaron R eng HHSN268201700002C/HL/NHLBI NIH HHS/ HHSN268201700001I/HL/NHLBI NIH HHS/ HHSN268201700004I/HL/NHLBI NIH HHS/ HHSN268201700004C/HL/NHLBI NIH HHS/ R01 HL134320/HL/NHLBI NIH HHS/ HHSN268201700003I/HL/NHLBI NIH HHS/ HHSN268201700005C/HL/NHLBI NIH HHS/ HHSN268201700001C/HL/NHLBI NIH HHS/ HHSN268201700003C/HL/NHLBI NIH HHS/ HHSN268201700002I/HL/NHLBI NIH HHS/ HHSN268201700005I/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Menopause. 2022 Oct 1;29(10):1150-1160. doi: 10.1097/GME.0000000000002031. Epub 2022 Aug 20.I | 08/16/2022 | |
| ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19 | Pietzner M, et al. | 2022 | Nat Commun | 13 | 1 | 4484 | https://www.doi.org/10.1038/s41467-022-31999-6 | 35,970,849 | Angiotensin-Converting Enzyme 2/genetics *COVID-19/genetics *DNA-Binding Proteins/genetics Epithelial Cells/metabolism Humans Peptidyl-Dipeptidase A/metabolism Respiratory System SARS-CoV-2 *Transcription Factors/genetics | Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis of COVID-19 infection remain poorly understood. Here, we prioritise eight robust (e.g., ELF5) or suggestive but unreported (e.g., RAB2A) candidate protein mediators of COVID-19 outcomes by integrating results from the COVID-19 Host Genetics Initiative with population-based plasma proteomics using statistical colocalisation. The transcription factor ELF5 (ELF5) shows robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.88; 95%-CI: 2.47-9.63; p-value < 5.0 x 10(-6)) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a risk gene for severe COVID-19, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2. | Pietzner, Maik Chua, Robert Lorenz Wheeler, Eleanor Jechow, Katharina Willett, Julian D S Radbruch, Helena Trump, Saskia Heidecker, Bettina Zeberg, Hugo Heppner, Frank L Eils, Roland Mall, Marcus A Richards, J Brent Sander, Leif-Erik Lehmann, Irina Lukassen, Soren Wareham, Nicholas J Conrad, Christian Langenberg, Claudia eng MC_UU_12015/1/MRC_/Medical Research Council/United Kingdom MC_PC_13046/MRC_/Medical Research Council/United Kingdom MC_UU_00006/1/MRC_/Medical Research Council/United Kingdom 365825/CIHR/Canada 409511/CIHR/Canada 100558/CIHR/Canada 169303/CIHR/Canada C18281/A29019/CRUK_/Cancer Research UK/United Kingdom WT_/Wellcome Trust/United Kingdom DH_/Department of Health/United Kingdom Research Support, Non-U.S. Gov't England Nat Commun. 2022 Aug 15;13(1):4484. doi: 10.1038/s41467-022-31999-6.I | 08/16/2022 | |
| Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes | Kobayashi H, et al. | 2022 | Sci Transl Med | 14 | 657 | eabj2109 | https://www.doi.org/10.1126/scitranslmed.abj2109 | 35,947,673 | Cell Cycle Proteins/*blood *Diabetes Mellitus, Type 2/complications Disease Progression Humans *Kidney Failure, Chronic *Neuroblastoma Proteomics Transforming Growth Factor beta | Circulating proteins associated with transforming growth factor-beta (TGF-beta) signaling are implicated in the development of diabetic kidney disease (DKD). It remains to be comprehensively examined which of these proteins are involved in the pathogenesis of DKD and its progression to end-stage kidney disease (ESKD) in humans. Using the SOMAscan proteomic platform, we measured concentrations of 25 TGF-beta signaling family proteins in four different cohorts composed in total of 754 Caucasian or Pima Indian individuals with type 1 or type 2 diabetes. Of these 25 circulating proteins, we identified neuroblastoma suppressor of tumorigenicity 1 (NBL1, aliases DAN and DAND1), a small secreted protein known to inhibit members of the bone morphogenic protein family, to be most strongly and independently associated with progression to ESKD during 10-year follow-up in all cohorts. The extent of damage to podocytes and other glomerular structures measured morphometrically in 105 research kidney biopsies correlated strongly with circulating NBL1 concentrations. Also, in vitro exposure to NBL1 induced apoptosis in podocytes. In conclusion, circulating NBL1 may be involved in the disease process underlying progression to ESKD, and its concentration in circulation may identify subjects with diabetes at increased risk of progression to ESKD. | Kobayashi, Hiroki Looker, Helen C Satake, Eiichiro D'Addio, Francesca Wilson, Jonathan M Saulnier, Pierre Jean Md Dom, Zaipul I O'Neil, Kristina Ihara, Katsuhito Krolewski, Bozena Badger, Hannah S Petrazzuolo, Adriana Corradi, Domenico Galecki, Andrzej Wilson, Parker C Najafian, Behzad Mauer, Michael Niewczas, Monika A Doria, Alessandro Humphreys, Benjamin D Duffin, Kevin L Fiorina, Paolo Nelson, Robert G Krolewski, Andrzej S eng P30 DK036836/DK/NIDDK NIH HHS/ R01 DK041526/DK/NIDDK NIH HHS/ R01 DK110350/DK/NIDDK NIH HHS/ R01 DK126799/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Sci Transl Med. 2022 Aug 10;14(657):eabj2109. doi: 10.1126/scitranslmed.abj2109. Epub 2022 Aug 10.I | 08/11/2022 | |
| High Dimensional Immune Profiling of Smoldering Multiple Myeloma Distinguishes Distinct Tumor Microenvironments | Fernandez N, et al. | 2022 | Clin Lymphoma Myeloma Leuk | 22 | 11 | 853-862 | https://www.doi.org/10.1016/j.clml.2022.07.001 | 35,945,129 | Humans *Smoldering Multiple Myeloma Tumor Microenvironment *Monoclonal Gammopathy of Undetermined Significance/pathology *Multiple Myeloma/pathology Plasma Cells/pathology Disease Progression | BACKGROUND: Multiple myeloma (MM) is a malignancy of plasma cells that arises from premalignant Monoclonal Gammopathy of Undetermined Significance (MGUS) and often progresses through an asymptomatic Smoldering (SMM) phase. Understanding the interactions between abnormal clonal plasma cells and the tumor microenvironment (TME) in the early disease states (MGUS, SMM) may inform risk assessment and therapy. PATIENTS AND METHODS: We performed high dimensional immunologic analysis of bone marrow specimens from 73 subjects with SMM by mass cytometry and T cell receptor sequencing of CD138-depleted bone marrow (BM) mononuclear cells, and proteomics and seromic profiling of BM plasma. Analysis of individual assay data identified self-organizing subgroups of SMM patients. We then applied novel bioinformatic methods to integrate data from pairs, trios, and quartets of assays. RESULTS: Mass cytometry, TCRSeq and proteomics identified three taxa (sing. taxon) of subjects that shared common characteristics across all three assays. Differential levels of BM plasma pleiotropin (PTN) and BM T cells and their productive clonality emerged as strong distinguishing factors among these taxa. CONCLUSION: These results suggest that the continuum from MGUS to MM does not consist of a single pathway in the TME, and that complex interactions between myeloma cells and the TME may ultimately determine progression and inform clinical management. | Fernandez, Nicolas Perumal, Deepak Rahman, Adeeb Kim-Schulze, Seunghee Yesil, Jen Auclair, Daniel Adams, Homer 3rd Parekh, Samir Gnjatic, Sacha Cho, Hearn Jay eng Research Support, Non-U.S. Gov't Clin Lymphoma Myeloma Leuk. 2022 Nov;22(11):853-862. doi: 10.1016/j.clml.2022.07.001. Epub 2022 Jul 16.I | 08/10/2022 | |
| Proteomic Profiling of Plasma Biomarkers Associated With Return to Sport Following Concussion: Findings From the NCAA and Department of Defense CARE Consortium | Vorn R, et al. | 2022 | Front Neurol | 13 | 901238 | https://www.doi.org/10.3389/fneur.2022.901238 | 35,928,129 | biomarker concussion proteomic return to sport (RTS) sport injuries research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | OBJECTIVE: To investigate the plasma proteomic profiling in identifying biomarkers related to return to sport (RTS) following a sport-related concussion (SRC). METHODS: This multicenter, prospective, case-control study was part of a larger cohort study conducted by the NCAA-DoD Concussion Assessment, Research, and Education (CARE) Consortium, athletes (n = 140) with blood collected within 48 h of injury and reported day to asymptomatic were included in this study, divided into two groups: (1) recovery <14-days (n = 99) and (2) recovery >/=14-days (n = 41). We applied a highly multiplexed proteomic technique that uses DNA aptamers assay to target 1,305 proteins in plasma samples from concussed athletes with <14-days and >/=14-days. RESULTS: We identified 87 plasma proteins significantly dysregulated (32 upregulated and 55 downregulated) in concussed athletes with recovery >/=14-days relative to recovery <14-days groups. The significantly dysregulated proteins were uploaded to Ingenuity Pathway Analysis (IPA) software for analysis. Pathway analysis showed that significantly dysregulated proteins were associated with STAT3 pathway, regulation of the epithelial mesenchymal transition by growth factors pathway, and acute phase response signaling. CONCLUSION: Our data showed the feasibility of large-scale plasma proteomic profiling in concussed athletes with a <14-days and >/= 14-days recovery. These findings provide a possible understanding of the pathophysiological mechanism in neurobiological recovery. Further study is required to determine whether these proteins can aid clinicians in RTS decisions. | Vorn, Rany Mithani, Sara Devoto, Christina Meier, Timothy B Lai, Chen Yun, Sijung Broglio, Steven P McAllister, Thomas W Giza, Christopher C Kim, Hyung-Suk Huber, Daniel Harezlak, Jaroslaw Cameron, Kenneth L McGinty, Gerald Jackson, Jonathan Guskiewicz, Kevin M Mihalik, Jason P Brooks, Alison Duma, Stefan Rowson, Steven Nelson, Lindsay D Pasquina, Paul McCrea, Michael A Gill, Jessica M eng Switzerland Front Neurol. 2022 Jul 19;13:901238. doi: 10.3389/fneur.2022.901238. eCollection 2022.I | 08/06/2022 | ||
| Serum proteomic profiling of rheumatoid arthritis-interstitial lung disease with a comparison to idiopathic pulmonary fibrosis | Wu X, et al. | 2022 | Thorax | epub ahead of print | https://www.doi.org/10.1136/thorax-2021-217822 | 35,907,639 | Interstitial Fibrosis Rheumatoid lung disease interest, all outside the submitted work: ST reports medical advisory group membership of Novo Nordisk and board membership at Droobi Health, Qatar. RG receives grant support from Canon Medical Systems. HH reports grants from Canon Medical Systems and Konica Minolta, and personal fees from Mitsubishi Chemical Co and Canon Medical Systems Inc. MN reports grants from AstraZeneca, Daiichi Sankyo, Canon Medical Systems, Merck investigator studies program personal fees from Daiichi Sankyo and AstraZeneca. MEW receives research support from Amgen, Bristol Myers Squibb and Eli Lilly and consultation fees from AbbVie, Aclaris, Amgen, Arena, Bayer, Bristol Myers Squibb, Corvitas, Eqrx, Genosco, GSK, Gilead, Horizon, Johnson & Johnson, Kiniksa, Lilly, Novartis, Pfizer, Rami Therapeutics, R Pharma, Roche, Sanofi, Scipher, Sci Rhom, Set Point and Tremeau. He holds stock/stock options of CanFite, Inmedix, Vorso and Scipher. NAS reports grants and other support from Bristol-Myers Squibb, grants from Mallinckrodt, Sanofi, Crescendo Biosciences, Lilly and Amgen. PFD reports grants from Bristol-Myers Squibb and Genentech, and other support from Boehringer Ingelheim. AMKC is a cofounder and equity stock holder for Proterris, which develops therapeutic uses for carbon monoxide, and also has a use patent on CO and a patent in chronic obstructive pulmonary disease. EYK is a member of the steering committees for and receives no financial remuneration from NCT04409834 (Prevention of arteriovenous thrombotic events in critically ill COVID-19 patients, TIMI group) and REMAP-CAP ACE2 renin-angiotensin system modulation domain, and receives unrelated research funding from Bayer AG, Roche Pharma Research and Early Development, Windtree Therapeutics, the US National Institutes of Health, the US Agency for International Development, the American Heart Association, American Lung Association and the Bell Family Fund. IOR reports grants from Genentech. FJM reports personal fees, non-financial support and other support from AstraZeneca, other support from Afferent/Merck, personal fees, non-financial support and other support from Boehringer Ingelheim, other support from Bristol Myers Squibb, other support from Chiesi, personal fees and non-financial support from the Canadian Respiratory Society, personal fees and non-financial support from CME Outfitters, personal fees and non-financial support from CSL Behring, personal fees from Dartmouth University, personal fees from France Foundation, personal fees from Gala, personal fees and non-financial support from Genentech, grants, personal fees, non-financial support and other support from GlaxoSmithKline, personal fees and non-financial support from Inova Fairfax, personal fees and non-financial support from MD Magazine, personal fees and non-financial support from NYP Methodist Hospital Brooklyn, personal fees and non-financial support from Miller Communications, personal fees and non-financial support from National Association for Continuing Education/Integritas, other support from Nitto, personal fees and non-financial support from Novartis, personal fees from New York University, personal fees and non-financial support from Patara/Respivant, personal fees from Pearl, personal fees and non-financial support from Peer View, personal fees from Physicians Education Resource, personal fees from ProMedior, personal fees and non-financial support from Rare Diseases Healthcare Communications, personal fees from Rockpointe Communications, personal fees and non-financial support from Sanofi/Regeneron, other support from Biogen, personal fees and non-financial support from Sunovion, personal fees and non-financial support from Teva, other support from two XAR, personal fees from University of Birmingham Alabama, personal fees from UpToDate, non-financial support from Veracyte, personal fees from Vindico, personal fees and non-financial support from WebMD/MedScape, non-financial support and other support from Zambon, non-financial support from ProTerrix Bio, and personal fees from IQVIA, Raziel, Abvie and Verona. TJD has received grant support from Bristol Myers Squibb, consulting fees from Boehringer Ingelheim and L.E.K. consulting, and has been part of a clinical trial funded by Genentech. The remaining authors have reported no conflicts of interest. | Although interstitial lung disease (ILD) causes significant morbidity and mortality in rheumatoid arthritis (RA), it is difficult to predict the development or progression of ILD, emphasising the need for improved discovery through minimally invasive diagnostic tests. Aptamer-based proteomic profiling was used to assess 1321 proteins from 159 patients with rheumatoid arthritis with interstitial lung disease (RA-ILD), RA without ILD, idiopathic pulmonary fibrosis and healthy controls. Differential expression and gene set enrichment analyses revealed molecular signatures that are strongly associated with the presence and severity of RA-ILD and provided insight into unexplored pathways of disease. These warrant further study as non-invasive diagnostic tools and future therapeutic targets. | Wu, Xiaoping Jeong, Yunju Poli de Frias, Sergio Easthausen, Imaani Hoffman, Katherine Oromendia, Clara Taheri, Shahrad Esposito, Anthony J Quesada Arias, Luisa Ayaub, Ehab A Maurer, Rie Gill, Ritu R Hatabu, Hiroto Nishino, Mizuki Frits, Michelle L Iannaccone, Christine K Weinblatt, Michael E Shadick, Nancy A Dellaripa, Paul F Choi, Augustine M K Kim, Edy Y Rosas, Ivan O Martinez, Fernando J Doyle, Tracy J eng F32 HL151132/HL/NHLBI NIH HHS/ K23 HL119558/HL/NHLBI NIH HHS/ L30 HL149048/HL/NHLBI NIH HHS/ R03 HL148484/HL/NHLBI NIH HHS/ England Thorax. 2022 Jul 30:thoraxjnl-2021-217822. doi: 10.1136/thorax-2021-217822.I | 07/31/2022 | |||
| Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence, Severity, and Treatment Response | Cederberg KLJ, et al. | 2022 | Int J Mol Sci | 23 | 14 | https://www.doi.org/10.3390/ijms23147983 | 35,887,329 | Biomarkers Continuous Positive Airway Pressure Humans Polysomnography *Proteomics *Sleep Apnea, Obstructive/complications/diagnosis/therapy apnea-hypopnea index machine learning obstructive sleep apnea proteomics treatment Hedou, Dr. Jing Zhang, Dr. Ling Lin, Dr. Suresh Kotagal, Dr. Adam Blackman, Dr. Clete Kushida, and Dr. Nayia Petousi declare no conflict of interest. Dr. Chris Turnbull declares consulting fees from Bayer and honoraria from Stowood, outside the scope of this work. Dr. Schneider reports personal fees from Jazz Pharmaceuticals, personal fees from Harmony Biosciences, personal fees from Eisai, outside the submitted work. Dr. Leary is an employee of Jazz Pharmaceuticals who, in the course of her employment, has received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Dr. Anne Marie Morse has received consulting fees from Jazz Pharmaceuticals, Harmony Biosciences, and Avadel, outside the scope of this work. Dr. Paula Schweitzer has received consulting fees from Apnimed and Jazz Pharmaceuticals her institution has received research funding from Apnimed, Avadel, Harmony Biosciences, Inspire Medical, and Suven Life Sciences, all outside the scope of this work. Dr. Richard Bogan is a shareholder in WaterMark Medical and Healthy Humming, LLC serves on the Board of Directors for WaterMark Medical is a consultant to Jazz, Harmony Biosciences, Takeda, Avadel, and Oventus has industry funded research for Avadel, BresoTec, Idorsia, Suven, Jazz, Balance, Vanda, Merck, Eisai, Philips, Fresca, Takeda, Liva Nova, Roche, Sommetrics, NLS, Sanofi, Apnimed and is on the Speakers Bureau for Jazz, Eisai, Harmony, Idorsia all outside the scope of this work. Dr. Yo-El Ju reports consulting fees from Applied Cognition, outside the scope of this work. Dr. Emmanuel Mignot occasionally consults and has received contracts from Jazz Pharmaceuticals, Orexia/Centessa, Tekeda, Dreem, and ActiGraph has received grant/clinical trial funding from Haromony, Tekeda, Apple, Humani, Sunovion, Indorsia, Eisai is and has been a Principal Investigator on clinical trials using sodium oxybate and Solriamfetol, Jazz Pharmaceutical products, for the treatment of Type 1 narcolepsy all outside the scope of this work. | Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea-hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI >/= 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke. | Cederberg, Katie L J Hanif, Umaer Peris Sempere, Vicente Hedou, Julien Leary, Eileen B Schneider, Logan D Lin, Ling Zhang, Jing Morse, Anne M Blackman, Adam Schweitzer, Paula K Kotagal, Suresh Bogan, Richard Kushida, Clete A Ju, Yo-El S Petousi, Nayia Turnbull, Chris D Mignot, Emmanuel The Stages Cohort Investigator Group eng N/A/Oxford Radcliffe Hospital Charitable Funds/ KL2TR000450/NH/NIH HHS/ T32HL110952/NH/NIH HHS/ N/A/ResMed UK/ K23NS089922/NH/NIH HHS/ UL1 TR002345/TR/NCATS NIH HHS/ N/A/Bryte Foundation/ N/A/National Institute for Health Research/ N/A/Philips Respironics/ N/A/Klarman Family Foundation/ UL1TR000448/Washington University Institute of Clinical and Translational Sciences/ UL1RR024992/NH/NIH HHS/ Switzerland Int J Mol Sci. 2022 Jul 20;23(14):7983. doi: 10.3390/ijms23147983.I | 07/28/2022 | ||
| Associations between circulating proteins and risk of breast cancer by intrinsic subtypes: a Mendelian randomisation analysis | Shu X, et al. | 2022 | Br J Cancer | 127 | 8 | 1507-1514 | https://www.doi.org/10.1038/s41416-022-01923-2 | 35,882,941 | Biomarkers, Tumor/genetics/metabolism *Breast Neoplasms/pathology Female Humans Mendelian Randomization Analysis *Protein Disulfide Reductase (Glutathione) Receptors, Phospholipase A2 *Triple Negative Breast Neoplasms | BACKGROUND: The aetiologic role of circulating proteins in the development of breast cancer subtypes is not clear. We aimed to examine the potential causal effects of circulating proteins on the risk of breast cancer by intrinsic-like subtypes within the Mendelian randomisation (MR) framework. METHODS: MR was performed using summary statistics from two sources: the INTERVAL protein quantitative trait loci (pQTL) Study (1890 circulating proteins and 3301 healthy individuals) and the Breast Cancer Association Consortium (BCAC; 106,278 invasive cases and 91,477 controls). The inverse-variance (IVW)-weighted method was used as the main analysis to evaluate the associations between genetically predicted proteins and the risk of five different intrinsic-like breast cancer subtypes and the weighted median MR method, the Egger regression, the MR-PRESSO, and the MRLocus method were performed as secondary analysis. RESULTS: We identified 98 unique proteins significantly associated with the risk of one or more subtypes (Benjamini-Hochberg false discovery rate < 0.05). Among them, 51 were potentially specific to luminal A-like subtype, 14 to luminal B/Her2-negative-like, 11 to triple negative, 3 to luminal B-like, and 2 to Her2-enriched-like breast cancer (n(total) = 81). Associations for three proteins (ICAM1, PLA2R1 and TXNDC12) showed evident heterogeneity across the subtypes. For example, higher levels of genetically predicted ICAM1 (per unit of increase) were associated with an increased risk of luminal B/HER2-negative-like cancer (OR = 1.06, 95% CI = 1.03-1.08, BH-FDR = 2.43 x 10(-4)) while inversely associated with triple-negative breast cancer with borderline significance (OR = 0.97, 95% CI = 0.95-0.99, BH-FDR = 0.065, P(heterogeneity) < 0.005). CONCLUSIONS: Our study found potential causal associations with the risk of subtypes of breast cancer for 98 proteins. Associations of ICAM1, PLA2R1 and TXNDC12 varied substantially across the subtypes. The identified proteins may partly explain the heterogeneity in the aetiology of distinct subtypes of breast cancer and facilitate the personalised risk assessment of the malignancy. | Shu, Xiang Zhou, Qin Sun, Xiaohui Flesaker, Michelle Guo, Xingyi Long, Jirong Robson, Mark E Shu, Xiao-Ou Zheng, Wei Bernstein, Jonine L eng R00 CA230205/CA/NCI NIH HHS/ K99 CA230205/CA/NCI NIH HHS/ R25 CA214255/CA/NCI NIH HHS/ R01 CA202981/CA/NCI NIH HHS/ R01 CA235553/CA/NCI NIH HHS/ P30 CA008748/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Br J Cancer. 2022 Nov;127(8):1507-1514. doi: 10.1038/s41416-022-01923-2. Epub 2022 Jul 26.I | 07/27/2022 | |
| Comparative Analysis of Alzheimer's Disease Cerebrospinal Fluid Biomarkers Measurement by Multiplex SOMAscan Platform and Immunoassay-Based Approach | Timsina J, et al. | 2022 | J Alzheimers Dis | 89 | 1 | 193-207 | https://www.doi.org/10.3233/JAD-220399 | 35,871,346 | *Alzheimer Disease/cerebrospinal fluid/diagnosis Amyloid beta-Peptides/cerebrospinal fluid Biomarkers/cerebrospinal fluid Humans Immunoassay Neurogranin/cerebrospinal fluid ROC Curve tau Proteins/cerebrospinal fluid Alzheimer's disease SOMAscan assays cerebrospinal fluid biomarkers correlation | BACKGROUND: The SOMAscan assay has an advantage over immunoassay-based methods because it measures a large number of proteins in a cost-effective manner. However, the performance of this technology compared to the routinely used immunoassay techniques needs to be evaluated. OBJECTIVE: We performed comparative analyses of SOMAscan and immunoassay-based protein measurements for five cerebrospinal fluid (CSF) proteins associated with Alzheimer's disease (AD) and neurodegeneration: NfL, Neurogranin, sTREM2, VILIP-1, and SNAP-25. METHODS: We compared biomarkers measured in ADNI (N = 689), Knight-ADRC (N = 870), DIAN (N = 115), and Barcelona-1 (N = 92) cohorts. Raw protein values were transformed using z-score in order to combine measures from the different studies. sTREM2 and VILIP-1 had more than one analyte in SOMAscan; all available analytes were evaluated. Pearson's correlation coefficients between SOMAscan and immunoassays were calculated. Receiver operating characteristic curve and area under the curve were used to compare prediction accuracy of these biomarkers between the two platforms. RESULTS: Neurogranin, VILIP-1, and NfL showed high correlation between SOMAscan and immunoassay measures (r > 0.9). sTREM2 had a fair correlation (r > 0.6), whereas SNAP-25 showed weak correlation (r = 0.06). Measures in both platforms provided similar predicted performance for all biomarkers except SNAP-25 and one of the sTREM2 analytes. sTREM2 showed higher AUC for SOMAscan based measures. CONCLUSION: Our data indicate that SOMAscan performs as well as immunoassay approaches for NfL, Neurogranin, VILIP-1, and sTREM2. Our study shows promise for using SOMAscan as an alternative to traditional immunoassay-based measures. Follow-up investigation will be required for SNAP-25 and additional established biomarkers. | Timsina, Jigyasha Gomez-Fonseca, Duber Wang, Lihua Do, Anh Western, Dan Alvarez, Ignacio Aguilar, Miquel Pastor, Pau Henson, Rachel L Herries, Elizabeth Xiong, Chengjie Schindler, Suzanne E Fagan, Anne M Bateman, Randall J Farlow, Martin Morris, John C Perrin, Richard J Moulder, Krista Hassenstab, Jason Voglein, Jonathan Chhatwal, Jasmeer Mori, Hiroshi Sung, Yun Ju Cruchaga, Carlos eng R01 AG044546/AG/NIA NIH HHS/ RF1 AG053303/AG/NIA NIH HHS/ RF1 AG074007/AG/NIA NIH HHS/ P01 AG003991/AG/NIA NIH HHS/ RF1 AG058501/AG/NIA NIH HHS/ P30 AG066444/AG/NIA NIH HHS/ P01 AG026276/AG/NIA NIH HHS/ U19 AG032438/AG/NIA NIH HHS/ Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Netherlands J Alzheimers Dis. 2022;89(1):193-207. doi: 10.3233/JAD-220399.I | 07/25/2022 | |
| Identification of 969 protein quantitative trait loci in an African American population with kidney disease attributed to hypertension | Surapaneni A, et al. | 2022 | Kidney Int | 102 | 5 | 1167-1177 | https://www.doi.org/10.1016/j.kint.2022.07.005 | 35,870,639 | Humans Quantitative Trait Loci African Americans/genetics Proteome Genome-Wide Association Study Polymorphism, Single Nucleotide *Hypertension/genetics *Kidney Diseases/genetics Genetic Predisposition to Disease pQTL protein quantitative trait loci | Investigations into the causal underpinnings of disease processes can be aided by the incorporation of genetic information. Genetic studies require populations varied in both ancestry and prevalent disease in order to optimize discovery and ensure generalizability of findings to the global population. Here, we report the genetic determinants of the serum proteome in 466 African Americans with chronic kidney disease attributed to hypertension from the richly phenotyped African American Study of Kidney Disease and Hypertension (AASK) study. Using the largest aptamer-based protein profiling platform to date (6,790 proteins or protein complexes), we identified 969 genetic associations with 900 unique proteins; including 52 novel cis (local) associations and 379 novel trans (distant) associations. The genetic effects of previously published cis-protein quantitative trait loci (pQTLs) were found to be highly reproducible, and we found evidence that our novel genetic signals colocalize with gene expression and disease processes. Many trans- pQTLs were found to reflect associations mediated by the circulating cis protein, and the common trans-pQTLs are enriched for processes involving extracellular vesicles, highlighting a plausible mechanism for distal regulation of the levels of secreted proteins. Thus, our study generates a valuable resource of genetic associations linking variants to protein levels and disease in an understudied patient population to inform future studies of drug targets and physiology. | Surapaneni, Aditya Schlosser, Pascal Zhou, Linda Liu, Celina Chatterjee, Nilanjan Arking, Dan E Dutta, Diptavo Coresh, Josef Rhee, Eugene P Grams, Morgan E eng Kidney Int. 2022 Nov;102(5):1167-1177. doi: 10.1016/j.kint.2022.07.005. Epub 2022 Jul 21.I | 07/24/2022 | |
| The circulating proteomic signature of alcohol-associated liver disease | Luther J, et al. | 2022 | JCI Insight | 7 | 14 | https://www.doi.org/10.1172/jci.insight.159775 | 35,866,482 | Biomarkers Humans *Liver Diseases, Alcoholic/metabolism Proteome *Proteomics Hepatitis Hepatology Proteomics | Despite being a leading cause of advanced liver disease, alcohol-associated liver disease (ALD) has no effective medical therapies. The circulating proteome, which comprises proteins secreted by different cells and tissues in the context of normal physiological function or in the setting of disease and illness, represents an attractive target for uncovering novel biology related to the pathogenesis of ALD. In this work, we used the aptamer-based SomaScan proteomics platform to quantify the relative concentration of over 1300 proteins in a well-characterized cohort of patients with the spectrum of ALD. We found a distinct circulating proteomic signature that correlated with ALD severity, including over 600 proteins that differed significantly between ALD stages, many of which have not previously been associated with ALD to our knowledge. Notably, certain proteins that were markedly dysregulated in patients with alcohol-associated hepatitis were also altered, to a lesser degree, in patients with subclinical ALD and may represent early biomarkers for disease progression. Taken together, our work highlights the vast and distinct changes in the circulating proteome across the wide spectrum of ALD, identifies potentially novel biomarkers and therapeutic targets, and provides a proteomic resource atlas for ALD researchers and clinicians. | Luther, Jay Vannier, Augustin Gl Schaefer, Esperance A Goodman, Russell P eng K08 DK115881/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't JCI Insight. 2022 Jul 22;7(14):e159775. doi: 10.1172/jci.insight.159775.I | 07/23/2022 | ||
| Proteomic biomarkers of Kleine-Levin syndrome | Hedou J, et al. | 2022 | Sleep | 45 | 9 | https://www.doi.org/10.1093/sleep/zsac097 | 35,859,339 | Biomarkers *Cognitive Dysfunction *Disorders of Excessive Somnolence Humans *Kleine-Levin Syndrome Proteomics Csf Kleine-Levine syndrome aptamers brain immunity hypersomnia microglia serum | STUDY OBJECTIVES: Kleine-Levin syndrome (KLS) is characterized by relapsing-remitting episodes of hypersomnia, cognitive impairment, and behavioral disturbances. We quantified cerebrospinal fluid (CSF) and serum proteins in KLS cases and controls. METHODS: SomaScan was used to profile 1133 CSF proteins in 30 KLS cases and 134 controls, while 1109 serum proteins were profiled in serum from 26 cases and 65 controls. CSF and serum proteins were both measured in seven cases. Univariate and multivariate analyses were used to find differentially expressed proteins (DEPs). Pathway and tissue enrichment analyses (TEAs) were performed on DEPs. RESULTS: Univariate analyses found 28 and 141 proteins differentially expressed in CSF and serum, respectively (false discovery rate <0.1%). Upregulated CSF proteins included IL-34, IL-27, TGF-b, IGF-1, and osteonectin, while DKK4 and vWF were downregulated. Pathway analyses revealed microglial alterations and disrupted blood-brain barrier permeability. Serum profiles show upregulation of Src-family kinases (SFKs), proteins implicated in cellular growth, motility, and activation. TEA analysis of up- and downregulated proteins revealed changes in brain proteins (p < 6 x 10-5), notably from the pons, medulla, and midbrain. A multivariate machine-learning classifier performed robustly, achieving a receiver operating curve area under the curve of 0.90 (95% confidence interval [CI] = 0.78-1.0, p = 0.0006) in CSF and 1.0 (95% CI = 1.0-1.0, p = 0.0002) in serum in validation cohorts, with some commonality across tissues, as the model trained on serum sample also discriminated CSF samples of controls versus KLS cases. CONCLUSIONS: Our study identifies proteomic KLS biomarkers with diagnostic potential and provides insight into biological mechanisms that will guide future research in KLS. | Hedou, Julien Cederberg, Katie L Ambati, Aditya Lin, Ling Farber, Neal Dauvilliers, Yves Quadri, Mohammed Bourgin, Patrice Plazzi, Giuseppe Andlauer, Olivier Hong, Seung-Chul Huang, Yu-Shu Leu-Semenescu, Smaranda Arnulf, Isabelle Taheri, Shahrad Mignot, Emmanuel eng S10 OD023452/OD/NIH HHS/ R01MH080957/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Sleep. 2022 Sep 8;45(9):zsac097. doi: 10.1093/sleep/zsac097.I | 07/22/2022 | ||
| High Dimensional Multiomics Reveals Unique Characteristics of Early Plasma Administration in Polytrauma Patients With TBI | Wu J, et al. | 2022 | Ann Surg | 276 | 4 | 673-683 | https://www.doi.org/10.1097/SLA.0000000000005610 | 35,861,072 | *Brain Injuries, Traumatic/therapy *Emergency Medical Services/methods Humans *Multiple Trauma/therapy Plasma Proteomics | OBJECTIVES: The authors sought to identify causal factors that explain the selective benefit of prehospital administration of thawed plasma (TP) in traumatic brain injury (TBI) patients using mediation analysis of a multiomic database. BACKGROUND: The Prehospital Air Medical Plasma (PAMPer) Trial showed that patients with TBI and a pronounced systemic response to injury [defined as endotype 2 (E2)], have a survival benefit from prehospital administration of TP. An interrogation of high dimensional proteomics, lipidomics and metabolomics previously demonstrated unique patterns in circulating biomarkers in patients receiving prehospital TP, suggesting that a deeper analysis could reveal causal features specific to TBI patients. METHODS: A novel proteomic database (SomaLogic Inc., aptamer-based assay, 7K platform) was generated using admission blood samples from a subset of patients (n=149) from the PAMPer Trial. This proteomic dataset was combined with previously reported metabolomic and lipidomic datasets from these same patients. A 2-step analysis was performed to identify factors that promote survival in E2-TBI patients who had received early TP. First, features were selected using both linear and multivariate-latent-factor regression analyses. Then, the selected features were entered into the causal mediation analysis. RESULTS: Causal mediation analysis of observable features identified 16 proteins and 41 lipids with a high proportion of mediated effect (>50%) to explain the survival benefit of early TP in E2-TBI patients. The multivariate latent-factor regression analyses also uncovered 5 latent clusters of features with a proportion effect >30%, many in common with the observable features. Among the observable and latent features were protease inhibitors known to inhibit activated protein C and block fibrinolysis (SERPINA5 and CPB2), a clotting factor (factor XI), as well as proteins involved in lipid transport and metabolism (APOE3 and sPLA(2)-XIIA). CONCLUSIONS: These findings suggest that severely injured patients with TBI process exogenous plasma differently than those without TBI. The beneficial effects of early TP in E2-TBI patients may be the result of improved blood clotting and the effect of brain protective factors independent of coagulation. | Wu, Junru Moheimani, Hamed Li, Shimena Kar, Upendra K Bonaroti, Jillian Miller, Richard S Daley, Brian J Harbrecht, Brian G Claridge, Jeffrey A Gruen, Danielle S Phelan, Herbert A Guyette, Francis X Neal, Matthew D Das, Jishnu Sperry, Jason L Billiar, Timothy R eng R35 GM127027/GM/NIGMS NIH HHS/ R01 HL141080/HL/NHLBI NIH HHS/ R38 HL150207/HL/NHLBI NIH HHS/ T32 GM008516/GM/NIGMS NIH HHS/ R35 GM119526/GM/NIGMS NIH HHS/ DP2 AI164325/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Ann Surg. 2022 Oct 1;276(4):673-683. doi: 10.1097/SLA.0000000000005610. Epub 2022 Jul 19.I | 07/22/2022 | |
| Development and Validation of Prediction Models of Adverse Kidney Outcomes in the Population With and Without Diabetes | Grams ME, et al. | 2022 | Diabetes Care | 45 | 9 | 2055-2063 | https://www.doi.org/10.2337/dc22-0698 | 35,856,507 | Albuminuria *Diabetes Mellitus/epidemiology Glomerular Filtration Rate Humans Kidney *Renal Insufficiency *Renal Insufficiency, Chronic/epidemiology | OBJECTIVE: To predict adverse kidney outcomes for use in optimizing medical management and clinical trial design. RESEARCH DESIGN AND METHODS: In this meta-analysis of individual participant data, 43 cohorts (N = 1,621,817) from research studies, electronic medical records, and clinical trials with global representation were separated into development and validation cohorts. Models were developed and validated within strata of diabetes mellitus (presence or absence) and estimated glomerular filtration rate (eGFR; >/=60 or <60 mL/min/1.73 m2) to predict a composite of >/=40% decline in eGFR or kidney failure (i.e., receipt of kidney replacement therapy) over 2-3 years. RESULTS: There were 17,399 and 24,591 events in development and validation cohorts, respectively. Models predicting >/=40% eGFR decline or kidney failure incorporated age, sex, eGFR, albuminuria, systolic blood pressure, antihypertensive medication use, history of heart failure, coronary heart disease, atrial fibrillation, smoking status, and BMI, and, in those with diabetes, hemoglobin A1c, insulin use, and oral diabetes medication use. The median C-statistic was 0.774 (interquartile range [IQR] = 0.753, 0.782) in the diabetes and higher-eGFR validation cohorts; 0.769 (IQR = 0.758, 0.808) in the diabetes and lower-eGFR validation cohorts; 0.740 (IQR = 0.717, 0.763) in the no diabetes and higher-eGFR validation cohorts; and 0.750 (IQR = 0.731, 0.785) in the no diabetes and lower-eGFR validation cohorts. Incorporating the previous 2-year eGFR slope minimally improved model performance, and then only in the higher-eGFR cohorts. CONCLUSIONS: Novel prediction equations for a decline of >/=40% in eGFR can be applied successfully for use in the general population in persons with and without diabetes with higher or lower eGFR. | Grams, Morgan E Brunskill, Nigel J Ballew, Shoshana H Sang, Yingying Coresh, Josef Matsushita, Kunihiro Surapaneni, Aditya Bell, Samira Carrero, Juan J Chodick, Gabriel Evans, Marie Heerspink, Hiddo J L Inker, Lesley A Iseki, Kunitoshi Kalra, Philip A Kirchner, H Lester Lee, Brian J Levin, Adeera Major, Rupert W Medcalf, James Nadkarni, Girish N Naimark, David M J Ricardo, Ana C Sawhney, Simon Sood, Manish M Staplin, Natalie Stempniewicz, Nikita Stengel, Benedicte Sumida, Keiichi Traynor, Jamie P van den Brand, Jan Wen, Chi-Pang Woodward, Mark Yang, Jae Won Wang, Angela Yee-Moon Tangri, Navdeep Chalmers, John Hsu, Chi-Yuan Anderson, Amanda Rao, Panduranga Feldman, Harold Chang, Alex R Ho, Kevin Green, Jamie Siddiqui, Moneeza Palmer, Colin Shalev, Varda Metzger, Marie Flamant, Martin Houillier, Pascal Haymann, Jean-Philippe Cuddeback, John Ciemins, Elizabeth Kovesdy, Csaba P Trevisan, Marco Elinder, Carl Gustaf Wettermark, Bjorn Kalra, Philip Chinnadurai, Rajkumar Tollitt, James Green, Darren Gansevoort, Ron T Gutierrez, Orlando Konta, Tsuneo Kottgen, Anna Levey, Andrew S Polkinghorne, Kevan Schaffner, Elke Zhang, Luxia Chen, Jingsha eng R01 DK100446/DK/NIDDK NIH HHS/ Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Diabetes Care. 2022 Sep 1;45(9):2055-2063. doi: 10.2337/dc22-0698.I | 07/21/2022 | |
| Exploring the genetic relationship between deep vein thrombosis and plasma protein: a new research idea | Luo P, et al. | 2022 | Expert Rev Hematol | 15 | 9 | 867-873 | https://www.doi.org/10.1080/17474086.2022.2104707 | 35,857,435 | Blood Proteins/genetics Chromogranins Complement Factor B Humans Mendelian Randomization Analysis Proteome *Venous Thrombosis/genetics Deep venous thrombosis (DVT) causality genetic correlation genetics plasma protein | BACKGROUND: The aim of this article is to scan and analyze the genetic correlation between plasma proteome and deep venous thrombosis (DVT), and to explore the correlation between plasma protein and DVT. RESEARCH DESIGN AND METHODS: GWAS data of DVT and plasma proteins were analyzed with linkage disequilibrium scores, and plasma proteins that were genetically associated with DVT were screened out. To ascertain the causal link between potential plasma proteins and DVT, a Mendelian randomized (MR) study was used. This study used STRING to examine the pathogenesis of DVT in connection with the gene encoding plasma protein. RESULTS: Several suggestive plasma proteins were detected for DVT, such as Complement factor B (P value=0.0177), Chromogranin-A (P value=0.0158). Through MR analysis, we found that there was a significant positive causal relationship between Chromogranin-A (exposure) and DVT(outcome) (beta=-0.0117, P<0.0001). Our STRING analysis revealed that hsa04610 was associated with coagulation cascade in the KEGG pathway of Complement factor B(P<0.0001), which was based on GO and KEGG analysis of 8 selected plasma proteins. CONCLUSIONS: A genetic link between plasma protein and DVT was thoroughly investigated. Our findings provide a fresh perspective on the genetics and pathogenesis of DVT. | Luo, Pan Xu, Jiawen Xu, Ke Jing, Wensen Liu, Lin Xu, Peng eng Research Support, Non-U.S. Gov't England Expert Rev Hematol. 2022 Sep;15(9):867-873. doi: 10.1080/17474086.2022.2104707. Epub 2022 Aug 1.I | 07/21/2022 | |
| Genome-wide screening identifies DNA methylation sites that regulate the blood proteome | Nikpay M, et al. | 2022 | Epigenomics | epub ahead of print | https://www.doi.org/10.2217/epi-2022-0119 | 35,852,134 | DNA methylation Mendelian randomization biomarker epigenomics functional interaction proteomics | Background: Identifying DNA methylation sites that regulate the blood proteome is important for biomedical purposes. Materials & methods: Here the authors performed a genome-wide search to find DNA methylation sites that impact proteins. Results: The authors identified 165 methylation sites associated with 138 proteins. The authors noted hotspot genomic regions that control the levels of several proteins. For example, methylation of the ABO locus impacted 37 proteins and contributed to cardiometabolic comorbidities, including the severity of SARS-CoV-2 infection. The authors made these findings publicly available as a Unix software that identifies methylation sites that cause disease and reveals the underlying proteins. The authors underlined the software application by showing that components of innate immunity contribute to systolic blood pressure. Conclusion: This study provides a catalog of DNA methylation sites that regulate the proteome, and the results are available as freeware for biological insight. Our lifestyle choices and interactions with the world around us are continuously printed in our DNA through a biochemical process known as epigenomic modification. Excessive epigenomic modification at a DNA site may cause disease. To prevent or treat disease, it is important to find such sites and remove the excessive epigenomic modification with medications or lifestyle changes. Here the authors searched for DNA sites that undergo epigenomic modification. The authors also investigated the mechanism whereby these sites cause disease. The authors found that there are DNA sites where reverting the epigenomic modification could have a big impact on the body. The authors have made these findings publicly available. eng | Nikpay, Majid Ravati, Sepehr McPherson, Ruth eng FDN-154308/CAPMC/CIHR/Canada England Epigenomics. 2022 Jul 19. doi: 10.2217/epi-2022-0119.I | 07/20/2022 | |||
| Genome- and transcriptome-wide association studies show that pulmonary embolism is associated with bone-forming proteins | Feng R, et al. | 2022 | Expert Rev Hematol | 15 | 10 | 951-958 | https://www.doi.org/10.1080/17474086.2022.2103534 | 35,848,930 | Humans *Transcriptome Genome-Wide Association Study RNA, Messenger/genetics *Pulmonary Embolism/genetics Defensins/genetics Genetic Predisposition to Disease Polymorphism, Single Nucleotide Bmp Gwas Ldsc Pulmonary embolism Twas | BACKGROUND: Pulmonary embolism (PE) is a leading cause of death in stroke patients and a severe health burden worldwide. There is a pressing need to understand the mechanisms by which it occurs and to identify at-risk patients efficiently and accurately. METHODS: First, based on data from GWAS in European populations, we performed a linkage disequilibrium score regression (LDSC) analysis of plasma proteins and PE in 3,283 individuals and additionally analyzed the genetic association between PE and fracture. Then, we performed a TWAS on PE GWAS data using skeletal muscle and blood for gene expression references. Finally, we validated the genetic correlation between PE and human plasma proteins by co-matching the genes encoding the identified proteins and those identified using TWAS with the differentially expressed genes obtained from mRNA expression profiling of PE. RESULTS: We identified five plasma proteins associated with PE, including hydroxycarboxylic acid receptor 2, defensin 118, and bone morphogenetic protein (BMP) 7, as well as a relationship between PE and fracture. Comparison of genes encoding these proteins with genes obtained from TWAS and then with differentially expressed genes obtained from PE mRNA expression profiling revealed that PE was highly correlated with the BMP family of genes. | Feng, Ruoyang Lu, Mengnan Yang, Yanni Luo, Pan Liu, Lin Xu, Ke Xu, Peng eng England Expert Rev Hematol. 2022 Oct;15(10):951-958. doi: 10.1080/17474086.2022.2103534. Epub 2022 Sep 25.I | 07/19/2022 | |
| The amniotic fluid proteome predicts imminent preterm delivery in asymptomatic women with a short cervix | Gudicha DW, et al. | 2022 | Sci Rep | 12 | 1 | 11781 | https://www.doi.org/10.1038/s41598-022-15392-3 | 35,821,507 | Amniotic Fluid/metabolism Cervix Uteri/diagnostic imaging Female Humans Infant, Newborn Matrix Metalloproteinase 8/metabolism *Obstetric Labor, Premature/metabolism Pregnancy *Premature Birth/metabolism Proteome/metabolism Retrospective Studies | Preterm birth, the leading cause of perinatal morbidity and mortality, is associated with increased risk of short- and long-term adverse outcomes. For women identified as at risk for preterm birth attributable to a sonographic short cervix, the determination of imminent delivery is crucial for patient management. The current study aimed to identify amniotic fluid (AF) proteins that could predict imminent delivery in asymptomatic patients with a short cervix. This retrospective cohort study included women enrolled between May 2002 and September 2015 who were diagnosed with a sonographic short cervix (< 25 mm) at 16-32 weeks of gestation. Amniocenteses were performed to exclude intra-amniotic infection; none of the women included had clinical signs of infection or labor at the time of amniocentesis. An aptamer-based multiplex platform was used to profile 1310 AF proteins, and the differential protein abundance between women who delivered within two weeks from amniocentesis, and those who did not, was determined. The analysis included adjustment for quantitative cervical length and control of the false-positive rate at 10%. The area under the receiver operating characteristic curve was calculated to determine whether protein abundance in combination with cervical length improved the prediction of imminent preterm delivery as compared to cervical length alone. Of the 1,310 proteins profiled in AF, 17 were differentially abundant in women destined to deliver within two weeks of amniocentesis independently of the cervical length (adjusted p-value < 0.10). The decreased abundance of SNAP25 and the increased abundance of GPI, PTPN11, OLR1, ENO1, GAPDH, CHI3L1, RETN, CSF3, LCN2, CXCL1, CXCL8, PGLYRP1, LDHB, IL6, MMP8, and PRTN3 were associated with an increased risk of imminent delivery (odds ratio > 1.5 for each). The sensitivity at a 10% false-positive rate for the prediction of imminent delivery by a quantitative cervical length alone was 38%, yet it increased to 79% when combined with the abundance of four AF proteins (CXCL8, SNAP25, PTPN11, and MMP8). Neutrophil-mediated immunity, neutrophil activation, granulocyte activation, myeloid leukocyte activation, and myeloid leukocyte-mediated immunity were biological processes impacted by protein dysregulation in women destined to deliver within two weeks of diagnosis. The combination of AF protein abundance and quantitative cervical length improves prediction of the timing of delivery compared to cervical length alone, among women with a sonographic short cervix. | Gudicha, Dereje W Romero, Roberto Gomez-Lopez, Nardhy Galaz, Jose Bhatti, Gaurav Done, Bogdan Jung, Eunjung Gallo, Dahiana M Bosco, Mariachiara Suksai, Manaphat Diaz-Primera, Ramiro Chaemsaithong, Piya Gotsch, Francesca Berry, Stanley M Chaiworapongsa, Tinnakorn Tarca, Adi L eng Contract No. HHSN275201300006C/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural England Sci Rep. 2022 Jul 11;12(1):11781. doi: 10.1038/s41598-022-15392-3.I | 07/14/2022 | |
| Serum Protein Signatures Using Aptamer-Based Proteomics for Minimal Change Disease and Membranous Nephropathy | Muruve DA, et al. | 2022 | Kidney Int Rep | 7 | 7 | 1539-1556 | https://www.doi.org/10.1016/j.ekir.2022.04.006 | 35,812,291 | membranous nephropathy minimal change disease proteomics systems biology | INTRODUCTION: Minimal change disease (MCD) and membranous nephropathy (MN) are glomerular diseases (glomerulonephritis [GN]) that present with the nephrotic syndrome. Although circulating PLA2R antibodies have been validated as a biomarker for MN, the diagnosis of MCD and PLA2R-negative MN still relies on the results of kidney biopsy or empirical corticosteroids in children. We aimed to identify serum protein biomarker signatures associated with MCD and MN pathogenesis using aptamer-based proteomics. METHODS: Quantitative SOMAscan proteomics was applied to the serum of adult patients with MCD (n = 15) and MN (n = 37) and healthy controls (n = 20). Associations between the 1305 proteins detected with SOMAscan were assessed using multiple statistical tests, expression pattern analysis, and systems biology analysis. RESULTS: A total of 208 and 244 proteins were identified that differentiated MCD and MN, respectively, with high statistical significance from the healthy controls (Benjamin-Hochberg [BH] P < 0.0001). There were 157 proteins that discriminated MN from MCD (BH P < 0.05). In MCD, 65 proteins were differentially expressed as compared with MN and healthy controls. When compared with MCD and healthy controls, 44 discriminatory proteins were specifically linked to MN. Systems biology analysis of these signatures identified cell death and inflammation as key pathways differentiating MN from MCD and healthy controls. Dysregulation of fatty acid metabolism pathways was confirmed in both MN and MCD as compared with the healthy subjects. CONCLUSION: SOMAscan represents a promising proteomic platform for biomarker development in GN. Validation of a greater number of discovery biomarkers in larger patient cohorts is needed before these data can be translated for clinical care. | Muruve, Daniel A Debiec, Hanna Dillon, Simon T Gu, Xuesong Plaisier, Emmanuelle Can, Handan Otu, Hasan H Libermann, Towia A Ronco, Pierre eng Kidney Int Rep. 2022 Apr 14;7(7):1539-1556. doi: 10.1016/j.ekir.2022.04.006. eCollection 2022 Jul.I | 07/12/2022 | |
| Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing | Austin TR, et al. | 2022 | Eur J Epidemiol | 37 | 7 | 755-765 | https://www.doi.org/10.1007/s10654-022-00888-z | 35,790,642 | Biomarkers Cohort Studies Female Humans *Information Dissemination Male Prospective Studies *Proteomics/methods Cardiovascular Disease Cohort Study Genomics Proteomics funded by Johnson & Johnson. Elkind receives study drug in kind from the BMS-Pfizer Alliance for Eliquis(R) and funding from Roche for a NIH-funded stroke prevention trial royalties from UpToDate for chapters on stroke and serves as an unpaid Officer of the American Heart Association. Floyd has consulted for Shionogi Inc. Kizer has stock ownership in Abbott, Bristol Myers Squibb, Johnson & Johnson, Medtronic, Merck and Pfizer. Odden is a consultant for Cricket Health, Inc. | BACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology. METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations. CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults. | Austin, Thomas R McHugh, Caitlin P Brody, Jennifer A Bis, Joshua C Sitlani, Colleen M Bartz, Traci M Biggs, Mary L Bansal, Nisha Buzkova, Petra Carr, Steven A deFilippi, Christopher R Elkind, Mitchell S V Fink, Howard A Floyd, James S Fohner, Alison E Gerszten, Robert E Heckbert, Susan R Katz, Daniel H Kizer, Jorge R Lemaitre, Rozenn N Longstreth, W T McKnight, Barbara Mei, Hao Mukamal, Kenneth J Newman, Anne B Ngo, Debby Odden, Michelle C Vasan, Ramachandran S Shojaie, Ali Simon, Noah Smith, George Davey Davies, Neil M Siscovick, David S Sotoodehnia, Nona Tracy, Russell P Wiggins, Kerri L Zheng, Jie Psaty, Bruce M eng U01HL080295/HL/NHLBI NIH HHS/ HL144483/HL/NHLBI NIH HHS/ U01 HL080295/HL/NHLBI NIH HHS/ U01 HL130114/HL/NHLBI NIH HHS/ HHSN268200800007C/HL/NHLBI NIH HHS/ N01HC55222/HL/NHLBI NIH HHS/ N01HC85086/HL/NHLBI NIH HHS/ RF1 AG063507/AG/NIA NIH HHS/ K01 AG071689/AG/NIA NIH HHS/ WT_/Wellcome Trust/United Kingdom U01HL130114/HL/NHLBI NIH HHS/ N01HC85080/HL/NHLBI NIH HHS/ N01HC85081/HL/NHLBI NIH HHS/ HHSN268201200036C/HL/NHLBI NIH HHS/ R01 HL144483/HL/NHLBI NIH HHS/ HHSN268201800001C/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ R01AG023629/AG/NIA NIH HHS/ 75N92021D00006/HL/NHLBI NIH HHS/ N01HC85082/HL/NHLBI NIH HHS/ N01HC85083/HL/NHLBI NIH HHS/ RF1AG063507/AG/NIA NIH HHS/ R01HL132320/HL/NHLBI NIH HHS/ N01HC85079/HL/NHLBI NIH HHS/ R01 AG023629/AG/NIA NIH HHS/ Netherlands Eur J Epidemiol. 2022 Jul;37(7):755-765. doi: 10.1007/s10654-022-00888-z. Epub 2022 Jul 5.I | 07/06/2022 | |
| Placenta-derived proteins across gestation in healthy pregnancies-a novel approach to assess placental function? | Degnes ML, et al. | 2022 | BMC Med | 20 | 1 | 227 | https://www.doi.org/10.1186/s12916-022-02415-z | 35,773,701 | Biomarkers *Cesarean Section Cross-Sectional Studies Female Humans Placenta Pregnancy *Proteomics Aptamer Four vessel sampling Human Proteomics SomaLogic | BACKGROUND: Placenta-derived proteins in the systemic maternal circulation are suggested as potential biomarkers for placental function. However, the identity and longitudinal patterns of such proteins are largely unknown due to the inaccessibility of the human placenta and limitations in assay technologies. We aimed to identify proteins derived from and taken up by the placenta in the maternal circulation. Furthermore, we aimed to describe the longitudinal patterns across gestation of placenta-derived proteins as well as identify placenta-derived proteins that can serve as reference curves for placental function. METHODS: We analyzed proteins in plasma samples collected in two cohorts using the Somalogic 5000-plex platform. Antecubital vein samples were collected at three time points (gestational weeks 14-16, 22-24, and 30-32) across gestation in 70 healthy pregnancies in the longitudinal STORK cohort. In the cross sectional 4-vessel cohort, blood samples were collected simultaneously from the maternal antecubital vein (AV), radial artery (RA), and uterine vein (UV) during cesarean section in 75 healthy pregnancies. Placenta-derived proteins and proteins taken up by the placenta were identified using venoarterial differences (UV-RA). Placenta-derived proteins were defined as placenta-specific by comparison to the venoarterial difference in the antecubital vein-radial artery (AV-RA). These proteins were described longitudinally based on the STORK cohort samples using a linear mixed effects model per protein. Using a machine learning algorithm, we identified placenta-derived proteins that could predict gestational age, meaning that they closely tracked gestation, and were potential read-outs of placental function. RESULTS: Among the nearly 5000 measured proteins, we identified 256 placenta-derived proteins and 101 proteins taken up by the placenta (FDR < 0.05). Among the 256 placenta-derived proteins released to maternal circulation, 101 proteins were defined as placenta-specific. These proteins formed two clusters with distinct developmental patterns across gestation. We identified five placenta-derived proteins that closely tracked gestational age when measured in the systemic maternal circulation, termed a placental proteomic clock." CONCLUSIONS: Together, these data may serve as a first step towards a reference for the healthy placenta-derived proteome that can be measured in the systemic maternal circulation and potentially serve as biomarkers of placental function. The "placental proteomic clock" represents a novel concept that warrants further investigation. Deviations in the proteomic pattern across gestation of such proteomic clock proteins may serve as an indication of placental dysfunction." | Degnes, Maren-Helene Langeland Westerberg, Ane Cecilie Zucknick, Manuela Powell, Theresa L Jansson, Thomas Henriksen, Tore Roland, Marie Cecilie Paasche Michelsen, Trond Melbye eng Research Support, Non-U.S. Gov't England BMC Med. 2022 Jul 1;20(1):227. doi: 10.1186/s12916-022-02415-z.I | 07/01/2022 | |
| Circulating proteomic profiles associated with endometriosis in adolescents and young adults | Sasamoto N, et al. | 2022 | Hum Reprod | 37 | 9 | 2042-2053 | https://www.doi.org/10.1093/humrep/deac146 | 35,770,801 | Adolescent Adult Boston Cohort Studies Cross-Sectional Studies *Endometriosis/metabolism Female Humans Observational Studies as Topic Proteomics United States Young Adult adolescents angiogenesis endometriosis lesion color | STUDY QUESTION: What are the systemic molecular profiles of endometriosis diagnosed in adolescents and young adults? SUMMARY ANSWER: Significant enrichment and increased activation of proteins related to angiogenesis and cell migration pathways were observed in endometriosis cases compared to controls (P-value < 2.4 x 10-8). WHAT IS KNOWN ALREADY: Little is known about the pathophysiology of adolescent endometriosis despite the fact that over 50% of adults with endometriosis report onset of severe pelvic pain during adolescence. STUDY DESIGN, SIZE, DURATION: A cross-sectional analysis using data on 142 laparoscopically confirmed endometriosis cases and 74 controls from the observational longitudinal cohort of Women's Health Study: From Adolescence to Adulthood (A2A). PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured 1305 plasma protein levels using the validated, multiplex aptamer-based proteomics discovery platform, SOMAscan. We calculated odds ratios and 95% CIs using logistic regression adjusting for age, BMI, fasting status and hormone use at blood draw for differentially expressed proteins (P < 0.05). Ingenuity Pathway Analysis and STRING analysis were performed to identify biological pathways and protein interactions. We also examined proteins and pathways associated with superficial peritoneal lesion colors (i.e. red, vascularized, white, blue/black, brown). MAIN RESULTS AND THE ROLE OF CHANCE: Average age at blood draw was 18 years for endometriosis cases and 22 years for controls. We identified 63 proteins associated with endometriosis with type-I error set at 0.05, and absolute fold change >1.2, revealing significant enrichment of dysregulated proteins in biological pathways associated with endometriosis. Increased activation of pathways related to angiogenesis and cell migration was observed in plasma from endometriosis cases compared to controls (P-value < 2.4 x 10-8). Furthermore, when we examined proteins and pathways associated with lesion colors, vascularized lesions were associated with upregulation of pathways related to immune cell migration/activation and inflammation, whereas white, blue/black and brown lesions were associated with downregulation of these pathways. LIMITATIONS, REASONS FOR CAUTION: Validation of our results in independent datasets and mechanistic studies are warranted to further our understanding of the pathophysiological characteristics of this common but understudied patient population. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this was the first study to comprehensively examine circulating proteins in predominantly adolescents and young adult women with and without endometriosis. Results from this study provide novel biological insight that will build toward further research to elucidate endometriosis pathophysiology during the earlier course of the disease trajectory. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Department of Defense (W81XWH1910318) and the 2017 Boston Center for Endometriosis Trainee Award. Financial support for establishment of and data collection within the A2A cohort were provided by the J. Willard and Alice S. Marriott Foundation. N.S., A.F.V., S.A.M., K.L.T. have received funding from Marriott Family Foundation. S.A.M. and K.L.T. are supported by NICHD (R01 HD94842). S.A.M. serves as an advisory board member for AbbVie and Roche; neither are related to this study. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A. | Sasamoto, Naoko Ngo, Long Vitonis, Allison F Dillon, Simon T Missmer, Stacey A Libermann, Towia A Terry, Kathryn L eng Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Hum Reprod. 2022 Aug 25;37(9):2042-2053. doi: 10.1093/humrep/deac146.I | 07/01/2022 | |
| CCL17 acts as a novel therapeutic target in pathological cardiac hypertrophy and heart failure | Zhang Y, et al. | 2022 | J Exp Med | 219 | 8 | https://www.doi.org/10.1084/jem.20200418 | 35,687,056 | Angiotensin II Animals Cardiomegaly Chemokine CCL17/metabolism Chemokines/metabolism Fibrosis *Heart Failure Humans Ligands Mice Mice, Inbred C57BL Myocardium/pathology Myocytes, Cardiac/metabolism *Proteomics | Circulating proteomic signatures of age are closely associated with aging and age-related diseases; however, the utility of changes in secreted proteins in identifying therapeutic targets for diseases remains unclear. Serum proteomic profiling of an age-stratified healthy population and further community-based cohort together with heart failure patients study demonstrated that circulating C-C motif chemokine ligand 17 (CCL17) level increased with age and correlated with cardiac dysfunction. Subsequent animal experiments further revealed that Ccll7-KO significantly repressed aging and angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis, accompanied by the plasticity and differentiation of T cell subsets. Furthermore, the therapeutic administration of an anti-CCL17 neutralizing antibody inhibited Ang II-induced pathological cardiac remodeling. Our findings reveal that chemokine CCL17 is identifiable as a novel therapeutic target in age-related and Ang II-induced pathological cardiac hypertrophy and heart failure. | Zhang, Yang Ye, Yicong Tang, Xiaoqiang Wang, Hui Tanaka, Toshiko Tian, Ran Yang, Xufei Wang, Lun Xiao, Ying Hu, Xiaomin Jin, Ye Pang, Haiyu Du, Tian Liu, Honghong Sun, Lihong Xiao, Shuo Dong, Ruijia Ferrucci, Luigi Tian, Zhuang Zhang, Shuyang eng 2021-I2M-1-003/Chinese Academy of Medical Sciences Initiative for Innovative Medicine/ 7192155/Beijing Natural Science Foundation/ 2016YFC0901500/National Key Research and Development Program of China/ PX2021028/Beijing Hospital Authority/ 81970426/National Natural Science Foundation of China/ AG/NIA NIH HHS/ Research Support, Non-U.S. Gov't J Exp Med. 2022 Aug 1;219(8):e20200418. doi: 10.1084/jem.20200418. Epub 2022 Jun 10.I | 06/11/2022 | ||
| Serologic Biomarkers of Progression Toward Diagnosis of Rheumatoid Arthritis in Active Component Military Personnel | Loza MJ, et al. | 2022 | Arthritis Rheumatol | 74 | 11 | 1766-1775 | https://www.doi.org/10.1002/art.42260 | 35,671,369 | Humans *Military Personnel Proteomics Programmed Cell Death 1 Receptor *Arthritis, Rheumatoid Biomarkers *Arthritis, Reactive | OBJECTIVE: To identify a panel of serum biomarkers that could specifically identify imminent cases of rheumatoid arthritis (RA) before diagnosis. METHODS: Serum samples were collected at 4 time points from active component US military personnel, including 157 anti-citrullinated protein antibody (ACPA)-seropositive and 50 ACPA-seronegative RA subjects, 100 reactive arthritis (ReA) subjects, and 76 healthy controls. The cohorts were split into 2 phases, with samples tested on independent proteomic platforms for each phase. Classification models of RA diagnosis based on samples obtained within 6 months prior to diagnosis were developed both in univariate analyses and by multivariate random forest modeling of training sample sets and testing sample sets from each phase. RESULTS: Increases in serum analytes, including C-reactive protein levels, serum amyloid A, and soluble programmed cell death 1 (PD-1), were observed in seropositive RA subjects at the time point closest to diagnosis, up to several years before diagnosis. Only a small fraction of RA subjects had levels above the 95th percentile of healthy control levels until the time period within 6 months of diagnosis. For classification of RA diagnosis using samples obtained within 6 months prior to diagnosis, soluble PD-1 provided superior specificity compared to ReA cases (>89%), with a sensitivity of 48% for RA classification. An 8-analyte model provided superior sensitivity (69%), with comparable specificity relative to ReA (>82%). CONCLUSION: Our findings demonstrate that imminent RA diagnosis could be classified with high specificity, relative to healthy controls and ReA cases, using a panel of cytokines measured in serum samples collected within 6 months before actual diagnosis. | Loza, Matthew J Nagpal, Sunil Cole, Suzanne Laird, Renee M Alcala, Ashley Rao, Navin L Riddle, Mark S Porter, Chad K eng Research Support, Non-U.S. Gov't Arthritis Rheumatol. 2022 Nov;74(11):1766-1775. doi: 10.1002/art.42260. Epub 2022 Oct 7.I | 06/08/2022 | |
| Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis | Nocera AL, et al. | 2022 | J Allergy Clin Immunol | 150 | 4 | 872-881 | https://www.doi.org/10.1016/j.jaci.2022.04.034 | 35,660,375 | Allergens Animals Chronic Disease Cysteine Proteinase Inhibitors Cytokines Inflammation Mice *Nasal Polyps/pathology Peptide Hydrolases Proteomics *Rhinitis/metabolism *Salivary Cystatins/genetics/metabolism *Sinusitis/pathology Epithelium P-glycoprotein cystatin SA cystatin SN exome posttranslational modification sinonasal mucus transcriptome from the MEEI Curing Kids Fund, Cook Medical, Medtronics has consultant arrangements with Olympus, Medtronics, 3D Matrix, Third Wave Therapeutics, Bear-ENT, and Karl Storz has provided expert testimony on ear, nose, and throat-related cases has a patent for P-gp and cystatin inhibition for chronic rhinosinusitis and receives royalties from this patent and has stock and/or stock options in Interscope, Inquis Medical, and Diceros Therapeutics. The rest of the authors declare that they have no relevant conflicts of interest. | BACKGROUND: Cystatin SN (CST1) and cystatin SA (CST2) are cysteine protease inhibitors that protect against allergen, viral, and bacterial proteases. Cystatins are overexpressed in the setting of allergic rhinitis and chronic rhinosinusitis with nasal polyps (CRSwNP); however, their role in promoting type 2 inflammation remains poorly characterized. OBJECTIVE: The purpose of this study was to use integrated poly-omics and a murine exposure model to explore the link between cystatin overexpression in CRSwNP and type 2 inflammation. METHODS: In this institutional review board- and institutional animal care and use committee-approved study, we compared tissue, exosome, and mucus CST1 and CST2 between CRSwNP and controls (n = 10 per group) by using matched whole exome sequencing, transcriptomic, proteomic, posttranslational modification, histologic, functional, and bioinformatic analyses. C57/BL6 mice were dosed with 3.9 mug/mL of CST1 or PBS intranasally for 5 to 18 days in the presence or absence of epithelial ABCB1a knockdown. Inflammatory cytokines were quantified by using Quansys multiplex assays or ELISAs. RESULTS: Of the 1305 proteins quantified, CST1 and CST2 were among the most overexpressed protease inhibitors in tissue, exosome, and mucus samples; they were localized to the epithelial layer. Multiple posttranslational modifications were identified in the polyp tissue. Exosomal CST1 and CST2 were strongly and significantly correlated with eosinophils and Lund-Mackay scores. Murine type 2 cytokine secretion and T(H)2 cell infiltration increased in a time-dependent manner following CST1 exposure and was abrogated by epithelial knockdown of ABCB1a, a regulator of epithelial cytokine secretion. CONCLUSION: CST1 is a potent upstream initiator of epithelial-derived type 2 inflammation in CRSwNP. Therapeutic strategies targeting CST activity and its associated posttranslational modifications deserve further interrogation. | Nocera, Angela L Mueller, Sarina K Workman, Alan D Wu, Dawei McDonnell, Kristen Sadow, Peter M Amiji, Mansoor M Bleier, Benjamin S eng P01 CA240239/CA/NCI NIH HHS/ R01 NS108968/NS/NINDS NIH HHS/ Research Support, N.I.H., Extramural J Allergy Clin Immunol. 2022 Oct;150(4):872-881. doi: 10.1016/j.jaci.2022.04.034. Epub 2022 May 31.I | 06/07/2022 | |
| A novel non-invasive method allowing for discovery of pathologically relevant proteins from small airways | Ostling J, et al. | 2022 | Clin Proteomics | 19 | 1 | 20 | https://www.doi.org/10.1186/s12014-022-09348-y | 35,668,386 | Asthma Biomarker Breath Exhaled air Non-invasive Non-volatiles Precision medicine Proteomics Small airways of the PExA method, and boardmember and chairholder of PExA AB. Emilia Viklund is reporting a minor chairhold in PExA AB. Dr Ostling reports personal fees from PExA AB during the conduct of the study and Employed by PExA AB while writing the manuscript but not during the planning and completion of the study. | BACKGROUND: There is a lack of early and precise biomarkers for personalized respiratory medicine. Breath contains an aerosol of droplet particles, which are formed from the epithelial lining fluid when the small airways close and re-open during inhalation succeeding a full expiration. These particles can be collected by impaction using the PExA((R)) method (Particles in Exhaled Air), and are derived from an area of high clinical interest previously difficult to access, making them a potential source of biomarkers reflecting pathological processes in the small airways. RESEARCH QUESTION: Our aim was to investigate if PExA method is useful for discovery of biomarkers that reflect pathology of small airways. METHODS AND ANALYSIS: Ten healthy controls and 20 subjects with asthma, of whom 10 with small airway involvement as indicated by a high lung clearance index (LCI >/= 2.9 z-score), were examined in a cross-sectional design, using the PExA instrument. The samples were analysed with the SOMAscan proteomics platform (SomaLogic Inc.). RESULTS: Two hundred-seven proteins were detected in up to 80% of the samples. Nine proteins showed differential abundance in subjects with asthma and high LCI as compared to healthy controls. Two of these were less abundant (ALDOA4, C4), and seven more abundant (FIGF, SERPINA1, CD93, CCL18, F10, IgM, IL1RAP). sRAGE levels were lower in ex-smokers (n = 14) than in never smokers (n = 16). Gene Ontology (GO) annotation database analyses revealed that the PEx proteome is enriched in extracellular proteins associated with extracellular exosome-vesicles and innate immunity. CONCLUSION: The applied analytical method was reproducible and allowed identification of pathologically interesting proteins in PEx samples from asthmatic subjects with high LCI. The results suggest that PEx based proteomics is a novel and promising approach to study respiratory diseases with small airway involvement. | Ostling, Jorgen Van Geest, Marleen Olsson, Henric K Dahlen, Sven-Erik Viklund, Emilia Gustafsson, Per M Mirgorodskaya, Ekaterina Olin, Anna-Carin eng England Clin Proteomics. 2022 Jun 6;19(1):20. doi: 10.1186/s12014-022-09348-y.I | 06/07/2022 | |
| Genetic architecture of band neutrophil fraction in Iceland | Oskarsson GR, et al. | 2022 | Commun Biol | 5 | 1 | 525 | https://www.doi.org/10.1038/s42003-022-03462-1 | 35,650,273 | Genome-Wide Association Study Granulocytes/metabolism Humans Iceland Neutrophils/metabolism *Pelger-Huet Anomaly/genetics | The characteristic lobulated nuclear morphology of granulocytes is partially determined by composition of nuclear envelope proteins. Abnormal nuclear morphology is primarily observed as an increased number of hypolobulated immature neutrophils, called band cells, during infection or in rare envelopathies like Pelger-Huet anomaly. To search for sequence variants affecting nuclear morphology of granulocytes, we performed a genome-wide association study using band neutrophil fraction from 88,101 Icelanders. We describe 13 sequence variants affecting band neutrophil fraction at nine loci. Five of the variants are at the Lamin B receptor (LBR) locus, encoding an inner nuclear membrane protein. Mutations in LBR are linked to Pelger-Huet anomaly. In addition, we identify cosegregation of a rare stop-gain sequence variant in LBR and Pelger Huet anomaly in an Icelandic eight generation pedigree, initially reported in 1963. Two of the other loci include genes which, like LBR, play a role in the nuclear membrane function and integrity. These GWAS results highlight the role proteins of the inner nuclear membrane have as important for neutrophil nuclear morphology. | Oskarsson, Gudjon R Magnusson, Magnus K Oddsson, Asmundur Jensson, Brynjar O Fridriksdottir, Run Arnadottir, Gudny A Katrinardottir, Hildigunnur Rognvaldsson, Solvi Halldorsson, Gisli H Sveinbjornsson, Gardar Ivarsdottir, Erna V Stefansdottir, Lilja Ferkingstad, Egil Norland, Kristjan Tragante, Vinicius Saemundsdottir, Jona Jonasdottir, Aslaug Jonasdottir, Adalbjorg Sigurjonsdottir, Svanhvit Petursdottir, Karen O Davidsson, Olafur B Rafnar, Thorunn Holm, Hilma Olafsson, Isleifur Onundarson, Pall T Vidarsson, Brynjar Sigurdardottir, Olof Masson, Gisli Gudbjartsson, Daniel F Jonsdottir, Ingileif Norddahl, Gudmundur L Thorsteinsdottir, Unnur Sulem, Patrick Stefansson, Kari eng England Commun Biol. 2022 Jun 1;5(1):525. doi: 10.1038/s42003-022-03462-1.I | 06/02/2022 | |
| Aptamers Targeting Cardiac Biomarkers as an Analytical Tool for the Diagnostics of Cardiovascular Diseases: A Review | Komarova N, et al. | 2022 | Biomedicines | 10 | 5 | https://www.doi.org/10.3390/biomedicines10051085 | 35,625,822 | aptamer biosensor cardiac biomarkers cardiovascular disease detection diagnostics | The detection of cardiac biomarkers is used for diagnostics, prognostics, and the risk assessment of cardiovascular diseases. The analysis of cardiac biomarkers is routinely performed with high-sensitivity immunological assays. Aptamers offer an attractive alternative to antibodies for analytical applications but, to date, are not widely practically implemented in diagnostics and medicinal research. This review summarizes the information on the most common cardiac biomarkers and the current state of aptamer research regarding these biomarkers. Aptamers as an analytical tool are well established for troponin I, troponin T, myoglobin, and C-reactive protein. For the rest of the considered cardiac biomarkers, the isolation of novel aptamers or more detailed characterization of the known aptamers are required. More attention should be addressed to the development of dual-aptamer sandwich detection assays and to the studies of aptamer sensing in alternative biological fluids. The universalization of aptamer-based biomarker detection platforms and the integration of aptamer-based sensing to clinical studies are demanded for the practical implementation of aptamers to routine diagnostics. Nevertheless, the wide usage of aptamers for the diagnostics of cardiovascular diseases is promising for the future, with respect to both point-of-care and laboratory testing. | Komarova, Natalia Panova, Olga Titov, Alexey Kuznetsov, Alexander eng 21-79-10175/Russian Science Foundation/ Review Switzerland Biomedicines. 2022 May 6;10(5):1085. doi: 10.3390/biomedicines10051085.I | 05/29/2022 | ||
| Results of untargeted analysis using the SOMAscan proteomics platform indicates novel associations of circulating proteins with risk of progression to kidney failure in diabetes | Kobayashi H, et al. | 2022 | Kidney Int | 102 | 2 | 370-381 | https://www.doi.org/10.1016/j.kint.2022.04.022 | 35,618,095 | Biomarkers/metabolism *Diabetes Mellitus, Type 2/complications *Diabetic Nephropathies/complications/etiology Disease Progression Endostatins Humans Lectins, C-Type Proteomics/methods *Renal Insufficiency circulating biomarker diabetes diabetic kidney disease end-stage kidney disease proteomics analysis patent for predicting risk of ESRD | This study applies a large proteomics panel to search for new circulating biomarkers associated with progression to kidney failure in individuals with diabetic kidney disease. Four independent cohorts encompassing 754 individuals with type 1 and type 2 diabetes and early and late diabetic kidney disease were followed to ascertain progression to kidney failure. During ten years of follow-up, 227 of 754 individuals progressed to kidney failure. Using the SOMAscan proteomics platform, we measured baseline concentration of 1129 circulating proteins. In our previous publications, we analyzed 334 of these proteins that were members of specific candidate pathways involved in diabetic kidney disease and found 35 proteins strongly associated with risk of progression to kidney failure. Here, we examined the remaining 795 proteins using an untargeted approach. Of these remaining proteins, 11 were significantly associated with progression to kidney failure. Biological processes previously reported for these proteins were related to neuron development (DLL1, MATN2, NRX1B, KLK8, RTN4R and ROR1) and were implicated in the development of kidney fibrosis (LAYN, DLL1, MAPK11, MATN2, endostatin, and ROR1) in cellular and animal studies. Specific mechanisms that underlie involvement of these proteins in progression of diabetic kidney disease must be further investigated to assess their value as targets for kidney-protective therapies. Using multivariable LASSO regression analysis, five proteins (LAYN, ESAM, DLL1, MAPK11 and endostatin) were found independently associated with risk of progression to kidney failure. Thus, our study identified proteins that may be considered as new candidate prognostic biomarkers to predict risk of progression to kidney failure in diabetic kidney disease. Furthermore, three of these proteins (DLL1, ESAM, and MAPK11) were selected as candidate biomarkers when all SOMAscan results were evaluated. | Kobayashi, Hiroki Looker, Helen C Satake, Eiichiro Saulnier, Pierre Jean Md Dom, Zaipul I O'Neil, Kristina Ihara, Katsuhito Krolewski, Bozena Galecki, Andrzej T Niewczas, Monika A Wilson, Jonathan M Doria, Alessandro Duffin, Kevin L Nelson, Robert G Krolewski, Andrzej S eng ZIA DK069062/ImNIH/Intramural NIH HHS/ R01 DK126799/DK/NIDDK NIH HHS/ P30 DK036836/DK/NIDDK NIH HHS/ R01 DK110350/DK/NIDDK NIH HHS/ R01 DK041526/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Kidney Int. 2022 Aug;102(2):370-381. doi: 10.1016/j.kint.2022.04.022. Epub 2022 May 23.I | 05/27/2022 | |
| Association between vascular endothelial growth factor-mediated blood-brain barrier dysfunction and stress-induced depression | Matsuno H, et al. | 2022 | Mol Psychiatry | 27 | 9 | 3822-3832 | https://www.doi.org/10.1038/s41380-022-01618-3 | 35,618,888 | Animals Mice Blood-Brain Barrier/metabolism Vascular Endothelial Growth Factor A/metabolism Endothelial Cells/metabolism *Depressive Disorder, Major/metabolism Depression *Brain Diseases/pathology Mice, Inbred BALB C Capillary Permeability/physiology | Several lines of evidence suggest that stress induces the neurovascular dysfunction associated with increased blood-brain barrier (BBB) permeability, which could be an important pathology linking stress and psychiatric disorders, including major depressive disorder (MDD). However, the detailed mechanism resulting in BBB dysfunction associated in the pathophysiology of MDD still remains unclear. Herein, we demonstrate the role of vascular endothelial growth factor (VEGF), a key mediator of vascular angiogenesis and BBB permeability, in stress-induced BBB dysfunction and depressive-like behavior development. We implemented an animal model of depression, chronic restraint stress (RS) in BALB/c mice, and found that the BBB permeability was significantly increased in chronically stressed mice. Immunohistochemical and electron microscopic observations revealed that increased BBB permeability was associated with both paracellular and transcellular barrier alterations in the brain endothelial cells. Pharmacological inhibition of VEGF receptor 2 (VEGFR2) using a specific monoclonal antibody (DC101) prevented chronic RS-induced BBB permeability and anhedonic behavior. Considered together, these results indicate that VEGF/VEGFR2 plays a crucial role in the pathogenesis of depression by increasing the BBB permeability, and suggest that VEGFR2 inhibition could be a potential therapeutic strategy for the MDD subtype associated with BBB dysfunction. | Matsuno, Hitomi Tsuchimine, Shoko O'Hashi, Kazunori Sakai, Kazuhisa Hattori, Kotaro Hidese, Shinsuke Nakajima, Shingo Chiba, Shuichi Yoshimura, Aya Fukuzato, Noriko Kando, Mayumi Tatsumi, Megumi Ogawa, Shintaro Ichinohe, Noritaka Kunugi, Hiroshi Sohya, Kazuhiro eng 17K01983/MEXT | Japan Society for the Promotion of Science (JSPS)/ 20K07985/MEXT | Japan Society for the Promotion of Science (JSPS)/ 19K17102/MEXT | Japan Society for the Promotion of Science (JSPS)/ 16KT0199/MEXT | Japan Society for the Promotion of Science (JSPS)/ 19ak0101043h0205/Japan Agency for Medical Research and Development (AMED)/ 19ak0101044h0404/Japan Agency for Medical Research and Development (AMED)/ England Mol Psychiatry. 2022 Sep;27(9):3822-3832. doi: 10.1038/s41380-022-01618-3. Epub 2022 May 26.I | 05/27/2022 | |
| Stability and reproducibility of proteomic profiles in epidemiological studies: comparing the Olink and SOMAscan platforms | Haslam DE, et al. | 2022 | Proteomics | 22 | 13 | e2100170 | https://www.doi.org/10.1002/pmic.202100170 | 35,598,103 | Epidemiologic Studies Follow-Up Studies Humans *Proteomics Reproducibility of Results *Specimen Handling Aptamers biomarkers epidemiology studies laboratory methods and tools multiplexing systems biology | Limited data exist on the performance of high-throughput proteomics profiling in epidemiological settings, including the impact of specimen collection and within-person variability over time. Thus, the Olink (972 proteins) and SOMAscan7Kv4.1 (7322 proteoforms of 6596 proteins) assays were utilized to measure protein concentrations in archived plasma samples from the Nurses' Health Studies and Health Professionals Follow-Up Study. Spearman's correlation coefficients (r) and intraclass correlation coefficients (ICCs) were used to assess agreement between (1) 42 triplicate samples processed immediately, 24-h or 48-h after blood collection from 14 participants; and (2) 80 plasma samples from 40 participants collected 1-year apart. When comparing samples processed immediately, 24-h, and 48-h later, 55% of assays had an ICC/r >/= 0.75 and 87% had an ICC/r >/= 0.40 in Olink compared to 44% with an ICC/r >/= 0.75 and 72% with an ICC/r >/= 0.40 in SOMAscan7K. For both platforms, >90% of the assays were stable (ICC/r >/= 0.40) in samples collected 1-year apart. Among 817 proteins measured with both platforms, Spearman's correlations were high (r > 0.75) for 14.7% and poor (r < 0.40) for 44.8% of proteins. High-throughput proteomics profiling demonstrated reproducibility in archived plasma samples and stability after delayed processing in epidemiological studies, yet correlations between proteins measured with the Olink and SOMAscan7K platforms were highly variable. | Haslam, Danielle E Li, Jun Dillon, Simon T Gu, Xuesong Cao, Yin Zeleznik, Oana A Sasamoto, Naoko Zhang, Xuehong Eliassen, A Heather Liang, Liming Stampfer, Meir J Mora, Samia Chen, Zsu-Zsu Terry, Kathryn L Gerszten, Robert E Hu, Frank B Chan, Andrew T Libermann, Towia A Bhupathiraju, Shilpa N eng P30 CA006516/NH/NIH HHS/ R01 CA49449/NH/NIH HHS/ T32 CA009001/NH/NIH HHS/ U01 CA167552/NH/NIH HHS/ U01 CA176726/NH/NIH HHS/ UM1 CA186107/NH/NIH HHS/ CRUK_/Cancer Research UK/United Kingdom R01 CA67262/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Germany Proteomics. 2022 Jul;22(13-14):e2100170. doi: 10.1002/pmic.202100170. Epub 2022 May 31.I | 05/23/2022 | |
| Validation of disease-specific biomarkers for the early detection of bronchopulmonary dysplasia | Kindt ASD, et al. | 2022 | Pediatr Res | epub ahead of print | https://www.doi.org/10.1038/s41390-022-02093-w | 35,595,912 | OBJECTIVE: To demonstrate and validate the improvement of current risk stratification for bronchopulmonary dysplasia (BPD) early after birth by plasma protein markers (sialic acid-binding Ig-like lectin 14 (SIGLEC-14), basal cell adhesion molecule (BCAM), angiopoietin-like 3 protein (ANGPTL-3)) in extremely premature infants. METHODS AND RESULTS: Proteome screening in first-week-of-life plasma samples of n = 52 preterm infants <32 weeks gestational age (GA) on two proteomic platforms (SomaLogic((R)), Olink-Proteomics((R))) confirmed three biomarkers with significant predictive power: BCAM, SIGLEC-14, and ANGPTL-3. We demonstrate high sensitivity (0.92) and specificity (0.86) under consideration of GA, show the proteins' critical contribution to the predictive power of known clinical risk factors, e.g., birth weight and GA, and predicted the duration of mechanical ventilation, oxygen supplementation, as well as neonatal intensive care stay. We confirmed significant predictive power for BPD cases when switching to a clinically applicable method (enzyme-linked immunosorbent assay) in an independent sample set (n = 25, p < 0.001) and demonstrated disease specificity in different cohorts of neonatal and adult lung disease. CONCLUSION: While successfully addressing typical challenges of clinical biomarker studies, we demonstrated the potential of BCAM, SIGLEC-14, and ANGPTL-3 to inform future clinical decision making in the preterm infant at risk for BPD. TRIAL REGISTRATION: Deutsches Register Klinische Studien (DRKS) No. 00004600; https://www.drks.de . IMPACT: The urgent need for biomarkers that enable early decision making and personalized monitoring strategies in preterm infants with BPD is challenged by targeted marker analyses, cohort size, and disease heterogeneity. We demonstrate the potential of the plasma proteins BCAM, SIGLEC-14, and ANGPTL-3 to identify infants with BPD early after birth while improving the predictive power of clinical variables, confirming the robustness toward proteome assays and proving disease specificity. Our comprehensive analysis enables a phase-III clinical trial that allows full implementation of the biomarkers into clinical routine to enable early risk stratification in preterms with BPD. | Kindt, Alida S D Forster, Kai M Cochius-den Otter, Suzan C M Flemmer, Andreas W Hauck, Stefanie M Flatley, Andrew Kamphuis, Juliette Karrasch, Stefan Behr, Jurgen Franz, Axel Hartel, Christoph Krumsiek, Jan Tibboel, Dick Hilgendorff, Anne eng Pediatr Res. 2022 May 20. doi: 10.1038/s41390-022-02093-w.I | 05/21/2022 | ||||
| Mendelian randomization analysis of plasma levels of CD209 and MICB proteins and the risk of varicose veins of lower extremities | Shadrina AS, et al. | 2022 | PLoS One | 17 | 5 | e0268725 | https://www.doi.org/10.1371/journal.pone.0268725 | 35,594,287 | Genome-Wide Association Study Humans Lower Extremity/pathology *Mendelian Randomization Analysis Polymorphism, Single Nucleotide *Varicose Veins/genetics/pathology | Varicose veins of lower extremities (VVs) are a highly prevalent condition, the pathogenesis of which is still not fully elucidated. Mendelian randomization (MR) can provide useful preliminary information on the traits that are potentially causally related to the disease. The aim of the present study is to replicate the effects of the plasma levels of MHC class I polypeptide-related sequence B (MICB) and cluster of differentiation 209 (CD209) proteins reported in a previous hypothesis-free MR study. We conducted MR analysis using a fixed effects inverse-variance weighted meta-analysis of Wald ratios method. For MICB and CD209, we used data from a large-scale genome-wide association study (GWAS) for plasma protein levels (N = 3,301). For VVs, we used GWAS data obtained in the FinnGen project (N = 128,698), the eMERGE network (phase 3, N = 48,429), and the UK Biobank data available in the Gene ATLAS (N = 452,264). The data used in the study were obtained in individuals of European descent. The results for MICB did not pass criteria for statistical significance and replication. The results for CD209 passed all statistical significance thresholds, indicating that the genetically predicted increase in CD209 level is associated with increased risk of VVs (betaMR (SE) = 0.07 (0.01), OR (95% CI) = 1.08 (1.05-1.10), P-value = 5.9 x10-11 in the meta-analysis of three cohorts). Our findings provide further support that CD209 can potentially be involved in VVs. In future studies, independent validation of our results using data from more powerful GWASs for CD209 measured by different methods would be beneficial. | Shadrina, Alexandra S Elgaeva, Elizaveta E Stanaway, Ian B Jarvik, Gail P Namjou, Bahram Wei, Wei-Qi Glessner, Joe Hakonarson, Hakon Suri, Pradeep Tsepilov, Yakov A eng U01 HG008676/HG/NHGRI NIH HHS/ U01 HG008657/HG/NHGRI NIH HHS/ U01 HG008684/HG/NHGRI NIH HHS/ U01 HG008679/HG/NHGRI NIH HHS/ U01 HG008666/HG/NHGRI NIH HHS/ U01 HG008680/HG/NHGRI NIH HHS/ U01 HG008673/HG/NHGRI NIH HHS/ U01 HG008685/HG/NHGRI NIH HHS/ U01 HG006379/HG/NHGRI NIH HHS/ U01 HG008664/HG/NHGRI NIH HHS/ U01 HG008701/HG/NHGRI NIH HHS/ U01 HG008672/HG/NHGRI NIH HHS/ P30 AR072572/AR/NIAMS NIH HHS/ Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS One. 2022 May 20;17(5):e0268725. doi: 10.1371/journal.pone.0268725. eCollection 2022.I | 05/21/2022 | |
| Effects of age, amyloid, sex, and APOE epsilon4 on the CSF proteome in normal cognition | Wesenhagen KEJ, et al. | 2022 | Alzheimers Dement (Amst) | 14 | 1 | e12286 | https://www.doi.org/10.1002/dad2.12286 | 35,571,963 | INTRODUCTION: It is important to understand which biological processes change with aging, and how such changes are associated with increased Alzheimer's disease (AD) risk. We studied how cerebrospinal fluid (CSF) proteomics changed with age and tested if associations depended on amyloid status, sex, and apolipoprotein E E4 genotype. METHODS: We included 277 cognitively intact individuals aged 46 to 89 years from Alzheimer's Disease Neuroimaging Initiative, European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery, and Metabolic Syndrome in Men. In total, 1149 proteins were measured with liquid chromatography mass spectrometry with multiple reaction monitoring/Rules-Based Medicine, tandem mass tag mass spectrometry, and SOMAscan. We tested associations between age and protein levels in linear models and tested enrichment for Reactome pathways. RESULTS: Levels of 252 proteins increased with age independently of amyloid status. These proteins were associated with immune and signaling processes. Levels of 21 proteins decreased with older age exclusively in amyloid abnormal participants and these were enriched for extracellular matrix organization. DISCUSSION: We found amyloid-independent and -dependent CSF proteome changes with older age, perhaps representing physiological aging and early AD pathology. | Wesenhagen, Kirsten E J Gobom, Johan Bos, Isabelle Vos, Stephanie J B Martinez-Lage, Pablo Popp, Julius Tsolaki, Magda Vandenberghe, Rik Freund-Levi, Yvonne Verhey, Frans Lovestone, Simon Streffer, Johannes Dobricic, Valerija Bertram, Lars Blennow, Kaj Pikkarainen, Maria Hallikainen, Merja Kuusisto, Johanna Laakso, Markku Soininen, Hilkka Scheltens, Philip Zetterberg, Henrik Teunissen, Charlotte E Visser, Pieter Jelle Tijms, Betty M eng Alzheimers Dement (Amst). 2022 May 6;14(1):e12286. doi: 10.1002/dad2.12286. eCollection 2022.I | 05/17/2022 | ||
| Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites | Bomba L, et al. | 2022 | Am J Hum Genet | 109 | 6 | 1038-1054 | https://www.doi.org/10.1016/j.ajhg.2022.04.009 | 35,568,032 | *Exome/genetics Gene Frequency/genetics Humans Prospective Studies Whole Exome Sequencing/methods Whole Genome Sequencing Wes Wgs drug targets endophenotypes loss-of-function metabolomics metabolon proteomics rare genetic variant sequencing non-financial support from Merck Sharp & Dohme (MSD) grants, personal fees, and non-financial support from Novartis grants from Pfizer and grants from AstraZeneca outside the submitted work. John Danesh sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010) the Steering Committee of UK Biobank (since 2011) the MRC International Advisory Group (ING) member, London (since 2013) the MRC High Throughput Science 'Omics Panel Member, London (since 2013) the Scientific Advisory Committee for Sanofi (since 2013) the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis and the AstraZeneca Genomics Advisory Board (2018). Adam Butterworth reports institutional grants from AstraZeneca, Bayer, Biogen, BioMarin, Bioverativ, Merk and Sanofi. During the course of the project Praveen Surendran became an employee of GSK, Lorenzo Bomba became an employee of BioMarin, Mohd Karim became an employee of Variant Bio and Qi Guo became an employee of BenevolentAI. | Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] < 0.1%) in protein-coding regions and tested their associations with 995 metabolites measured in plasma by using ultra-high-performance liquid chromatography-tandem mass spectrometry. We identified 40 novel associations implicating rare coding variants (27 genes and 38 metabolites), of which 28 (15 genes and 28 metabolites) were replicated. We developed algorithms to prioritize putative driver variants at each locus and used mediation and Mendelian randomization analyses to test directionality at associations of metabolite and protein levels at the ACY1 locus. Overall, 66% of reported associations implicate gene targets of approved drugs or bioactive drug-like compounds, contributing to drug targets' validating efforts. | Bomba, Lorenzo Walter, Klaudia Guo, Qi Surendran, Praveen Kundu, Kousik Nongmaithem, Suraj Karim, Mohd Anisul Stewart, Isobel D Langenberg, Claudia Danesh, John Di Angelantonio, Emanuele Roberts, David J Ouwehand, Willem H Dunham, Ian Butterworth, Adam S Soranzo, Nicole eng Am J Hum Genet. 2022 Jun 2;109(6):1038-1054. doi: 10.1016/j.ajhg.2022.04.009. Epub 2022 May 13.I | 05/15/2022 | |
| Analytical Considerations of Large-Scale Aptamer-Based Datasets for Translational Applications | Jiang W, et al. | 2022 | Cancers (Basel) | 14 | 9 | https://www.doi.org/10.3390/cancers14092227 | 35,565,358 | aptamers bioinformatics biomarkers proteomics translational | The development and advancement of aptamer technology has opened a new realm of possibilities for unlocking the biocomplexity available within proteomics. With ultra-high-throughput and multiplexing, alongside remarkable specificity and sensitivity, aptamers could represent a powerful tool in disease-specific research, such as supporting the discovery and validation of clinically relevant biomarkers. One of the fundamental challenges underlying past and current proteomic technology has been the difficulty of translating proteomic datasets into standards of practice. Aptamers provide the capacity to generate single panels that span over 7000 different proteins from a singular sample. However, as a recent technology, they also present unique challenges, as the field of translational aptamer-based proteomics still lacks a standardizing methodology for analyzing these large datasets and the novel considerations that must be made in response to the differentiation amongst current proteomic platforms and aptamers. We address these analytical considerations with respect to surveying initial data, deploying proper statistical methodologies to identify differential protein expressions, and applying datasets to discover multimarker and pathway-level findings. Additionally, we present aptamer datasets within the multi-omics landscape by exploring the intersectionality of aptamer-based proteomics amongst genomics, transcriptomics, and metabolomics, alongside pre-existing proteomic platforms. Understanding the broader applications of aptamer datasets will substantially enhance current efforts to generate translatable findings for the clinic. | Jiang, Will Jones, Jennifer C Shankavaram, Uma Sproull, Mary Camphausen, Kevin Krauze, Andra V eng ZID BC010990/ImNIH/Intramural NIH HHS/ ZID BC 010990/CA/NCI NIH HHS/ Review Switzerland Cancers (Basel). 2022 Apr 29;14(9):2227. doi: 10.3390/cancers14092227.I | 05/15/2022 | ||
| Assay-related differences in SuPAR levels: implications for measurement and data interpretation | Vasbinder A, et al. | 2022 | J Nephrol | 3-Jan | https://www.doi.org/10.1007/s40620-022-01344-7 | 35,567,697 | Olink Quantikine SOMAScan Soluble urokinase plasminogen activator receptor Virogates suPARnostic | Vasbinder, Alexi Raffield, Laura Marie Gao, Yan Engstrom, Gunnar Quyyumi, Arshed Ali Reiner, Alexander Paul Reiser, Jochen Hayek, Salim Salim eng KL2TR002490/TR/NCATS NIH HHS/ T32 HL007853/HL/NHLBI NIH HHS/ U01-DK119083/DK/NIDDK NIH HHS/ U-M G024231/University of Michigan Frankel Cardiovascular Center/ HHSN268201800014C/HL/NHLBI NIH HHS/ R01HL153384/HL/NHLBI NIH HHS/ HHSN268201800013I/MD/NIMHD NIH HHS/ HHSN268201800011C/HL/NHLBI NIH HHS/ KL2 TR002490/TR/NCATS NIH HHS/ T32HL129982/HL/NHLBI NIH HHS/ HHSN268201800015I/HB/NHLBI NIH HHS/ HHSN268201800010I/HB/NHLBI NIH HHS/ HHSN268201800011I/HB/NHLBI NIH HHS/ R01 DK109720/DK/NIDDK NIH HHS/ HHSN268201800012I/HB/NHLBI NIH HHS/ R01 HL132947/HL/NHLBI NIH HHS/ HHSN268201800012C/HL/NHLBI NIH HHS/ T32-HL007853/HL/NHLBI NIH HHS/ HHSN268201800014I/HB/NHLBI NIH HHS/ R01HL132947/HL/NHLBI NIH HHS/ R01-DK109720/DK/NIDDK NIH HHS/ Letter Italy J Nephrol. 2022 May 14:1-3. doi: 10.1007/s40620-022-01344-7.I | 05/15/2022 | ||||
| Proteomic Analysis of Plasma Markers in Patients Maintained on Antipsychotics: Comparison to Patients Off Antipsychotics and Normal Controls | Engelke R, et al. | 2022 | Front Psychiatry | 13 | 809071 | https://www.doi.org/10.3389/fpsyt.2022.809071 | 35,546,954 | antipsychotics biomarkers bipolar disorder metabolic syndrome proteomics schizophrenia declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | BACKGROUND: Schizophrenia (SZ) and bipolar disorder (BD) share many features: overlap in mood and psychotic symptoms, common genetic predisposition, treatment with antipsychotics (APs), and similar metabolic comorbidities. The pathophysiology of both is still not well defined, and no biomarkers can be used clinically for diagnosis and management. This study aimed to assess the plasma proteomics profile of patients with SZ and BD maintained on APs compared to those who had been off APs for 6 months and to healthy controls (HCs). METHODS: We analyzed the data using functional enrichment, random forest modeling to identify potential biomarkers, and multivariate regression for the associations with metabolic abnormalities. RESULTS: We identified several proteins known to play roles in the differentiation of the nervous system like NTRK2, CNTN1, ROBO2, and PLXNC1, which were downregulated in AP-free SZ and BD patients but were normalized" in those on APs. Other proteins (like NCAM1 and TNFRSF17) were "normal" in AP-free patients but downregulated in patients on APs, suggesting that these changes are related to medication's effects. We found significant enrichment of proteins involved in neuronal plasticity, mainly in SZ patients on APs. Most of the proteins associated with metabolic abnormalities were more related to APs use than having SZ or BD. The biomarkers identification showed specific and sensitive results for schizophrenia, where two proteins (PRL and MRC2) produced adequate results. CONCLUSIONS: Our results confirmed the utility of blood samples to identify protein signatures and mechanisms involved in the pathophysiology and treatment of SZ and BD." | Engelke, Rudolf Ouanes, Sami Ghuloum, Suhaila Chamali, Rifka Kiwan, Nancy Sarwath, Hina Schmidt, Frank Suhre, Karsten Al-Amin, Hassen eng Switzerland Front Psychiatry. 2022 Apr 25;13:809071. doi: 10.3389/fpsyt.2022.809071. eCollection 2022.I | 05/14/2022 | ||
| Plasma Proteomics of COVID-19-Associated Cardiovascular Complications: Implications for Pathophysiology and Therapeutics | Roh JD, et al. | 2022 | JACC Basic Transl Sci | 7 | 5 | 425-441 | https://www.doi.org/10.1016/j.jacbts.2022.01.013 | 35,530,264 | ADAMTS13, A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, member 13 Covid-19 FSTL3, follistatin-like 3 NT-proBNP, N-terminal pro-B-type natriuretic peptide SASP, senescence associated secretory phenotype TGFbeta, transforming growth factor beta hsTnT, high sensitivity troponin T myocardial injury proteomics senescence R35HL15531 [to Dr Rosenzweig] R01HL092577, R01HL128914, and K24HL105780 [to Dr Ellinor] R01HL134893, R01HL140224, K24HL153669 [to Dr Ho] T32HL094301 [to Dr Weber] K08HL140200 [to Dr Rhee] and K76AG064328 [to Dr Roh]), the Fondation Leducq (14CVD01 [to Dr Ellinor]), the American Heart Association (18SFRN34110082 [to Dr Ellinor]), a Sarnoff Cardiovascular Research Foundation Fellowship award (to Dr Trager), the Fred and Ines Yeatts Fund for Innovative Research (to Dr Roh), the Hassenfeld Scholars Award (to Dr Roh), Fast Grants, Emergent Ventures, Mercatus Center at George Mason University (to Dr Martinot), and a research grant from Bayer AG to the Broad Institute (to Drs Ellinor and Ho). Dr Ellinor is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases and has served on advisory boards or consulted for Bayer AG, Quest Diagnostics, MyoKardia and Novartis. Dr Ho has received research grants from Bayer AG and Gilead Sciences and has received research supplies from EcoNugenics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. | To gain insights into the mechanisms driving cardiovascular complications in COVID-19, we performed a case-control plasma proteomics study in COVID-19 patients. Our results identify the senescence-associated secretory phenotype, a marker of biological aging, as the dominant process associated with disease severity and cardiac involvement. FSTL3, an indicator of senescence-promoting Activin/TGFbeta signaling, and ADAMTS13, the von Willebrand Factor-cleaving protease whose loss-of-function causes microvascular thrombosis, were among the proteins most strongly associated with myocardial stress and injury. Findings were validated in a larger COVID-19 patient cohort and the hamster COVID-19 model, providing new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications. | Roh, Jason D Kitchen, Robert R Guseh, J Sawalla McNeill, Jenna N Aid, Malika Martinot, Amanda J Yu, Andy Platt, Colin Rhee, James Weber, Brittany Trager, Lena E Hastings, Margaret H Ducat, Sarah Xia, Peng Castro, Claire Singh, Abhilasha Atlason, Bjarni Churchill, Timothy W Di Carli, Marcelo F Ellinor, Patrick T Barouch, Dan H Ho, Jennifer E Rosenzweig, Anthony eng K08 HL140200/HL/NHLBI NIH HHS/ R01 AG061034/AG/NIA NIH HHS/ JACC Basic Transl Sci. 2022 May;7(5):425-441. doi: 10.1016/j.jacbts.2022.01.013. Epub 2022 May 4.I | 05/10/2022 | |
| Proteomics in thrombosis research | Edfors F, et al. | 2022 | Res Pract Thromb Haemost | 6 | 3 | e12706 | https://www.doi.org/10.1002/rth2.12706 | 35,494,505 | Vte biomarker mass spectrometry plasma protein proteome proteomics thrombosis venous thromboembolism | A State of the Art lecture titled Proteomics in Thrombosis Research" was presented at the ISTH Congress in 2021. In clinical practice, there is a need for improved plasma biomarker-based tools for diagnosis and risk prediction of venous thromboembolism (VTE). Analysis of blood, to identify plasma proteins with potential utility for such tools, could enable an individualized approach to treatment and prevention. Technological advances to study the plasma proteome on a large scale allows broad screening for the identification of novel plasma biomarkers, both by targeted and nontargeted proteomics methods. However, assay limitations need to be considered when interpreting results, with orthogonal validation required before conclusions are drawn. Here, we review and provide perspectives on the application of affinity- and mass spectrometry-based methods for the identification and analysis of plasma protein biomarkers, with potential application in the field of VTE. We also provide a future perspective on discovery strategies and emerging technologies for targeted proteomics in thrombosis research. Finally, we summarize relevant new data on this topic, presented during the 2021 ISTH Congress." | Edfors, Fredrik Iglesias, Maria Jesus Butler, Lynn M Odeberg, Jacob eng Res Pract Thromb Haemost. 2022 Apr 25;6(3):e12706. doi: 10.1002/rth2.12706. eCollection 2022 Mar.I | 05/03/2022 | |
| Lymphocyte activation gene-3-associated protein networks are associated with HDL-cholesterol and mortality in the Trans-omics for Precision Medicine program | Manichaikul A, et al. | 2022 | Commun Biol | 5 | 1 | 362 | https://www.doi.org/10.1038/s42003-022-03304-0 | 35,501,457 | *Atherosclerosis Cholesterol, HDL Chromatin Humans Lymphocyte Activation Membrane Proteins *Precision Medicine | Deficiency of the immune checkpoint lymphocyte activation gene-3 (LAG3) protein is significantly associated with both elevated HDL-cholesterol (HDL-C) and myocardial infarction risk. We determined the association of genetic variants within +/-500 kb of LAG3 with plasma LAG3 and defined LAG3-associated plasma proteins with HDL-C and clinical outcomes. Whole genome sequencing and plasma proteomics were obtained from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study (FHS) cohorts as part of the Trans-Omics for Precision Medicine program. In situ Hi-C chromatin capture was performed in EBV-transformed cell lines isolated from four MESA participants. Genetic association analyses were performed in MESA using multivariate regression models, with validation in FHS. A LAG3-associated protein network was tested for association with HDL-C, coronary heart disease, and all-cause mortality. We identify an association between the LAG3 rs3782735 variant and plasma LAG3 protein. Proteomics analysis reveals 183 proteins significantly associated with LAG3 with four proteins associated with HDL-C. Four proteins discovered for association with all-cause mortality in FHS shows nominal associations in MESA. Chromatin capture analysis reveals significant cis interactions between LAG3 and C1S, LRIG3, TNFRSF1A, and trans interactions between LAG3 and B2M. A LAG3-associated protein network has significant associations with HDL-C and mortality. | Manichaikul, Ani Lin, Honghuang Kang, Chansuk Yang, Chaojie Rich, Stephen S Taylor, Kent D Guo, Xiuqing Rotter, Jerome I Craig Johnson, W Cornell, Elaine Tracy, Russell P Peter Durda, J Liu, Yongmei Vasan, Ramachandran S Adrienne Cupples, L Gerszten, Robert E Clish, Clary B Jain, Deepti Conomos, Matthew P Blackwell, Thomas Papanicolaou, George J Rodriguez, Annabelle eng N01HC95169/HL/NHLBI NIH HHS/ 75N92020D00007/HL/NHLBI NIH HHS/ R01 HL071251/HL/NHLBI NIH HHS/ 75N92020D00005/HL/NHLBI NIH HHS/ N01HC95165/HL/NHLBI NIH HHS/ N01HC95159/HL/NHLBI NIH HHS/ N01HC95163/HL/NHLBI NIH HHS/ 75N92020D00002/HL/NHLBI NIH HHS/ UL1 RR033176/RR/NCRR NIH HHS/ R01 HL131862/HL/NHLBI NIH HHS/ UL1 TR000040/TR/NCATS NIH HHS/ R01 HL117626/HL/NHLBI NIH HHS/ N01HC95161/HL/NHLBI NIH HHS/ 75N92020D00001/HL/NHLBI NIH HHS/ UL1 TR001881/TR/NCATS NIH HHS/ 75N92019D00031/HL/NHLBI NIH HHS/ R01 HL120393/HL/NHLBI NIH HHS/ R01 HL071259/HL/NHLBI NIH HHS/ N01HC95168/HL/NHLBI NIH HHS/ HHSN268201500014C/HL/NHLBI NIH HHS/ N01HC95162/HL/NHLBI NIH HHS/ R01 HL071051/HL/NHLBI NIH HHS/ 75N92020D00004/HL/NHLBI NIH HHS/ UL1 TR001420/TR/NCATS NIH HHS/ HHSN268201500001I/HL/NHLBI NIH HHS/ R01 HL105756/HL/NHLBI NIH HHS/ R01 HL071205/HL/NHLBI NIH HHS/ R01 HL071258/HL/NHLBI NIH HHS/ N01HC95167/HL/NHLBI NIH HHS/ 75N92020D00003/HL/NHLBI NIH HHS/ N01HC25195/HL/NHLBI NIH HHS/ U54 HG003067/HG/NHGRI NIH HHS/ HHSN268201500003I/HL/NHLBI NIH HHS/ N01HC95164/HL/NHLBI NIH HHS/ R01 HL092577/HL/NHLBI NIH HHS/ 75N92020D00006/HL/NHLBI NIH HHS/ UL1 TR001079/TR/NCATS NIH HHS/ N01HC95166/HL/NHLBI NIH HHS/ R01 HL071250/HL/NHLBI NIH HHS/ N01HC95160/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Commun Biol. 2022 May 2;5(1):362. doi: 10.1038/s42003-022-03304-0.I | 05/03/2022 | |
| Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies | Zhang J, et al. | 2022 | Nat Genet | 54 | 5 | 593-602 | https://www.doi.org/10.1038/s41588-022-01051-w | 35,501,419 | Genetic Predisposition to Disease Genome-Wide Association Study *Gout/genetics Humans Polymorphism, Single Nucleotide *Proteome/genetics | Improved understanding of genetic regulation of the proteome can facilitate identification of the causal mechanisms for complex traits. We analyzed data on 4,657 plasma proteins from 7,213 European American (EA) and 1,871 African American (AA) individuals from the Atherosclerosis Risk in Communities study, and further replicated findings on 467 AA individuals from the African American Study of Kidney Disease and Hypertension study. Here, we identified 2,004 proteins in EA and 1,618 in AA, with most overlapping, which showed associations with common variants in cis-regions. Availability of AA samples led to smaller credible sets and notable number of population-specific cis-protein quantitative trait loci. Elastic Net produced powerful models for protein prediction in both populations. An application of proteome-wide association studies to serum urate and gout implicated several proteins, including IL1RN, revealing the promise of the drug anakinra to treat acute gout flares. Our study demonstrates the value of large and diverse ancestry study to investigate the genetic mechanisms of molecular phenotypes and their relationship with complex traits. | Zhang, Jingning Dutta, Diptavo Kottgen, Anna Tin, Adrienne Schlosser, Pascal Grams, Morgan E Harvey, Benjamin Yu, Bing Boerwinkle, Eric Coresh, Josef Chatterjee, Nilanjan eng R01 HG010480/HG/NHGRI NIH HHS/ R01 AR073178/AR/NIAMS NIH HHS/ R01 DK124399/DK/NIDDK NIH HHS/ R01 HL148218/HL/NHLBI NIH HHS/ R01 HL134320/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Nat Genet. 2022 May;54(5):593-602. doi: 10.1038/s41588-022-01051-w. Epub 2022 May 2.I | 05/03/2022 | |
| Clinical applications of plasma proteomics and peptidomics: Towards precision medicine | He B, et al. | 2022 | Proteomics Clin Appl | 16 | 6 | e2100097 | https://www.doi.org/10.1002/prca.202100097 | 35,490,333 | Humans *Proteomics/methods Proteome/metabolism Precision Medicine/methods *COVID-19/diagnosis Biomarkers/metabolism biomarkers human proteome project peptidomics plasma precision medicine proteomics | In the context of precision medicine, disease treatment requires individualized strategies based on the underlying molecular characteristics to overcome therapeutic challenges posed by heterogeneity. For this purpose, it is essential to develop new biomarkers to diagnose, stratify, or possibly prevent diseases. Plasma is an available source of biomarkers that greatly reflects the physiological and pathological conditions of the body. An increasing number of studies are focusing on proteins and peptides, including many involving the Human Proteome Project (HPP) of the Human Proteome Organization (HUPO), and proteomics and peptidomics techniques are emerging as critical tools for developing novel precision medicine preventative measures. Excitingly, the emerging plasma proteomics and peptidomics toolbox exhibits a huge potential for studying pathogenesis of diseases (e.g., COVID-19 and cancer), identifying valuable biomarkers and improving clinical management. However, the enormous complexity and wide dynamic range of plasma proteins makes plasma proteome profiling challenging. Herein, we summarize the recent advances in plasma proteomics and peptidomics with a focus on their emerging roles in COVID-19 and cancer research, aiming to emphasize the significance of plasma proteomics and peptidomics in clinical applications and precision medicine. | He, Bo Huang, Zhao Huang, Canhua Nice, Edouard C eng 2020YFC2002705/National Key Research and Development Project of China/ 82103168/the National Natural Science Foundation of China/ 82102738/the National Natural Science Foundation of China/ Review Germany Proteomics Clin Appl. 2022 Nov;16(6):e2100097. doi: 10.1002/prca.202100097. Epub 2022 May 11.I | 05/02/2022 | |
| Proteomics of lung tissue reveals differences in inflammation and alveolar-capillary barrier response between atelectasis and aerated regions | Rashid A, et al. | 2022 | Sci Rep | 12 | 1 | 7065 | https://www.doi.org/10.1038/s41598-022-11045-7 | 35,487,970 | *Acute Lung Injury/metabolism Humans Inflammation/metabolism Lipopolysaccharides/metabolism Lung/metabolism Proteomics *Pulmonary Atelectasis/metabolism | Atelectasis is a frequent clinical condition, yet knowledge is limited and controversial on its biological contribution towards lung injury. We assessed the regional proteomics of atelectatic versus normally-aerated lung tissue to test the hypothesis that immune and alveolar-capillary barrier functions are compromised by purely atelectasis and dysregulated by additional systemic inflammation (lipopolysaccharide, LPS). Without LPS, 130 proteins were differentially abundant in atelectasis versus aerated lung, mostly (n = 126) with less abundance together with negatively enriched processes in immune, endothelial and epithelial function, and Hippo signaling pathway. Instead, LPS-exposed atelectasis produced 174 differentially abundant proteins, mostly (n = 108) increased including acute lung injury marker RAGE and chemokine CCL5. Functional analysis indicated enhanced leukocyte processes and negatively enriched cell-matrix adhesion and cell junction assembly with LPS. Additionally, extracellular matrix organization and TGF-beta signaling were negatively enriched in atelectasis with decreased adhesive glycoprotein THBS1 regardless of LPS. Concordance of a subset of transcriptomics and proteomics revealed overlap of leukocyte-related gene-protein pairs and processes. Together, proteomics of exclusively atelectasis indicates decreased immune response, which converts into an increased response with LPS. Alveolar-capillary barrier function-related proteomics response is down-regulated in atelectasis irrespective of LPS. Specific proteomics signatures suggest biological mechanistic and therapeutic targets for atelectasis-associated lung injury. | Rashid, Azman Zeng, Congli Motta-Ribeiro, Gabriel Dillon, Simon T Libermann, Towia A Lessa, Marcos Adriano Bagchi, Aranya Hutchinson, John Vidal Melo, Marcos F eng R01 HL121228/NH/NIH HHS/ Research Support, N.I.H., Extramural England Sci Rep. 2022 Apr 29;12(1):7065. doi: 10.1038/s41598-022-11045-7.I | 04/30/2022 | |
| Harnessing Big Data to Advance Treatment and Understanding of Pulmonary Hypertension | Rhodes CJ, et al. | 2022 | Circ Res | 130 | 9 | 1423-1444 | https://www.doi.org/10.1161/CIRCRESAHA.121.319969 | 35,482,840 | *Big Data Humans *Hypertension, Pulmonary/diagnosis/drug therapy/genetics Machine Learning Precision Medicine/methods big data information dissemination phenotype precision medicine pulmonary arterial hypertension Maron discloses Consultant roles for Actelion Pharmaceuticals and Tenax, and a Grant / Contract from Deerfield Company. | Pulmonary hypertension is a complex disease with multiple causes, corresponding to phenotypic heterogeneity and variable therapeutic responses. Advancing understanding of pulmonary hypertension pathogenesis is likely to hinge on integrated methods that leverage data from health records, imaging, novel molecular -omics profiling, and other modalities. In this review, we summarize key data sets generated thus far in the field and describe analytical methods that hold promise for deciphering the molecular mechanisms that underpin pulmonary vascular remodeling, including machine learning, network medicine, and functional genetics. We also detail how genetic and subphenotyping approaches enable earlier diagnosis, refined prognostication, and optimized treatment prediction. We propose strategies that identify functionally important molecular pathways, bolstered by findings across multi-omics platforms, which are well-positioned to individualize drug therapy selection and advance precision medicine in this highly morbid disease. | Rhodes, Christopher J Sweatt, Andrew J Maron, Bradley A eng K23 HL151892/HL/NHLBI NIH HHS/ R01 HL139613/HL/NHLBI NIH HHS/ R01 HL153502/HL/NHLBI NIH HHS/ R01 HL155096/HL/NHLBI NIH HHS/ FS/15/59/31839/BHF_/British Heart Foundation/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review Circ Res. 2022 Apr 29;130(9):1423-1444. doi: 10.1161/CIRCRESAHA.121.319969. Epub 2022 Apr 28.I | 04/29/2022 | |
| Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset | Saevarsdottir S, et al. | 2022 | Ann Rheum Dis | 81 | 8 | 1085-1095 | https://www.doi.org/10.1136/annrheumdis-2021-221754 | 35,470,158 | *Arthritis, Rheumatoid/genetics Genetic Predisposition to Disease/genetics *Genome-Wide Association Study Humans Interferon-alpha Janus Kinases/genetics Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics Proteomics STAT Transcription Factors/genetics Signal Transduction/genetics autoantibodies polymorphism, genetic rheumatoid arthritis competing financial interests as employees. OAA is a consultant to HealthLytix. The following coauthors report the following but unrelated to the current report: Karolinska Institutet, with JA as principal investigator, has entered into agreements with the following entities, mainly but not exclusively for safety monitoring of rheumatology immunomodulators: Abbvie, BMS, Eli Lilly, Janssen, MSD, Pfizer, Roche, Samsung Bioepis and Sanofi, unrelated to the present study. SB has ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S and managing board memberships in Proscion A/S and Intomics A/S. BG has received research grants from AbbVie, Bristol Myers-Squibb and Pfizer OH has received research grants from AbbVie, Novartis and Pfizer, DVJ has received speaker and consultation fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB, AGL has received speaking and/or consulting fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB and CT has received consulting fees from Roche, speaker fees from Abbvie, Bristol Myers-Squibb, Nordic Drugs, Pfizer and Roche, and an unrestricted grant from Bristol Myers-Squibb. | OBJECTIVES: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. METHODS: We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ~1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). RESULTS: We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. CONCLUSION: Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce. | Saevarsdottir, Saedis Stefansdottir, Lilja Sulem, Patrick Thorleifsson, Gudmar Ferkingstad, Egil Rutsdottir, Gudrun Glintborg, Bente Westerlind, Helga Grondal, Gerdur Loft, Isabella C Sorensen, Signe Bek Lie, Benedicte A Brink, Mikael Arlestig, Lisbeth Arnthorsson, Asgeir Orn Baecklund, Eva Banasik, Karina Bank, Steffen Bjorkman, Lena I Ellingsen, Torkell Erikstrup, Christian Frei, Oleksandr Gjertsson, Inger Gudbjartsson, Daniel F Gudjonsson, Sigurjon A Halldorsson, Gisli H Hendricks, Oliver Hillert, Jan Hogdall, Estrid Jacobsen, Soren Jensen, Dorte Vendelbo Jonsson, Helgi Kastbom, Alf Kockum, Ingrid Kristensen, Salome Kristjansdottir, Helga Larsen, Margit H Linauskas, Asta Hauge, Ellen-Margrethe Loft, Anne G Ludviksson, Bjorn R Lund, Sigrun H Markusson, Thorsteinn Masson, Gisli Melsted, Pall Moore, Kristjan H S Munk, Heidi Nielsen, Kaspar R Norddahl, Gudmundur L Oddsson, Asmundur Olafsdottir, Thorunn A Olason, Pall I Olsson, Tomas Ostrowski, Sisse Rye Horslev-Petersen, Kim Rognvaldsson, Solvi Sanner, Helga Silberberg, Gilad N Stefansson, Hreinn Sorensen, Erik Sorensen, Inge J Turesson, Carl Bergman, Thomas Alfredsson, Lars Kvien, Tore K Brunak, Soren Steinsson, Kristjan Andersen, Vibeke Andreassen, Ole A Rantapaa-Dahlqvist, Solbritt Hetland, Merete Lund Klareskog, Lars Askling, Johan Padyukov, Leonid Pedersen, Ole Bv Thorsteinsdottir, Unnur Jonsdottir, Ingileif Stefansson, Kari (SRQb) eng Research Support, Non-U.S. Gov't England Ann Rheum Dis. 2022 Aug;81(8):1085-1095. doi: 10.1136/annrheumdis-2021-221754. Epub 2022 Apr 25.I | 04/27/2022 | |
| Proteomics of human biological fluids for biomarker discoveries: technical advances and recent applications | Dayon L, et al. | 2022 | Expert Rev Proteomics | 19 | 2 | 131-151 | https://www.doi.org/10.1080/14789450.2022.2070477 | 35,466,824 | Biomarkers/metabolism *Body Fluids/metabolism Humans Proteome/metabolism *Proteomics/methods Automation Ms biofluid biomarker cohort human mass spectrometry plasma proteomics | INTRODUCTION: Biological fluids are routine samples for diagnostic testing and monitoring. Blood samples are typically measured because of their moderate invasive collection and high information content on health and disease. Several body fluids, such as cerebrospinal fluid (CSF), are also studied and suited to specific pathologies. Over the last two decades, proteomics has quested to identify protein biomarkers but with limited success. Recent technologies and refined pipelines have accelerated the profiling of human biological fluids. AREAS COVERED: We review proteomic technologies for the identification of biomarkers. These are based on antibodies/aptamers arrays or mass spectrometry (MS), but new ones are emerging. Advances in scalability and throughput have allowed to better design studies and cope with the limited sample size that has until now prevailed due to technological constraints. With these enablers, plasma/serum, CSF, saliva, tears, urine, and milk proteomes have been further profiled; we provide a non-exhaustive picture of some recent highlights (mainly covering literature from the last 5 years in the Scopus database) using MS-based proteomics. EXPERT OPINION: While proteomics has been in the shadow of genomics for years, proteomic tools and methodologies have reached certain maturity. They are now better suited to discover innovative and robust biofluid biomarkers. | Dayon, Loic Cominetti, Ornella Affolter, Michael eng Research Support, Non-U.S. Gov't Review England Expert Rev Proteomics. 2022 Feb;19(2):131-151. doi: 10.1080/14789450.2022.2070477. Epub 2022 May 5.I | 04/26/2022 | |
| Identifying causal genes for stroke via integrating the proteome and transcriptome from brain and blood | Wu BS, et al. | 2022 | J Transl Med | 20 | 1 | 181 | https://www.doi.org/10.1186/s12967-022-03377-9 | 35,449,099 | Bayes Theorem Brain/metabolism Genetic Predisposition to Disease *Genome-Wide Association Study Humans Polymorphism, Single Nucleotide/genetics Proteome/genetics/metabolism *Stroke/complications Transcriptome/genetics Bayesian colocalization Mendelian randomization Proteome-wide association study Stroke Transcriptome-wide association study | BACKGROUND: Genome-wide association studies (GWAS) have revealed numerous loci associated with stroke. However, the underlying mechanisms at these loci in the pathogenesis of stroke and effective stroke drug targets are elusive. Therefore, we aimed to identify causal genes in the pathogenesis of stroke and its subtypes. METHODS: Utilizing multidimensional high-throughput data generated, we integrated proteome-wide association study (PWAS), transcriptome-wide association study (TWAS), Mendelian randomization (MR), and Bayesian colocalization analysis to prioritize genes that contribute to stroke and its subtypes risk via affecting their expression and protein abundance in brain and blood. RESULTS: Our integrative analysis revealed that ICA1L was associated with small-vessel stroke (SVS), according to robust evidence at both protein and transcriptional levels based on brain-derived data. We also identified NBEAL1 that was causally related to SVS via its cis-regulated brain expression level. In blood, we identified 5 genes (MMP12, SCARF1, ABO, F11, and CKAP2) that had causal relationships with stroke and stroke subtypes. CONCLUSIONS: Together, via using an integrative analysis to deal with multidimensional data, we prioritized causal genes in the pathogenesis of SVS, which offered hints for future biological and therapeutic studies. | Wu, Bang-Sheng Chen, Shu-Fen Huang, Shu-Yi Ou, Ya-Nan Deng, Yue-Ting Chen, Shi-Dong Dong, Qiang Yu, Jin-Tai eng Research Support, Non-U.S. Gov't England J Transl Med. 2022 Apr 21;20(1):181. doi: 10.1186/s12967-022-03377-9.I | 04/23/2022 | |
| Effects of ivacaftor on systemic inflammation and the plasma proteome in people with CF and G551D | Hoppe JE, et al. | 2022 | J Cyst Fibros | epub ahead of print | https://www.doi.org/10.1016/j.jcf.2022.03.012 | 35,440,409 | CFTR modulation Extrapulmonary Inflammation Proteomics Foundation, outside the submitted work, SMR reports grants, personal fees, non-financial support and other from Vertex Pharmaceuticals Inc., during the conduct of the study grants and personal fees from Novartis, grants and personal fees from Bayer, grants from Translate Bio, non-financial support from Proteostasis, grants, personal fees and non-financial support from Galapagos/Abbvie, grants, personal fees and other from Synedgen/Synspira, grants from Eloxx, grants and personal fees from Celtaxsys, grants, personal fees, non-financial support and other from Vertex Pharmaceuticals Inc, personal fees from Renovion, grants and personal fees from Arrowhead, grants and other from Ionis, grants from Astra Zenica, personal fees from Cystetic Medicines, personal fees from Arcturus, outside the submitted work EMD reports other from EvoEndoscopy (formerly Triple Endoscopy), outside the submitted work and is a consultant for Boehringer Ingelheim, not related to this work. SDS reports grants from the Cystic Fibrosis Foundation that funds the work under consideration, and grants from the Cystic Fibrosis Foundation and National Institutes of Health funding activities outside the submitted work. BDW, JKH and SLH have nothing to disclose. | BACKGROUND: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator for people with CF and the G551D mutation. We aimed to investigate the biology of CFTR modulation and systemic effects of CFTR restoration by examining changes in circulating measurements of inflammation and growth and novel proteins with ivacaftor treatment. METHODS: Blood samples from 64 CF subjects with G551D-CFTR were analyzed for inflammatory and growth-related proteins at baseline, 1 and 6 months after ivacaftor initiation. In 30 subjects, plasma was assayed for 1,322 proteins using the SomaScan proteomic platform at baseline and 6 months post-ivacaftor. Correlations with clinical outcomes were assessed. MEASUREMENTS AND MAIN RESULTS: Significant reductions in high mobility group box-1 protein (HMGB-1), calprotectin, serum amyloid A, and granulocyte colony-stimulating factor (G-CSF), and an increase in insulin-like growth factor (IGF-1) occurred 1 month after ivacaftor. This treatment effect was sustained at 6 months for HMGB-1 and calprotectin. Correcting for multiple comparisons in the proteomic analysis, 9 proteins (albumin, afamin, leptin, trypsin, pancreatic stone protein [PSP], pituitary adenylate cyclase-activating polypeptide-38, repulsive guidance molecule A [RGMA], calreticulin, GTPase KRas) changed significantly with ivacaftor. Proteins changing with treatment are involved in lipid digestion and transport and extracellular matrix organization biological processes. Reductions in calprotectin and G-CSF and increases in calreticulin, and RGMA correlated with improved lung function, while increasing IGF-1, leptin and afamin and decreasing PSP correlated with increased weight. CONCLUSIONS: Ivacaftor led to changes in inflammatory, lipid digestion, and extracellular matrix proteins, lending insights into the extrapulmonary effects of CFTR modulation. | Hoppe, Jordana E Wagner, Brandie D Kirk Harris, J Rowe, Steven M Heltshe, Sonya L DeBoer, Emily M Sagel, Scott D eng P30 DK072482/DK/NIDDK NIH HHS/ P30 DK089507/DK/NIDDK NIH HHS/ UL1 TR002535/TR/NCATS NIH HHS/ UL1 TR003096/TR/NCATS NIH HHS/ Netherlands J Cyst Fibros. 2022 Apr 16:S1569-1993(22)00089-3. doi: 10.1016/j.jcf.2022.03.012.I | 04/21/2022 | |||
| The Proteomic Profile of Interstitial Lung Abnormalities | Axelsson GT, et al. | 2022 | Am J Respir Crit Care Med | 206 | 3 | 337-346 | https://www.doi.org/10.1164/rccm.202110-2296OC | 35,438,610 | Genetic Predisposition to Disease Humans Lung *Lung Diseases, Interstitial/epidemiology/genetics Prospective Studies Proteomics *Respiratory System Abnormalities Tomography, X-Ray Computed biomarkers idiopathic pulmonary fibrosis interstitial lung abnormalities interstitial lung disease | Rationale: Knowledge on biomarkers of interstitial lung disease is incomplete. Interstitial lung abnormalities (ILAs) are radiologic changes that may present in its early stages. Objectives: To uncover blood proteins associated with ILAs using large-scale proteomics methods. Methods: Data from two prospective cohort studies, the AGES-Reykjavik (Age, Gene/Environment Susceptibility-Reykjavik) study (N = 5,259) for biomarker discovery and the COPDGene (Genetic Epidemiology of COPD) study (N = 4,899) for replication, were used. Blood proteins were measured using DNA aptamers, targeting more than 4,700 protein analytes. The association of proteins with ILAs and ILA progression was assessed with regression modeling, as were associations with genetic risk factors. Adaptive Least Absolute Shrinkage and Selection Operator models were applied to bootstrap data samples to discover sets of proteins predictive of ILAs and their progression. Measurements and Main Results: Of 287 associations, SFTPB (surfactant protein B) (odds ratio [OR], 3.71 [95% confidence interval (CI), 3.20-4.30]; P = 4.28 x 10(-67)), SCGB3A1 (Secretoglobin family 3A member 1) (OR, 2.43 [95% CI, 2.13-2.77]; P = 8.01 x 10(-40)), and WFDC2 (WAP four-disulfide core domain protein 2) (OR, 2.42 [95% CI, 2.11-2.78]; P = 4.01 x 10(-36)) were most significantly associated with ILA in AGES-Reykjavik and were replicated in COPDGene. In AGES-Reykjavik, concentrations of SFTPB were associated with the rs35705950 MUC5B (mucin 5B) promoter polymorphism, and SFTPB and WFDC2 had the strongest associations with ILA progression. Multivariate models of ILAs in AGES-Reykjavik, ILAs in COPDGene, and ILA progression in AGES-Reykjavik had validated areas under the receiver operating characteristic curve of 0.880, 0.826, and 0.824, respectively. Conclusions: Novel, replicated associations of ILA, its progression, and genetic risk factors with numerous blood proteins are demonstrated as well as machine-learning-based models with favorable predictive potential. Several proteins are revealed as potential markers of early fibrotic lung disease. | Axelsson, Gisli Thor Gudmundsson, Gunnar Pratte, Katherine A Aspelund, Thor Putman, Rachel K Sanders, Jason L Gudmundsson, Elias F Hatabu, Hiroto Gudmundsdottir, Valborg Gudjonsson, Alexander Hino, Takuya Hida, Tomoyuki Hobbs, Brian D Cho, Michael H Silverman, Edwin K Bowler, Russell P Launer, Lenore J Jennings, Lori L Hunninghake, Gary M Emilsson, Valur Gudnason, Vilmundur eng R01CA203636/NH/NIH HHS/ R01 HL113264/NH/NIH HHS/ U01 HL089856/NH/NIH HHS/ R01 HL137927/NH/NIH HHS/ U01 HL089856/HL/NHLBI NIH HHS/ R01 HL137927/HL/NHLBI NIH HHS/ R01 HL129937/HL/NHLBI NIH HHS/ HHSN27120120022C/NH/NIH HHS/ R01 133135/NH/NIH HHS/ N01-AG-1-2100/NH/NIH HHS/ K08 HL136928/NH/NIH HHS/ 5U01CA209414-03/NH/NIH HHS/ R01 HL111024/NH/NIH HHS/ R01 HL152735/NH/NIH HHS/ P01 HL114501/NH/NIH HHS/ P50HL084948/HL/NHLBI NIH HHS/ R01 135142/NH/NIH HHS/ R01 137927/NH/NIH HHS/ R01 HL135142/NH/NIH HHS/ R21HL129917/HL/NHLBI NIH HHS/ K08 HL140087/NH/NIH HHS/ R01 HL137995/NH/NIH HHS/ R01 HL137995/HL/NHLBI NIH HHS/ U01 HL089897/HL/NHLBI NIH HHS/ R01 HL130974/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Am J Respir Crit Care Med. 2022 Aug 1;206(3):337-346. doi: 10.1164/rccm.202110-2296OC.I | 04/20/2022 | |
| Chemical Modifications for a Next Generation of Nucleic Acid Aptamers | Chan KY, et al. | 2022 | Chembiochem | 23 | 15 | e202200006 | https://www.doi.org/10.1002/cbic.202200006 | 35,416,400 | Antibodies *Aptamers, Nucleotide/metabolism Ligands *Nucleic Acids SELEX Aptamer Technique/methods Selex Xna aptamers chemical modifications nucleic acids | In the past three decades, in vitro systematic evolution of ligands by exponential enrichment (SELEX) has yielded many aptamers for translational applications in both research and clinical settings. Despite their promise as an alternative to antibodies, the low success rate of SELEX ( approximately 30 %) has been a major bottleneck that hampers the further development of aptamers. One hurdle is the lack of chemical diversity in nucleic acids. To address this, the aptamer chemical repertoire has been extended by introducing exotic chemical groups, which provide novel binding functionalities. This review will focus on how modified aptamers can be selected and evolved, with illustration of some successful examples. In particular, unique chemistries are exemplified. Various strategies of incorporating modified building blocks into the standard SELEX protocol are highlighted, with a comparison of the differences between pre-SELEX and post-SELEX modifications. Nucleic acid aptamers with extended functionality evolved from non-natural chemistries will open up new vistas for function and application of nucleic acids. | Chan, Kwing Yeung Kinghorn, Andrew Brian Hollenstein, Marcel Tanner, Julian Alexander eng Research Support, Non-U.S. Gov't Review Germany Chembiochem. 2022 Aug 3;23(15):e202200006. doi: 10.1002/cbic.202200006. Epub 2022 Apr 29.I | 04/14/2022 | |
| Severe iatrogenic hypoglycaemia modulates the fibroblast growth factor protein response | Nandakumar M, et al. | 2022 | Diabetes Obes Metab | 24 | 8 | 1483-1497 | https://www.doi.org/10.1111/dom.14716 | 35,415,885 | Case-Control Studies *Diabetes Mellitus, Type 2 *Fibroblast Growth Factors/metabolism Humans *Hypoglycemia/chemically induced/complications Iatrogenic Disease fibroblast growth factors hypoglycaemia proteomics type 2 diabetes | INTRODUCTION: There is evidence that fibroblast growth factor (FGF) levels may be implicated in hypoglycaemia, with FGF19 being a potential contributor to insulin-independent pathways driving postprandial hypoglycaemia following bariatric surgery and basic FGF (FGF2) being elevated following mild hypoglycaemia occurring after the glucose tolerance test. However, their response following severe iatrogenic hypoglycaemia is unknown and therefore this pilot exploratory study was undertaken. METHODS: A case-control study of aged-matched type 2 diabetes (T2D; n = 23) and control (n = 23) subjects who underwent a hyperinsulinaemic clamp, initially to euglycaemia in T2D (5 mmol/L; 90 mg/dl), and then to hypoglycaemia (<2 mmol/L; <36 mg/dl) with subsequent follow-up time course to 24 h. FGF and FGF receptor proteins were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. RESULTS: At baseline, FGF12 (p = .006) was higher and FGF20 (p = .004) was lower in T2D versus controls. At hypoglycaemia, FGF7 was lower in T2D. Post-hypoglycaemic levels of FGF18, FGF19, FGF20 and FGF23 were lower while FGF12 and FGF16 were higher in T2D versus control at different time points. No differences between T2D and controls were seen for FGF1, FGF2, FGF4, FGF6, FGF8, FGF9, FGF10, FGF21 or any of the FGF receptors. At 24 h post-hypoglycaemia, FGF20 (p = .01) differed between controls and T2D, while the levels for the other proteins measured returned to baseline. None of the FGF proteins altered from baseline to euglycaemia when clamped in T2D subjects. FGF23 negatively correlated with fasting blood glucose, but no FGFs correlated with body mass index in T2D. CONCLUSION: Severe transient hypoglycaemia modulated FGF7, 16, 19, 20 and 23 (known to be associated with diabetes), together with FGF18 and 12, not previously reported to be associated with diabetes but that may be important in the pathophysiology of hypoglycaemia; FGF20 remained low at 24 h. Taken together, these data suggest that recurrent hypoglycaemia may contribute to the development of complications through changes in FGF proteins. | Nandakumar, Manjula Moin, Abu Saleh Md Ramanjaneya, Manjunath Qaissi, Ahmed Al Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng England Diabetes Obes Metab. 2022 Aug;24(8):1483-1497. doi: 10.1111/dom.14716. Epub 2022 May 3.I | 04/14/2022 | |
| Epidermal growth factor receptor signaling in precancerous keratinocytes promotes neighboring head and neck cancer squamous cell carcinoma cancer stem cell-like properties and phosphoinositide 3-kinase inhibitor insensitivity | Nguyen KA, et al. | 2022 | Mol Carcinog | 61 | 7 | 664-676 | https://www.doi.org/10.1002/mc.23409 | 35,417,043 | *Carcinoma, Squamous Cell/genetics Cell Line, Tumor ErbB Receptors/metabolism *Head and Neck Neoplasms/drug therapy Humans Keratinocytes/metabolism Neoplastic Stem Cells/pathology Phosphatidylinositol 3-Kinase/metabolism Phosphatidylinositol 3-Kinases/metabolism Phosphoinositide-3 Kinase Inhibitors *Precancerous Conditions Receptors, Fibroblast Growth Factor Squamous Cell Carcinoma of Head and Neck/drug therapy Tumor Microenvironment Egfr Hnscc Pi3k cancer stem cell resistance squamous cell carcinoma | Head and neck squamous cell carcinoma (HNSCC) is commonly associated with tobacco and alcohol consumption that induce a precancerous field," with phosphoinositide 3-kinase (PI3K) signaling being a common driver. However, the preclinical effectiveness of PI3K inhibitors has not necessarily translated to remarkable benefit in HNSCC patients. Thus, we sought to determine how precancerous keratinocytes influence HNSCC proliferation, cancer stem cell (CSC) maintenance, and response to PI3K inhibitors. We used the NOK keratinocyte cell line as a model of preneoplastic keratinocytes because it harbors two frequent genetic events in HNSCC, CDKN2A promoter methylation and TP53 mutation, but does not form tumors. NOK cell coculture or NOK cell-conditioned media promoted HNSCC proliferation, PI3K inhibitor resistance, and CSC phenotypes. SOMAscan-targeted proteomics determined the relative levels of >1300 analytes in the media conditioned by NOK cells and HNSCC cells +/- PI3K inhibitor. These results demonstrated that NOK cells release abundant levels of ligands that activate epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR), two receptor tyrosine kinases with oncogenic activity. Inhibition of EGFR, but not FGFR, blunted PI3K inhibitor resistance and CSC phenotypes induced by NOK cells. Our results demonstrate that precancerous keratinocytes can directly support neighboring HNSCC by activating EGFR. Importantly, PI3K inhibitor sensitivity was not necessarily a cancer cell-intrinsic property, and the tumor microenvironment impacts therapeutic response and supports CSCs. Additionally, combined inhibition of EGFR with PI3K inhibitor diminished EGFR activation induced by PI3K inhibitor and potently inhibited cancer cell proliferation and CSC maintenance." | Nguyen, Khoa A Keith, Madison J Keysar, Stephen B Hall, Spencer C Bimali, Anamol Jimeno, Antonio Wang, Xiao-Jing Young, Christian D eng P50 CA261605/CA/NCI NIH HHS/ R01 DE024371/DE/NIDCR NIH HHS/ I01 BX003232/BX/BLRD VA/ IK6 BX005962/BX/BLRD VA/ P30 CA046934/CA/NCI NIH HHS/ R01 DE028420/DE/NIDCR NIH HHS/ R01 DE027329/DE/NIDCR NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Mol Carcinog. 2022 Jul;61(7):664-676. doi: 10.1002/mc.23409. Epub 2022 Apr 13.I | 04/14/2022 | |
| Ad26.COV2.S prevents upregulation of SARS-CoV-2 induced pathways of inflammation and thrombosis in hamsters and rhesus macaques | Aid M, et al. | 2022 | PLoS Pathog | 18 | 4 | e1009990 | https://www.doi.org/10.1371/journal.ppat.1009990 | 35,395,058 | Ad26COVS1 Animals Antibodies, Neutralizing *covid-19 COVID-19 Vaccines Cricetinae Humans Inflammation Macaca mulatta SARS-CoV-2 Spike Glycoprotein, Coronavirus *Thrombosis Up-Regulation | Syrian golden hamsters exhibit features of severe disease after SARS-CoV-2 WA1/2020 challenge and are therefore useful models of COVID-19 pathogenesis and prevention with vaccines. Recent studies have shown that SARS-CoV-2 infection stimulates type I interferon, myeloid, and inflammatory signatures similar to human disease and that weight loss can be prevented with vaccines. However, the impact of vaccination on transcriptional programs associated with COVID-19 pathogenesis and protective adaptive immune responses is unknown. Here we show that SARS-CoV-2 WA1/2020 challenge in hamsters stimulates myeloid and inflammatory programs as well as signatures of complement and thrombosis associated with human COVID-19. Notably, immunization with Ad26.COV2.S, an adenovirus serotype 26 vector (Ad26)-based vaccine expressing a stabilized SARS-CoV-2 spike protein, prevents the upregulation of these pathways, such that the mRNA expression profiles of vaccinated hamsters are comparable to uninfected animals. Using proteomics profiling, we validated these findings in rhesus macaques challenged with SARS-CoV-2 WA1/2020 or SARS-CoV-2 B.1.351. Finally, we show that Ad26.COV2.S vaccination induces T and B cell signatures that correlate with binding and neutralizing antibody responses weeks following vaccination. These data provide insights into the molecular mechanisms of Ad26.COV2.S protection against severe COVID-19 in animal models. | Aid, Malika Vidal, Samuel J Piedra-Mora, Cesar Ducat, Sarah Chan, Chi N Bondoc, Stephen Colarusso, Alessandro Starke, Carly E Nekorchuk, Michael Busman-Sahay, Kathleen Estes, Jacob D Martinot, Amanda J Barouch, Dan H eng P51 OD011092/OD/NIH HHS/ Research Support, Non-U.S. Gov't PLoS Pathog. 2022 Apr 8;18(4):e1009990. doi: 10.1371/journal.ppat.1009990. eCollection 2022 Apr.I | 04/09/2022 | |
| Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension | Harbaum L, et al. | 2022 | Am J Respir Crit Care Med | 205 | 12 | 1449-1460 | https://www.doi.org/10.1164/rccm.202109-2106OC | 35,394,406 | Blood Proteins/genetics Familial Primary Pulmonary Hypertension Humans *Hypertension, Pulmonary Netrins Pathology, Molecular Proteome *Pulmonary Arterial Hypertension Thrombospondins Mendelian randomization case-control studies genome protein quantitative trait loci | Rationale: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation of circulating proteins. Objectives: To quantify and analyze the plasma proteome of patients with PAH using inherited genetic variation to inform on underlying molecular drivers. Methods: An aptamer-based assay was used to measure plasma proteins in 357 patients with idiopathic or heritable PAH, 103 healthy volunteers, and 23 relatives of patients with PAH. In discovery and replication subgroups, the plasma proteomes of PAH and healthy individuals were compared, and the relationship to transplantation-free survival in PAH was determined. To examine causal relationships to PAH, protein quantitative trait loci (pQTL) that influenced protein levels in the patient population were used as instruments for Mendelian randomization (MR) analysis. Measurements and Main Results: From 4,152 annotated plasma proteins, levels of 208 differed between patients with PAH and healthy subjects, and 49 predicted long-term survival. MR based on cis-pQTL located in proximity to the encoding gene for proteins that were prognostic and distinguished PAH from health estimated an adverse effect for higher levels of netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.08) and a protective effect for higher levels of thrombospondin-2 (OR, 0.83; 95% CI, 0.74-0.94) on PAH. Both proteins tracked the development of PAH in previously healthy relatives and changes in thrombospondin-2 associated with pulmonary arterial pressure at disease onset. Conclusions: Integrated analysis of the plasma proteome and genome implicates two secreted matrix-binding proteins, netrin-4 and thrombospondin-2, in the pathobiology of PAH. | Harbaum, Lars Rhodes, Christopher J Wharton, John Lawrie, Allan Karnes, Jason H Desai, Ankit A Nichols, William C Humbert, Marc Montani, David Girerd, Barbara Sitbon, Olivier Boehm, Mario Novoyatleva, Tatyana Schermuly, Ralph T Ghofrani, H Ardeschir Toshner, Mark Kiely, David G Howard, Luke S Swietlik, Emilia M Graf, Stefan Pietzner, Maik Morrell, Nicholas W Wilkins, Martin R eng R01HL158686/NIH/NHLBI/ R01 HL156993/HL/NHLBI NIH HHS/ FS/13/48/30453/BHF_/British Heart Foundation/United Kingdom FS/15/59/31839/BHF_/British Heart Foundation/United Kingdom R24 HL105333/HL/NHLBI NIH HHS/ SP/12/12/29836/BHF_/British Heart Foundation/United Kingdom K01HL143137/NIH/NHLBI/ R01 HL158686/HL/NHLBI NIH HHS/ RE/18/4/34215/BHF_/British Heart Foundation/United Kingdom R01 HL136603/HL/NHLBI NIH HHS/ MR/K020919/1/MRC_/Medical Research Council/United Kingdom DH_/Department of Health/United Kingdom FS/18/52/33808/BHF_/British Heart Foundation/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Respir Crit Care Med. 2022 Jun 15;205(12):1449-1460. doi: 10.1164/rccm.202109-2106OC.I | 04/09/2022 | |
| Patterns and Persistence of Perioperative Plasma and Cerebrospinal Fluid Neuroinflammatory Protein Biomarkers After Elective Orthopedic Surgery Using SOMAscan | Dillon ST, et al. | 2022 | Anesth Analg | epub ahead of print | https://www.doi.org/10.1213/ANE.0000000000005991 | 35,389,379 | BACKGROUND: The neuroinflammatory response to surgery can be characterized by peripheral acute plasma protein changes in blood, but corresponding, persisting alterations in cerebrospinal fluid (CSF) proteins remain mostly unknown. Using the SOMAscan assay, we define acute and longer-term proteome changes associated with surgery in plasma and CSF. We hypothesized that biological pathways identified by these proteins would be in the categories of neuroinflammation and neuronal function and define neuroinflammatory proteome changes associated with surgery in older patients. METHODS: SOMAscan analyzed 1305 proteins in blood plasma (n = 14) and CSF (n = 15) samples from older patients enrolled in the Role of Inflammation after Surgery for Elders (RISE) study undergoing elective hip and knee replacement surgery with spinal anesthesia. Systems biology analysis identified biological pathways enriched among the surgery-associated differentially expressed proteins in plasma and CSF. RESULTS: Comparison of postoperative day 1 (POD1) to preoperative (PREOP) plasma protein levels identified 343 proteins with postsurgical changes (P < .05; absolute value of the fold change [|FC|] > 1.2). Comparing postoperative 1-month (PO1MO) plasma and CSF with PREOP identified 67 proteins in plasma and 79 proteins in CSF with altered levels (P < .05; |FC| > 1.2). In plasma, 21 proteins, primarily linked to immune response and inflammation, were similarly changed at POD1 and PO1MO. Comparison of plasma to CSF at PO1MO identified 8 shared proteins. Comparison of plasma at POD1 to CSF at PO1MO identified a larger number, 15 proteins in common, most of which are regulated by interleukin-6 (IL-6) or transforming growth factor beta-1 (TGFB1) and linked to the inflammatory response. Of the 79 CSF PO1MO-specific proteins, many are involved in neuronal function and neuroinflammation. CONCLUSIONS: SOMAscan can characterize both short- and long-term surgery-induced protein alterations in plasma and CSF. Acute plasma protein changes at POD1 parallel changes in PO1MO CSF and suggest 15 potential biomarkers for longer-term neuroinflammation that warrant further investigation. | Dillon, Simon T Otu, Hasan H Ngo, Long H Fong, Tamara G Vasunilashorn, Sarinnapha M Xie, Zhongcong Kunze, Lisa J Vlassakov, Kamen V Abdeen, Ayesha Lange, Jeffrey K Earp, Brandon E Cooper, Zara R Schmitt, Eva M Arnold, Steven E Hshieh, Tammy T Jones, Richard N Inouye, Sharon K Marcantonio, Edward R Libermann, Towia A eng R01 AG051658/AG/NIA NIH HHS/ R03 AG061582/AG/NIA NIH HHS/ K24 AG035075/AG/NIA NIH HHS/ K01 AG057836/AG/NIA NIH HHS/ P01 AG031720/AG/NIA NIH HHS/ R21 AG057955/AG/NIA NIH HHS/ R24 AG054259/AG/NIA NIH HHS/ Anesth Analg. 2022 Apr 7:10.1213/ANE.0000000000005991. doi: 10.1213/ANE.0000000000005991.I | 04/08/2022 | ||||
| A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk | Williams SA, et al. | 2022 | Sci Transl Med | 14 | 639 | eabj9625 | https://www.doi.org/10.1126/scitranslmed.abj9625 | 35,385,337 | Biomarkers *Cardiovascular Diseases *Heart Failure/drug therapy Humans *Myocardial Infarction/drug therapy Proteomics *Stroke/complications | A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c-statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a universal" surrogate end point for cardiovascular risk." | Williams, Stephen A Ostroff, Rachel Hinterberg, Michael A Coresh, Josef Ballantyne, Christie M Matsushita, Kunihiro Mueller, Christian E Walter, Joan Jonasson, Christian Holman, Rury R Shah, Svati H Sattar, Naveed Taylor, Roy Lean, Michael E Kato, Shintaro Shimokawa, Hiroaki Sakata, Yasuhiko Nochioka, Kotaro Parikh, Chirag R Coca, Steven G Omland, Torbjorn Chadwick, Jessica Astling, David Hagar, Yolanda Kureshi, Natasha Loupy, Kelsey Paterson, Clare Primus, Jeremy Simpson, Missy Trujillo, Nelson P Ganz, Peter eng R01 HL134320/HL/NHLBI NIH HHS/ HHSN268201700001I/HL/NHLBI NIH HHS/ HHSN268201700002I/HL/NHLBI NIH HHS/ HHSN268201700003I/HL/NHLBI NIH HHS/ HHSN268201700004I/HL/NHLBI NIH HHS/ HHSN268201700005I/HL/NHLBI NIH HHS/ R01 HL087641/HL/NHLBI NIH HHS/ R01 HL086694/HL/NHLBI NIH HHS/ U01 HG004402/HG/NHGRI NIH HHS/ R01 HL085757/HL/NHLBI NIH HHS/ U01 DK106962/DK/NIDDK NIH HHS/ R01 HL129856/HL/NHLBI NIH HHS/ U01 DK108809/DK/NIDDK NIH HHS/ R01 AG052964/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Sci Transl Med. 2022 Apr 6;14(639):eabj9625. doi: 10.1126/scitranslmed.abj9625. Epub 2022 Apr 6.I | 04/07/2022 | |
| Diagnostic Accuracy of Blood-Based Biomarker Panels: A Systematic Review | Hardy-Sosa A, et al. | 2022 | Front Aging Neurosci | 14 | 683689 | https://www.doi.org/10.3389/fnagi.2022.683689 | 35,360,215 | Alzheimer's disease (AD) biomarker panel blood-based biomarker diagnosis preclinical AD commercial or financial relationships that could be construed as a potential conflict of interest. | BACKGROUND: Because of high prevalence of Alzheimer's disease (AD) in low- and middle-income countries (LMICs), there is an urgent need for inexpensive and minimally invasive diagnostic tests to detect biomarkers in the earliest and asymptomatic stages of the disease. Blood-based biomarkers are predicted to have the most impact for use as a screening tool and predict the onset of AD, especially in LMICs. Furthermore, it has been suggested that panels of markers may perform better than single protein candidates. METHODS: Medline/Pubmed was searched to identify current relevant studies published from January 2016 to December 2020. We included all full-text articles examining blood-based biomarkers as a set of protein markers or panels to aid in AD's early diagnosis, prognosis, and characterization. RESULTS: Seventy-six articles met the inclusion criteria for systematic review. Majority of the studies reported plasma and serum as the main source for biomarker determination in blood. Protein-based biomarker panels were reported to aid in AD diagnosis and prognosis with better accuracy than individual biomarkers. Conventional (amyloid-beta and tau) and neuroinflammatory biomarkers, such as amyloid beta-42, amyloid beta-40, total tau, phosphorylated tau-181, and other tau isoforms, were the most represented. We found the combination of amyloid beta-42/amyloid beta-40 ratio and APOEepsilon4 status to be most represented with high accuracy for predicting amyloid beta-positron emission tomography status. CONCLUSION: Assessment of Alzheimer's disease biomarkers in blood as a non-invasive and cost-effective alternative will potentially contribute to early diagnosis and improvement of therapeutic interventions. Given the heterogeneous nature of AD, combination of markers seems to perform better in the diagnosis and prognosis of the disease than individual biomarkers. | Hardy-Sosa, Anette Leon-Arcia, Karen Llibre-Guerra, Jorge J Berlanga-Acosta, Jorge Baez, Saiyet de la C Guillen-Nieto, Gerardo Valdes-Sosa, Pedro A eng Switzerland Front Aging Neurosci. 2022 Mar 11;14:683689. doi: 10.3389/fnagi.2022.683689. eCollection 2022.I | 04/02/2022 | ||
| Acceptability and experience of a personalised proteomic risk intervention for type 2 diabetes in primary care: qualitative interview study with patients and healthcare providers | Honey S, et al. | 2022 | Prim Health Care Res Dev | 23 | e24 | https://www.doi.org/10.1017/S1463423621000591 | 35,361,303 | *Diabetes Mellitus, Type 2/prevention & control Health Personnel Humans Primary Health Care Proteomics Qualitative Research behaviour change pre-diabetes proteomic risk assessment type 2 diabetes | AIM: We explored the acceptability of a personalised proteomic risk intervention for patients at increased risk of type 2 diabetes and their healthcare providers, as well as their experience of participating in the delivery of proteomic-based risk feedback in UK primary care. BACKGROUND: Advances in proteomics now allow the provision of personalised proteomic risk reports, with the intention of achieving positive behaviour change. This technology has the potential to encourage behaviour change in people at risk of developing type 2 diabetes. METHODS: A semi-structured interview study was carried out with patients at risk of type 2 diabetes and their healthcare providers in primary care in the North of England. Participants (n = 17) and healthcare provider (n = 4) were interviewed either face to face or via telephone. Data were analysed using thematic analysis. This qualitative study was nested within a single-arm pilot trial and undertaken in primary care. FINDINGS: The personalised proteomic risk intervention was generally acceptable and the experience was positive. The personalised nature of the report was welcomed, especially the way it provided a holistic approach to risks of organ damage and lifestyle factors. Insights were provided as to how this may change behaviour. Some participants reported difficulties in understanding the format of the presentation of risk and expressed surprise at receiving risk estimates for conditions other than type 2 diabetes. Personalised proteomic risk interventions have the potential to provide holistic and comprehensive assessments of risk factors and lifestyle factors which may lead to positive behaviour change. | Honey, Stephanie Neal, Richard D Messenger, Michael Smith, Samuel G eng DH_/Department of Health/United Kingdom Research Support, Non-U.S. Gov't England Prim Health Care Res Dev. 2022 Apr 1;23:e24. doi: 10.1017/S1463423621000591.I | 04/02/2022 | ||
| Translation of aptamers toward clinical diagnosis and commercialization | Liu S, et al. | 2022 | Biosens Bioelectron | 208 | 114168 | https://www.doi.org/10.1016/j.bios.2022.114168 | 35,364,525 | *Aptamers, Nucleotide *Biosensing Techniques Point-of-Care Testing SELEX Aptamer Technique Aptamer Aptasensor Clinical diagnostic Point-of-care test Translation | The dominance of antibodies in diagnostics has gradually changed following the discovery of aptamers in the early 1990s. Aptamers offer inherent advantages over traditional antibodies, including higher specificity, higher affinity, smaller size, greater stability, ease of manufacture, and low immunogenicity, rendering them the best candidates for point-of-care testing (POCT). In the past 20 years, the research community and pharmaceutical companies have made great efforts to promote the development of aptamer technology. Macugen(R) (pegaptanib) was the first aptamer drug approved by the US Food and Drug Administration (FDA), and various aptamer-based diagnostics show great promise in preclinical research and clinical trials. In this review, we introduce recent literature, ongoing clinical trials, commercial reagents of aptamer-based diagnostics, discuss the FDA regulatory mechanisms, and highlight the prospects and challenges in translating these studies into viable clinical diagnostic tools. | Liu, Shan Xu, Yixin Jiang, Xin Tan, Hong Ying, Binwu eng Review England Biosens Bioelectron. 2022 Jul 15;208:114168. doi: 10.1016/j.bios.2022.114168. Epub 2022 Mar 16.I | 04/02/2022 | ||
| Plasma Growth and Differentiation Factor 15 Predict Longitudinal Changes in Bone Parameters in Women, but Not in Men | Osawa Y, et al. | 2022 | J Gerontol A Biol Sci Med Sci | 77 | 10 | 1951-1958 | https://www.doi.org/10.1093/gerona/glac079 | 35,363,860 | Aged Aged, 80 and over Bone Density/physiology *Bone Diseases, Metabolic *Calcium Female Growth Differentiation Factor 15 Humans Male Parathyroid Hormone Radius/physiology Tibia/diagnostic imaging/physiology Cortical bone Growth/differentiation factor 15 Osteopenia Sex difference Trabecular bone | Bone fragility can progress with aging, but biomarkers to detect emerging osteopenia have not been fully elucidated. Growth/differentiation factor 15 (GDF-15) has pleiotropic roles in a broad range of age-related conditions, but its association with osteopenia is unknown. We examined the relationship between plasma GDF-15 levels and rate of change in bone parameters over 9 years of follow-up in 596 adults in the InCHIANTI study (baseline age, 65-94 years; women, 52.4%; mean follow-up, 7.0 +/- 3.0 years). Plasma GDF-15 concentrations were measured using the 1.3k HTS SOMAscan assay. Eight bone parameters were measured in the right tibia by peripheral quantitative computed tomography; total bone density, trabecular bone density, medullary plus trabecular bone density, cortical bone density, total bone area, cortical bone area, medullary bone area, and minimum moment of inertia (mMOI). We ran sex-specific linear mixed-effect models with random intercepts and slopes adjusted for age, age-squared, education, body mass index, the rate of change in weight, smoking, sedentary behavior, cross-sectional areas of calf muscles and fat, 25-hydroxyvitamin D, parathyroid hormone, calcium, diabetes mellitus, and follow-up time. We found a significant association of baseline GDF-15 x time" in models predicting cortical bone density and the mMOI in women, suggesting that the rates of decline in these bone parameters increased with higher GDF-15 (false discovery rate <0.05). Higher plasma levels GDF-15 predicted an accelerated decline in bone parameters in women, but was less associated in men. Furthermore studies are needed to understand the mechanisms underlying these sex differences." | Osawa, Yusuke Tanaka, Toshiko Semba, Richard D Fantoni, Giovanna Moaddel, Ruin Candia, Julian Simonsick, Eleanor M Bandinelli, Stefania Ferrucci, Luigi eng R21 HL112662/HL/NHLBI NIH HHS/ R01 MD009164/MD/NIMHD NIH HHS/ 21K10505/JSPS/ 263MD9164/AG/NIA NIH HHS/ R01 AG027012/AG/NIA NIH HHS/ R01 AG057723/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't J Gerontol A Biol Sci Med Sci. 2022 Oct 6;77(10):1951-1958. doi: 10.1093/gerona/glac079.I | 04/02/2022 | |
| A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome | Skuladottir AT, et al. | 2022 | Nat Commun | 13 | 1 | 1598 | https://www.doi.org/10.1038/s41467-022-29133-7 | 35,332,129 | Anthropometry *Carpal Tunnel Syndrome/genetics Genetic Loci Genome-Wide Association Study Humans Phenotype | Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 x 10(-24), OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in bilateral/recurrent/persistent cases than nonrecurrent/nonpersistent cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS. | Skuladottir, Astros Th Bjornsdottir, Gyda Ferkingstad, Egil Einarsson, Gudmundur Stefansdottir, Lilja Nawaz, Muhammad Sulaman Oddsson, Asmundur Olafsdottir, Thorunn A Saevarsdottir, Saedis Walters, G Bragi Magnusson, Sigurdur H Bjornsdottir, Anna Sveinsson, Olafur A Vikingsson, Arnor Hansen, Thomas Folkmann Jacobsen, Rikke Louise Erikstrup, Christian Schwinn, Michael Brunak, Soren Banasik, Karina Ostrowski, Sisse Rye Troelsen, Anders Henkel, Cecilie Pedersen, Ole Birger Jonsdottir, Ingileif Gudbjartsson, Daniel F Sulem, Patrick Thorgeirsson, Thorgeir E Stefansson, Hreinn Stefansson, Kari eng Meta-Analysis Research Support, Non-U.S. Gov't England Nat Commun. 2022 Mar 24;13(1):1598. doi: 10.1038/s41467-022-29133-7.I | 03/26/2022 | |
| Proteomic Studies of Psoriasis | Sobolev VV, et al. | 2022 | Biomedicines | 10 | 3 | https://www.doi.org/10.3390/biomedicines10030619 | 35,327,421 | Lc-ms/ms SOMAscan biomarkers comorbidities mass spectrometry predisposition proximity extension assay psoriasis risk factors | In this review paper, we discuss the contribution of proteomic studies to the discovery of disease-specific biomarkers to monitor the disease and evaluate available treatment options for psoriasis. Psoriasis is one of the most prevalent skin disorders driven by a Th17-specific immune response. Although potential patients have a genetic predisposition to psoriasis, the etiology of the disease remains unknown. During the last two decades, proteomics became deeply integrated with psoriatic research. The data obtained in proteomic studies facilitated the discovery of novel mechanisms and the verification of many experimental hypotheses of the disease pathogenesis. The detailed data analysis revealed multiple differentially expressed proteins and significant changes in proteome associated with the disease and drug efficacy. In this respect, there is a need for proteomic studies to characterize the role of the disease-specific biomarkers in the pathogenesis of psoriasis, develop clinical applications to choose the most efficient treatment options and monitor the therapeutic response. | Sobolev, Vladimir V Soboleva, Anna G Denisova, Elena V Pechatnikova, Eva A Dvoryankova, Eugenia Korsunskaya, Irina M Mezentsev, Alexandre eng Review Switzerland Biomedicines. 2022 Mar 7;10(3):619. doi: 10.3390/biomedicines10030619.I | 03/26/2022 | ||
| Diagnostic and Prognostic Protein Biomarkers of beta-Cell Function in Type 2 Diabetes and Their Modulation with Glucose Normalization | Moin ASM, et al. | 2022 | Metabolites | 12 | 3 | https://www.doi.org/10.3390/metabo12030196 | 35,323,639 | biomarkers diagnostic euglycemia glucose variability prognostic type 2 diabetes | Development of type-2 diabetes(T2D) is preceded by beta-cell dysfunction and loss. However, accurate measurement of beta-cell function remains elusive. Biomarkers have been reported to predict beta-cell functional decline but require validation. Therefore, we determined whether reported protein biomarkers could distinguish patients with T2D (onset < 10-years) from controls. A prospective, parallel study in T2D (n = 23) and controls (n = 23) was undertaken. In T2D subjects, insulin-induced blood glucose normalization from baseline 7.6 +/- 0.4 mmol/L (136.8 +/- 7.2 mg/dL) to 4.5 +/- 0.07 mmol/L (81 +/- 1.2 mg/dL) was maintained for 1-h. Controls were maintained at 4.9 +/- 0.1 mmol/L (88.2 +/- 1.8 mg/dL). Slow Off-rate Modified Aptamer (SOMA) -scan plasma protein measurement determined a 43-protein panel reported as diagnostic and/or prognostic for T2D. At baseline, 9 proteins were altered in T2D. Three of 13 prognostic/diagnostic proteins were lower in T2D: Adiponectin (p < 0.0001), Endocan (p < 0.05) and Mast/stem cell growth factor receptor-Kit (KIT) (p < 0.01). Two of 14 prognostic proteins [Cathepsin-D (p < 0.05) and Cadherin-E (p < 0.005)], and four of 16 diagnostic proteins [Kallikrein-4 (p = 0.001), Aminoacylase-1 (p = 0.001), Insulin-like growth factor-binding protein-4 (IGFBP4) (p < 0.05) and Reticulon-4 receptor (RTN4R) (p < 0.001)] were higher in T2D. Protein levels were unchanged following glucose normalization in T2D. Our results suggest that a focused biomarker panel may be useful for assessing beta-cell dysfunction and may complement clinical decision-making on insulin therapy. Unchanged post-glucose normalization levels indicate these are not acute-phase proteins or affected by glucose variability. | Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Switzerland Metabolites. 2022 Feb 22;12(3):196. doi: 10.3390/metabo12030196.I | 03/25/2022 | ||
| Proteins and pathways in atrial fibrillation and atrial cardiomyopathy underlying cryptogenic stroke | Pala E, et al. | 2022 | Int J Cardiol Heart Vasc | 39 | 100977 | https://www.doi.org/10.1016/j.ijcha.2022.100977 | 35,281,755 | Atrial cardiomyopathy Atrial fibrillation Atrial function Biomarkers Cryptogenic stroke personal relationships that could have appeared to influence the work reported in this paper. | BACKGROUND: Atrial fibrillation (AF) is one of the most prevalent causes of cryptogenic stroke. Also, apart from AF itself, structural and remodelling changes in the atria might be an underlying cause of cryptogenic stroke. We aimed to discover circulating proteins and reveal pathways altered in AF and atrial cardiomyopathy, measured by left atrial volume index (LAVI) and peak atrial longitudinal strain (PALS), in patients with cryptogenic stroke. METHODS: An aptamer array (including 1310 proteins) was measured in the blood of 20 cryptogenic stroke patients monitored during 28 days with a Holter device as a case-control study of the Crypto-AF cohort. Protein levels were compared between patients with (n = 10) and without AF (n = 10) after stroke, and the best candidates were tested in 111 patients from the same cohort (44 patients with AF and 67 without AF). In addition, in the first 20 patients, proteins were explored according to PALS and LAVI values. RESULTS: Forty-six proteins were differentially expressed in AF cases. Of those, four proteins were tested in a larger sample size. Only DPP7, presenting lower levels in AF patients, was further validated. Fifty-seven proteins correlated with LAVI, and 270 correlated with PALS. NT-proBNP was common in all the discovery analyses performed. Interestingly, many proteins and pathways were altered in patients with low PALS. CONCLUSIONS: Multiple proteins and pathways related to AF and atrial cardiomyopathy have been revealed. The role of DPP7 as a biomarker for stroke aetiology should be further explored. Moreover, the present study may be considered hypothesis-generating. | Pala, Elena Pagola, Jorge Juega, Jesus Francisco-Pascual, Jaume Penalba, Anna Rodriguez, Maite De Lera Alfonso, Mercedes Arenillas, Juan F Cabezas, Juan Antonio Moniche, Francisco de Torres, Reyes Perez-Sanchez, Soledad Gonzalez-Alujas, Teresa Molina, Carlos A Bustamante, Alejandro Montaner, Joan eng Ireland Int J Cardiol Heart Vasc. 2022 Mar 7;39:100977. doi: 10.1016/j.ijcha.2022.100977. eCollection 2022 Apr.I | 03/15/2022 | ||
| Diabetes, GDF-15 and incident heart failure: the atherosclerosis risk in communities study | Echouffo-Tcheugui JB, et al. | 2022 | Diabetologia | 65 | 6 | 955-963 | https://www.doi.org/10.1007/s00125-022-05678-6 | 35,275,240 | Adult *Atherosclerosis/epidemiology Biomarkers *Diabetes Mellitus/epidemiology Female Growth Differentiation Factor 15 *Heart Failure/epidemiology/etiology Humans Male Middle Aged Risk Factors Growth differentiation factor-15 Heart failure Prediction Type 2 diabetes | AIMS/HYPOTHESIS: Elevated circulating growth differentiation factor-15 (GDF-15), a marker of cellular stress, is associated with both heart failure (HF) and diabetes. However, it is unclear to what extent GDF-15 is associated with HF among individuals with and without diabetes. METHODS: We evaluated 10,570 participants free of HF at Visit 3 (1993-1995) of the Atherosclerosis Risk in Communities study. We used Cox regression to evaluate the joint associations of GDF-15 and diabetes with incident HF. Models were adjusted for traditional cardiovascular risk factors. RESULTS: Among a total of 10,570 individuals (mean age of 60.0 years, 54% women, 27% black adults), elevated GDF-15 (>/=75th percentile) was more common in people with diabetes compared with those without diabetes (32.8% vs 23.6%, p<0.0001). During 23 years of follow-up, there were 2429 incident HF events. GDF-15 (in quartiles) was independently associated with HF among those with and without diabetes, with a stronger association among individuals with diabetes (p-for-diabetes-GDF-15 interaction = 0.034): HR for highest vs lowest GDF-15 quartile (reference): 1.64 (95% CI 1.41, 1.91) among those without diabetes and 1.72 (95% CI 1.32, 2.23) among those with diabetes. Individuals with diabetes and elevated GDF-15 had the highest risk of incident HF (HR 2.46; 95% CI 1.99, 3.03). After accounting for HF risk factors, GDF-15 provided additional prognostic information among participants with diabetes (DeltaC statistic for model with vs model without GDF-15: +0.008, p = 0.001) and among those without diabetes (+0.006, p<0.0001). CONCLUSIONS/INTERPRETATION: In a community-based sample of US adults, GDF-15 provided complementary prognostic information on the HF risk, especially among individuals with diabetes. | Echouffo-Tcheugui, Justin B Daya, Natalie Ndumele, Chiadi E Matsushita, Kunihiro Hoogeveen, Ron C Ballantyne, Christie M Coresh, Josef Shah, Amil M Selvin, Elizabeth eng R01 DK089174/DK/NIDDK NIH HHS/ R01 HL143224/HL/NHLBI NIH HHS/ K24 HL152008/HL/NHLBI NIH HHS/ R01 HL150342/HL/NHLBI NIH HHS/ 75N92022D00003/HL/NHLBI NIH HHS/ 75N92022D00005/HL/NHLBI NIH HHS/ R01 HL148218/HL/NHLBI NIH HHS/ K23 HL153774/HL/NHLBI NIH HHS/ 75N92022D00001/HL/NHLBI NIH HHS/ 75N92022D00002/HL/NHLBI NIH HHS/ K24 HL152440/HL/NHLBI NIH HHS/ R01 HL135008/HL/NHLBI NIH HHS/ 75N92022D00004/HL/NHLBI NIH HHS/ R01 HL146907/HL/NHLBI NIH HHS/ R01 HL134320/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Germany Diabetologia. 2022 Jun;65(6):955-963. doi: 10.1007/s00125-022-05678-6. Epub 2022 Mar 11.I | 03/12/2022 | |
| Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus | Stacey D, et al. | 2022 | Nat Commun | 13 | 1 | 1222 | https://www.doi.org/10.1038/s41467-022-28729-3 | 35,264,566 | Antigens, CD/genetics Crosses, Genetic Endothelial Cells/metabolism Endothelial Protein C Receptor/genetics Humans Protein C/metabolism Receptors, Cell Surface/genetics *Thrombosis/genetics *Venous Thromboembolism/genetics | Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte-endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations. | Stacey, David Chen, Lingyan Stanczyk, Paulina J Howson, Joanna M M Mason, Amy M Burgess, Stephen MacDonald, Stephen Langdown, Jonathan McKinney, Harriett Downes, Kate Farahi, Neda Peters, James E Basu, Saonli Pankow, James S Tang, Weihong Pankratz, Nathan Sabater-Lleal, Maria de Vries, Paul S Smith, Nicholas L Gelinas, Amy D Schneider, Daniel J Janjic, Nebojsa Samani, Nilesh J Ye, Shu Summers, Charlotte Chilvers, Edwin R Danesh, John Paul, Dirk S eng MR/L003120/1/MRC_/Medical Research Council/United Kingdom BRC-1215-20014/DH_/Department of Health/United Kingdom MR/P502091/1/MRC_/Medical Research Council/United Kingdom UL1 RR025005/RR/NCRR NIH HHS/ NIHR133788/DH_/Department of Health/United Kingdom R01 HL059367/HL/NHLBI NIH HHS/ R01 HL086694/HL/NHLBI NIH HHS/ RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom R01 HL105756/HL/NHLBI NIH HHS/ RG/19/9/34655/BHF_/British Heart Foundation/United Kingdom HHSN268201700002C/HL/NHLBI NIH HHS/ HHSN268201700001I/HL/NHLBI NIH HHS/ HHSN268201700004I/HL/NHLBI NIH HHS/ RG/16/4/32218/BHF_/British Heart Foundation/United Kingdom R01 HL134894/HL/NHLBI NIH HHS/ MR/S004068/2/MRC_/Medical Research Council/United Kingdom RE/13/6/30180/BHF_/British Heart Foundation/United Kingdom U01 HG004402/HG/NHGRI NIH HHS/ HHSN268201700005C/HL/NHLBI NIH HHS/ HHSN268201700001C/HL/NHLBI NIH HHS/ HHSN268201700003C/HL/NHLBI NIH HHS/ HHSN268201700004C/HL/NHLBI NIH HHS/ WT_/Wellcome Trust/United Kingdom HHSN268201700002I/HL/NHLBI NIH HHS/ HHSN268201700005I/HL/NHLBI NIH HHS/ CSO_/Chief Scientist Office/United Kingdom R01 HL087641/HL/NHLBI NIH HHS/ HHSN268201700003I/HL/NHLBI NIH HHS/ RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom SP/19/2/344612/BHF_/British Heart Foundation/United Kingdom England Nat Commun. 2022 Mar 9;13(1):1222. doi: 10.1038/s41467-022-28729-3.I | 03/11/2022 | |
| Proteome-Wide Analysis Using SOMAscan Identifies and Validates Chitinase-3-Like Protein 1 as a Risk and Disease Marker of Delirium Among Older Adults Undergoing Major Elective Surgery | Vasunilashorn SM, et al. | 2022 | J Gerontol A Biol Sci Med Sci | 77 | 3 | 484-493 | https://www.doi.org/10.1093/gerona/glaa326 | 35,239,952 | Aged Biomarkers Case-Control Studies *Chitinase-3-Like Protein 1/genetics *Delirium/diagnosis/etiology Elective Surgical Procedures Humans Interleukin-6 *Postoperative Cognitive Complications/diagnosis/genetics Proteome Inflammation Postoperative Proteomics | BACKGROUND: Delirium (an acute change in cognition) is a common, morbid, and costly syndrome seen primarily in aging adults. Despite increasing knowledge of its epidemiology, delirium remains a clinical diagnosis with no established biomarkers to guide diagnosis or management. Advances in proteomics now provide opportunities to identify novel markers of risk and disease progression for postoperative delirium and its associated long-term consequences (eg, long-term cognitive decline and Alzheimer's disease [AD]). METHODS: In a nested matched case-control study (18 delirium/no-delirium pairs) within the Successful Aging after Elective Surgery study (N = 556), we evaluated the association of 1305 plasma proteins preoperatively [PREOP] and on postoperative day 2 [POD2]) with delirium using SOMAscan. Generalized linear models were applied to enzyme-linked immunosorbant assay (ELISA) validation data of one protein across the full cohort. Multi-protein modeling included delirium biomarkers identified in prior work (C-reactive protein, interleukin-6 [IL6]). RESULTS: We identified chitinase-3-like-protein-1 (CHI3L1/YKL-40) as the sole delirium-associated protein in both a PREOP and a POD2 predictor model, a finding confirmed by ELISA. Multi-protein modeling found high PREOP CHI3L1/YKL-40 and POD2 IL6 increased the risk of delirium (relative risk [95% confidence interval] Quartile [Q]4 vs Q1: 2.4[1.2-5.0] and 2.1[1.1-4.1], respectively). CONCLUSIONS: Our identification of CHI3L1/YKL-40 in postoperative delirium parallels reports of CHI3L1/YKL-40 and its association with aging, mortality, and age-related conditions including AD onset and progression. This highlights the type 2 innate immune response, involving CHI3L1/YKL-40, as an underlying mechanism of postoperative delirium, a common, morbid, and costly syndrome that threatens the independence of older adults. | Vasunilashorn, Sarinnapha M Dillon, Simon T Chan, Noel Y Fong, Tamara G Joseph, Marie Tripp, Bridget Xie, Zhongcong Ngo, Long H Lee, Chun Geun Elias, Jack A Otu, Hasan H Inouye, Sharon K Marcantonio, Edward R Libermann, Towia A eng R01 AG051658/AG/NIA NIH HHS/ R01 AG041274/AG/NIA NIH HHS/ K24 AG035075/AG/NIA NIH HHS/ K01 AG057836/AG/NIA NIH HHS/ R21 AG057955/AG/NIA NIH HHS/ R21 AG048600/AG/NIA NIH HHS/ R03 AG061582/AG/NIA NIH HHS/ ALZ/Alzheimer's Association/ R01AG051658/AG/NIA NIH HHS/ R24 AG054259/AG/NIA NIH HHS/ P01 AG031720/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Gerontol A Biol Sci Med Sci. 2022 Mar 3;77(3):484-493. doi: 10.1093/gerona/glaa326.I | 03/04/2022 | |
| Connecting Genomics and Proteomics to Identify Protein Biomarkers for Adult and Youth-Onset Type 2 Diabetes: A Two-Sample Mendelian Randomization Study | Ghanbari F, et al. | 2022 | Diabetes | 71 | 6 | 1324-1337 | https://www.doi.org/10.2337/db21-1046 | 35,234,851 | Adolescent Adult Biomarkers Child *Diabetes Mellitus, Type 2/metabolism Genome-Wide Association Study Genomics Humans *Mendelian Randomization Analysis Polymorphism, Single Nucleotide Proteomics | Type 2 diabetes shows an increasing prevalence in both adults and children. Identification of biomarkers for both youth and adult-onset type 2 diabetes is crucial for development of screening tools or drug targets. In this study, using two-sample Mendelian randomization (MR), we identified 22 circulating proteins causally linked to adult type 2 diabetes and 11 proteins with suggestive evidence for association with youth-onset type 2 diabetes. Among these, colocalization analysis further supported a role in type 2 diabetes for C-type mannose receptor 2 (MR odds ratio [OR] 0.85 [95% CI 0.79-0.92] per genetically predicted SD increase in protein level), MANS domain containing 4 (MR OR 0.90 [95% CI 0.88-0.92]), sodium/potassium-transporting ATPase subunit beta2 (MR OR 1.10 [95% CI 1.06-1.15]), endoplasmic reticulum oxidoreductase 1beta (MR OR 1.09 [95% CI 1.05-1.14]), spermatogenesis-associated protein 20 (MR OR 1.12 [95% CI 1.06-1.18]), haptoglobin (MR OR 0.96 [95% CI 0.94-0.98]), and alpha1-3-N-acetylgalactosaminyltransferase and alpha1-3-galactosyltransferase (MR OR 1.04 [95% CI 1.03-1.05]). Our findings support a causal role in type 2 diabetes for a set of circulating proteins, which represent promising type 2 diabetes drug targets. | Ghanbari, Faegheh Yazdanpanah, Nahid Yazdanpanah, Mojgan Richards, J Brent Manousaki, Despoina eng Diabetes. 2022 Jun 1;71(6):1324-1337. doi: 10.2337/db21-1046.I | 03/03/2022 | |
| Advances in proteomic profiling of pediatric kidney diseases | Cummins TD, et al. | 2022 | Pediatr Nephrol | 37 | 10 | 2255-2265 | https://www.doi.org/10.1007/s00467-022-05497-2 | 35,220,505 | Adult Biomarkers Child Glomerular Filtration Rate Humans *Kidney Diseases/diagnosis Proteomics Renal Dialysis *Renal Insufficiency, Chronic Biomarker Chronic kidney disease Mass spectrometry Pediatric glomerular disease Proteomics conflicts of interest to declare. | Chronic kidney disease (CKD) can progress to kidney failure and require dialysis or transplantation, while early diagnosis can alter the course of disease and lead to better outcomes in both pediatric and adult patients. Significant CKD comorbidities include the manifestation of cardiovascular disease, heart failure, coronary disease, and hypertension. The pathogenesis of chronic kidney diseases can present as subtle and especially difficult to distinguish between different glomerular pathologies. Early detection of adult and pediatric CKD and detailed mechanistic understanding of the kidney damage can be helpful in delaying or curtailing disease progression via precise intervention toward diagnosis and prognosis. Clinically, serum creatinine and albumin levels can be indicative of CKD, but often are a lagging indicator only significantly affected once kidney function has severely diminished. The evolution of proteomics and mass spectrometry technologies has begun to provide a powerful research tool in defining these mechanisms and identifying novel biomarkers of CKD. Many of the same challenges and advances in proteomics apply to adult and pediatric patient populations. Additionally, proteomic analysis of adult CKD patients can be transferred directly toward advancing our knowledge of pediatric CKD as well. In this review, we highlight applications of proteomics that have yielded such biomarkers as PLA2R, SEMA3B, and other markers of membranous nephropathy as well as KIM-1, MCP-1, and NGAL in lupus nephritis among other potential diagnostic and prognostic markers. The potential for improving the clinical toolkit toward better treatment of pediatric kidney diseases is significantly aided by current and future development of proteomic applications. | Cummins, Timothy D Korte, Erik A Bhayana, Sagar Merchant, Michael L Barati, Michelle T Smoyer, William E Klein, Jon B eng R01 DK110077/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review Germany Pediatr Nephrol. 2022 Oct;37(10):2255-2265. doi: 10.1007/s00467-022-05497-2. Epub 2022 Feb 26.I | 02/28/2022 | |
| Specialized interferon action in COVID-19 | Galbraith MD, et al. | 2022 | Proc Natl Acad Sci U S A | 119 | 11 | https://www.doi.org/10.1073/pnas.2116730119 | 35,217,532 | Blood/*metabolism COVID-19/blood/*immunology Case-Control Studies Datasets as Topic Humans Inpatients Interferons/*blood *Proteome *Transcriptome Covid-19 CyTOF SARS-CoV-2 cytokine interferon Board for Eli Lilly. | The impacts of interferon (IFN) signaling on COVID-19 pathology are multiple, with both protective and harmful effects being documented. We report here a multiomics investigation of systemic IFN signaling in hospitalized COVID-19 patients, defining the multiomics biosignatures associated with varying levels of 12 different type I, II, and III IFNs. The antiviral transcriptional response in circulating immune cells is strongly associated with a specific subset of IFNs, most prominently IFNA2 and IFNG. In contrast, proteomics signatures indicative of endothelial damage and platelet activation associate with high levels of IFNB1 and IFNA6. Seroconversion and time since hospitalization associate with a significant decrease in a specific subset of IFNs. Additionally, differential IFN subtype production is linked to distinct constellations of circulating myeloid and lymphoid immune cell types. Each IFN has a unique metabolic signature, with IFNG being the most associated with activation of the kynurenine pathway. IFNs also show differential relationships with clinical markers of poor prognosis and disease severity. For example, whereas IFNG has the strongest association with C-reactive protein and other immune markers of poor prognosis, IFNB1 associates with increased neutrophil to lymphocyte ratio, a marker of late severe disease. Altogether, these results reveal specialized IFN action in COVID-19, with potential diagnostic and therapeutic implications. | Galbraith, Matthew D Kinning, Kohl T Sullivan, Kelly D Araya, Paula Smith, Keith P Granrath, Ross E Shaw, Jessica R Baxter, Ryan Jordan, Kimberly R Russell, Seth Dzieciatkowska, Monika Reisz, Julie A Gamboni, Fabia Cendali, Francesca Ghosh, Tusharkanti Guo, Kejun Wilson, Cara C Santiago, Mario L Monte, Andrew A Bennett, Tellen D Hansen, Kirk C Hsieh, Elena W Y D'Alessandro, Angelo Espinosa, Joaquin M eng K23 AR070897/AR/NIAMS NIH HHS/ P30 CA046934/CA/NCI NIH HHS/ P30 DK048520/DK/NIDDK NIH HHS/ R01 AI150305/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Proc Natl Acad Sci U S A. 2022 Mar 15;119(11):e2116730119. doi: 10.1073/pnas.2116730119.I | 02/27/2022 | ||
| Biological Age Acceleration Is Lower in Women With Ischemic Stroke Compared to Men | Gallego-Fabrega C, et al. | 2022 | Stroke | 53 | 7 | 2320-2330 | https://www.doi.org/10.1161/STROKEAHA.121.037419 | 35,209,739 | Acceleration Aging Child, Preschool DNA Methylation *Epigenesis, Genetic Female Genetic Markers Humans *Ischemic Stroke Male Proteomics ischemic stroke men women | BACKGROUND: Stroke onset in women occurs later in life compared with men. The underlying mechanisms of these differences have not been established. Epigenetic clocks, based on DNA methylation (DNAm) profiles, are the most accurate biological age estimate. Epigenetic age acceleration (EAA) measures indicate whether an individual is biologically younger or older than expected. Our aim was to analyze whether sexual dichotomy at age of stroke onset is conditioned by EAA. METHODS: We used 2 DNAm datasets from whole blood samples of case-control genetic studies of ischemic stroke (IS), a discovery cohort of 374 IS patients (N women=163, N men=211), from GRECOS (Genotyping Recurrence Risk of Stroke) and SEDMAN (Dabigatran Study in the Early Phase of Stroke, New Neuroimaging Markers and Biomarkers) studies and a replication cohort of 981 IS patients (N women=411, N men=570) from BASICMAR register. We compared chronological age, 2 DNAm-based biomarkers of aging and intrinsic and extrinsic epigenetic age acceleration EAA (IEAA and extrinsic EAA, respectively), in IS as well as in individual IS etiologic subtypes. Horvath and Hannum epigenetic clocks were used to assess the aging rate. A proteomic study using the SOMAScan multiplex assay was performed on 26 samples analyzing 1305 proteins. RESULTS: Women present lower Hannum-extrinsic EAA values, whereas men have higher Hannum-extrinsic EAA values (women=-0.64, men=1.24, P=1.34x10(-2)); the same tendency was observed in the second cohort (women=-0.57, men=0.79, P=0.02). These differences seemed to be specific to cardioembolic and undetermined stroke subtypes. Additionally, 42 blood protein levels were associated with Hannum-extrinsic EAA (P<0.05), belonging to the immune effector process (P=1.54x10(-6)) and platelet degranulation (P<8.74x10(-6)) pathways. CONCLUSIONS: This study shows that sex-specific underlying biological mechanisms associated with stroke onset could be due to differences in biological age acceleration between men and women. | Gallego-Fabrega, Cristina Muino, Elena Cullell, Natalia Carcel-Marquez, Jara Lazcano, Uxue Soriano-Tarraga, Carolina Lledos, Miquel Llucia-Carol, Laia Aguilera-Simon, Ana Marin, Rebeca Prats-Sanchez, Luis Camps-Renom, Pol Delgado-Mederos, Raquel Martin-Campos, Jesus M Delgado, Pilar Marti-Fabregas, Joan Montaner, Joan Krupinski, Jerzy Jimenez-Conde, J Roquer, Jaume Fernandez-Cadenas, Israel eng Research Support, Non-U.S. Gov't Stroke. 2022 Jul;53(7):2320-2330. doi: 10.1161/STROKEAHA.121.037419. Epub 2022 Feb 25.I | 02/26/2022 | |
| Proteomic profiling identifies novel proteins for genetic risk of severe COVID-19: the Atherosclerosis Risk in Communities Study | Steffen BT, et al. | 2022 | Hum Mol Genet | 31 | 14 | 2452-2461 | https://www.doi.org/10.1093/hmg/ddac024 | 35,212,764 | *COVID-19/genetics *Genetic Predisposition to Disease Genome-Wide Association Study Humans Proteomics Risk Factors | BACKGROUND: Genome-wide association studies have identified six genetic variants associated with severe COVID-19, yet the mechanisms through which they may affect disease remains unclear. We investigated proteomic signatures related to COVID-19 risk variants rs657152 (ABO), rs10735079 (OAS1/OAS2/OAS3), rs2109069 (DPP9), rs74956615 (TYK2), rs2236757 (IFNAR2) and rs11385942 (SLC6A20/LZTFL1/CCR9/FYCO1/CXCR6/XCR1) as well as their corresponding downstream pathways that may promote severe COVID-19 in risk allele carriers and their potential relevancies to other infection outcomes. METHODS: A DNA aptamer-based array measured 4870 plasma proteins among 11 471 participants. Linear regression estimated associations between the COVID-19 risk variants and proteins with correction for multiple comparisons, and canonical pathway analysis was conducted. Cox regression assessed associations between proteins identified in the main analysis and risk of incident hospitalized respiratory infections (2570 events) over a 20.7-year follow-up. RESULTS: The ABO variant rs657152 was associated with 84 proteins in 7241 white participants with 24 replicated in 1671 Black participants. The TYK2 variant rs74956615 was associated with ICAM-1 and -5 in white participants with ICAM-5 replicated in Black participants. Of the 84 proteins identified in the main analysis, seven were significantly associated with incident hospitalized respiratory infections including Ephrin type-A receptor 4 (hazard ratio (HR): 0.87; P = 2.3 x 10-11) and von Willebrand factor type A (HR: 1.17; P = 1.6x10-13). CONCLUSIONS: Novel proteomics signatures and pathways for COVID-19-related risk variants TYK2 and ABO were identified. A subset of these proteins predicted greater risk of incident hospitalized pneumonia and respiratory infections. Further studies to examine these proteins in COVID-19 patients are warranted. | Steffen, Brian T Pankow, James S Lutsey, Pamela L Demmer, Ryan T Misialek, Jeffrey R Guan, Weihua Cowan, Logan T Coresh, Josef Norby, Faye L Tang, Weihong eng T32 HL007779/HL/NHLBI NIH HHS/ R01 HL134320/HL/NHLBI NIH HHS/ U01 HG004402/HG/NHGRI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Hum Mol Genet. 2022 Jul 21;31(14):2452-2461. doi: 10.1093/hmg/ddac024.I | 02/26/2022 | |
| Comparison of Aptamer-Based and Antibody-Based Assays for Protein Quantification in Chronic Kidney Disease | Lopez-Silva C, et al. | 2022 | Clin J Am Soc Nephrol | 17 | 3 | 350-360 | https://www.doi.org/10.2215/CJN.11700921 | 35,197,258 | Biomarkers Cystatin C Female Glomerular Filtration Rate Humans Interleukin-8 Male Receptors, Tumor Necrosis Factor Receptors, Urokinase Plasminogen Activator *Renal Insufficiency *Renal Insufficiency, Chronic AASK (African American Study of Kidney Disease and Hypertension) antibodies biological assay chronic inflammation chronic kidney disease end-stage renal disease mortality | BACKGROUND AND OBJECTIVES: Novel aptamer-based technologies can identify >7000 analytes per sample, offering a high-throughput alternative to traditional immunoassays in biomarker discovery. However, the specificity for distinct proteins has not been thoroughly studied in the context of CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We assessed the use of SOMAscan, an aptamer-based technology, for the quantification of eight immune activation biomarkers and cystatin C among 498 African American Study of Kidney Disease and Hypertension (AASK) participants using immunoassays as the gold standard. We evaluated correlations of serum proteins as measured by SOMAscan versus immunoassays with each other and with iothalamate-measured GFR. We then compared associations between proteins measurement with risks of incident kidney failure and all-cause mortality. RESULTS: Six biomarkers (IL-8, soluble TNF receptor superfamily member 1B [TNFRSF1B], cystatin C, soluble TNF receptor superfamily member 1A [TNFRSF1A], IL-6, and soluble urokinase-type plasminogen activator receptor [suPAR]) had non-negligible correlations (r=0.94, 0.93, 0.89, 0.85, 0.46, and 0.23, respectively) between SOMAscan and immunoassay measurements, and three (IL-10, IFN-gamma, and TNF-alpha) were uncorrelated (r=0.08, 0.07, and 0.02, respectively). Of the six biomarkers with non-negligible correlations, TNFRSF1B, cystatin C, TNFRSF1A, and suPAR were negatively correlated with measured GFR and associated with higher risk of kidney failure. IL-8, TNFRSF1B, cystatin C, TNFRSF1A, and suPAR were associated with a higher risk of mortality via both methods. On average, immunoassay measurements were more strongly associated with adverse outcomes than their SOMAscan counterparts. CONCLUSIONS: SOMAscan is an efficient and relatively reliable technique for quantifying IL-8, TNFRSF1B, cystatin C, and TNFRSF1A in CKD and detecting their potential associations with clinical outcomes. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_02_23_CJN11700921.mp3. | Lopez-Silva, Carolina Surapaneni, Aditya Coresh, Josef Reiser, Jochen Parikh, Chirag R Obeid, Wassim Grams, Morgan E Chen, Teresa K eng U01 DK048689/DK/NIDDK NIH HHS/ P20 RR011104/RR/NCRR NIH HHS/ P30 DK079310/DK/NIDDK NIH HHS/ U01 DK106962/DK/NIDDK NIH HHS/ K08 DK117068/DK/NIDDK NIH HHS/ M01 RR000071/RR/NCRR NIH HHS/ P20 RR011145/RR/NCRR NIH HHS/ K24 HL155861/HL/NHLBI NIH HHS/ R01 DK057867/DK/NIDDK NIH HHS/ M01 RR000052/RR/NCRR NIH HHS/ UL1 RR029887/RR/NCRR NIH HHS/ K24 DK002818/DK/NIDDK NIH HHS/ M01 RR000827/RR/NCRR NIH HHS/ M01 RR000080/RR/NCRR NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Clin J Am Soc Nephrol. 2022 Mar;17(3):350-360. doi: 10.2215/CJN.11700921. Epub 2022 Feb 23.I | 02/25/2022 | |
| Protein prediction for trait mapping in diverse populations | Schubert R, et al. | 2022 | PLoS One | 17 | 2 | e0264341 | https://www.doi.org/10.1371/journal.pone.0264341 | 35,202,437 | Atherosclerosis/ethnology/*genetics Female Gene Frequency *Genetic Association Studies Humans Male *Models, Genetic Pilot Projects Polymorphism, Single Nucleotide Proteins/*genetics Proteome/*genetics Quantitative Trait Loci | Genetically regulated gene expression has helped elucidate the biological mechanisms underlying complex traits. Improved high-throughput technology allows similar interrogation of the genetically regulated proteome for understanding complex trait mechanisms. Here, we used the Trans-omics for Precision Medicine (TOPMed) Multi-omics pilot study, which comprises data from Multi-Ethnic Study of Atherosclerosis (MESA), to optimize genetic predictors of the plasma proteome for genetically regulated proteome-wide association studies (PWAS) in diverse populations. We built predictive models for protein abundances using data collected in TOPMed MESA, for which we have measured 1,305 proteins by a SOMAscan assay. We compared predictive models built via elastic net regression to models integrating posterior inclusion probabilities estimated by fine-mapping SNPs prior to elastic net. In order to investigate the transferability of predictive models across ancestries, we built protein prediction models in all four of the TOPMed MESA populations, African American (n = 183), Chinese (n = 71), European (n = 416), and Hispanic/Latino (n = 301), as well as in all populations combined. As expected, fine-mapping produced more significant protein prediction models, especially in African ancestries populations, potentially increasing opportunity for discovery. When we tested our TOPMed MESA models in the independent European INTERVAL study, fine-mapping improved cross-ancestries prediction for some proteins. Using GWAS summary statistics from the Population Architecture using Genomics and Epidemiology (PAGE) study, which comprises approximately 50,000 Hispanic/Latinos, African Americans, Asians, Native Hawaiians, and Native Americans, we applied S-PrediXcan to perform PWAS for 28 complex traits. The most protein-trait associations were discovered, colocalized, and replicated in large independent GWAS using proteome prediction model training populations with similar ancestries to PAGE. At current training population sample sizes, performance between baseline and fine-mapped protein prediction models in PWAS was similar, highlighting the utility of elastic net. Our predictive models in diverse populations are publicly available for use in proteome mapping methods at https://doi.org/10.5281/zenodo.4837327. | Schubert, Ryan Geoffroy, Elyse Gregga, Isabelle Mulford, Ashley J Aguet, Francois Ardlie, Kristin Gerszten, Robert Clish, Clary Van Den Berg, David Taylor, Kent D Durda, Peter Johnson, W Craig Cornell, Elaine Guo, Xiuqing Liu, Yongmei Tracy, Russell Conomos, Matthew Blackwell, Tom Papanicolaou, George Lappalainen, Tuuli Mikhaylova, Anna V Thornton, Timothy A Cho, Michael H Gignoux, Christopher R Lange, Leslie Lange, Ethan Rich, Stephen S Rotter, Jerome I Manichaikul, Ani Im, Hae Kyung Wheeler, Heather E eng R15 HG009569/HG/NHGRI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS One. 2022 Feb 24;17(2):e0264341. doi: 10.1371/journal.pone.0264341. eCollection 2022.I | 02/25/2022 | |
| Protein and miRNA profile of circulating extracellular vesicles in patients with primary sclerosing cholangitis | Povero D, et al. | 2022 | Sci Rep | 12 | 1 | 3027 | https://www.doi.org/10.1038/s41598-022-06809-0 | 35,194,091 | Adult Aged Biomarkers/blood Cholangitis, Sclerosing/*diagnosis Extracellular Vesicles/*genetics/*metabolism Female Gene Expression Humans Interleukin-13 Receptor alpha1 Subunit/*genetics/*metabolism Liver Cirrhosis/diagnosis Male MicroRNAs/*genetics/*metabolism Middle Aged Young Adult | Primary sclerosing cholangitis (PSC) is an idiopathic and heterogenous cholestatic liver disease characterized by chronic inflammation and fibrosis of the biliary tree. Currently, no effective therapies are available for this condition, whose incidence is rising. At present, specificity and sensitivity of current serum markers used to diagnose PSC are limited and often unreliable. In this study, we characterize circulating extracellular vesicles and provide supporting data on their potential use as novel surrogate biomarkers for PSC. EVs are membrane surrounded structures, 100-1000 nm in size, released by cells under various conditions and which carry a variety of bioactive molecules, including small non-coding RNAs, lipids and proteins. In recent years, a large body of evidence has pointed to diagnostic implications of EVs and relative cargo in various human diseases. We isolated EVs from serum of well-characterized patients with PSC or control subjects by differential centrifugation and size-exclusion chromatography. A complete characterization identified elevated levels of circulating EVs in PSC patients compared to healthy control subjects (2000 vs. 500 Calcein-FITC + EVs/muL). Tissue and cell specificity of circulating EVs was assessed by identification of liver-specific markers and cholangiocyte marker CK-19. Further molecular characterization identified 282 proteins that were differentially regulated in PSC-derived compared to healthy control-EVs. Among those, IL-13Ra1 was the most significantly and differentially expressed protein in PSC-derived EVs and correlated with the degree of liver fibrosis. In addition to protein profiling, we performed a miRNA-sequencing analysis which identified 11 among established, liver-specific (e.g., miR-122 and miR-192) and novel miRNAs. One of the newly identified miRNAs, miR-4645-3p, was significantly up-regulated fourfold in PSC-derived EVs compared to circulating EVs isolated from healthy controls. This study provides supporting evidence of the potential role of circulating EVs and associated protein and miRNA cargo as surrogate noninvasive and reliable biomarker for PSC. | Povero, Davide Tameda, Masahiko Eguchi, Akiko Ren, Wenhua Kim, Jihoon Myers, Robert Goodman, Zachary D Harrison, Stephen A Sanyal, Arun J Bosch, Jaime Ohno-Machado, Lucila Feldstein, Ariel E eng Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. 2022 Feb 22;12(1):3027. doi: 10.1038/s41598-022-06809-0.I | 02/24/2022 | |
| Identification of Distinct Inflammatory Programs and Biomarkers in Systemic Juvenile Idiopathic Arthritis and Related Lung Disease by Serum Proteome Analysis | Chen G, et al. | 2022 | Arthritis Rheumatol | 74 | 7 | 1271-1283 | https://www.doi.org/10.1002/art.42099 | 35,189,047 | *Arthritis, Juvenile/complications Biomarkers Humans *Lung Diseases/epidemiology *Macrophage Activation Syndrome Matrix Metalloproteinase 7 Proteome | OBJECTIVE: Recent observations in systemic juvenile idiopathic arthritis (JIA) suggest an increasing incidence of high-mortality interstitial lung disease often characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in systemic JIA suggests a shared pathology, but patients with lung disease associated with systemic JIA (designated SJIA-LD) also commonly experience features of drug reaction such as atypical rashes and eosinophilia. This study was undertaken to investigate immunopathology and identify biomarkers in systemic JIA, MAS, and SJIA-LD. METHODS: We used SOMAscan to measure ~1,300 analytes in sera from healthy controls and patients with systemic JIA, MAS, SJIA-LD, or other related diseases. We verified selected findings by enzyme-linked immunosorbent assay and lung immunostaining. Because the proteome of a sample may reflect multiple states (systemic JIA, MAS, or SJIA-LD), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort. RESULTS: Proteome alterations in active systemic JIA and MAS overlapped substantially, including known systemic JIA biomarkers such as serum amyloid A and S100A9, and novel elevations in the levels of heat-shock proteins and glycolytic enzymes. Interleukin-18 levels were elevated in all systemic JIA groups, particularly MAS and SJIA-LD. We also identified an MAS-independent SJIA-LD signature notable for elevated levels of intercellular adhesion molecule 5 (ICAM-5), matrix metalloproteinase 7 (MMP-7), and allergic/eosinophilic chemokines, which have been previously associated with lung damage. Immunohistochemistry localized ICAM-5 and MMP-7 in the lungs of patients with SJIA-LD. The ability of ICAM-5 to distinguish SJIA-LD from systemic JIA/MAS was independently validated. CONCLUSION: Serum proteins support a systemic JIA-to-MAS continuum; help distinguish systemic JIA, systemic JIA/MAS, and SJIA-LD; and suggest etiologic hypotheses. Select biomarkers, such as ICAM-5, could aid in early detection and management of SJIA-LD. | Chen, Guangbo Deutsch, Gail H Schulert, Grant S Zheng, Hong Jang, SoRi Trapnell, Bruce Lee, Pui Y Macaubas, Claudia Ho, Katherine Schneider, Corinne Saper, Vivian E de Jesus, Adriana Almeida Krasnow, Mark A Grom, Alexei Goldbach-Mansky, Raphaela Khatri, Purvesh Mellins, Elizabeth D Canna, Scott W eng R01 HD098428/HD/NICHD NIH HHS/ R01 AR061297/AR/NIAMS NIH HHS/ R01 AR066551/AR/NIAMS NIH HHS/ U19 AI109662/AI/NIAID NIH HHS/ R01 AI125197/AI/NIAID NIH HHS/ U19 AI057229/AI/NIAID NIH HHS/ K22 AI123366/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Arthritis Rheumatol. 2022 Jul;74(7):1271-1283. doi: 10.1002/art.42099. Epub 2022 May 31.I | 02/22/2022 | |
| Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19 | Sacco K, et al. | 2022 | Nat Med | 28 | 5 | 1050-1062 | https://www.doi.org/10.1038/s41591-022-01724-3 | 35,177,862 | *COVID-19/complications/genetics Child Humans SARS-CoV-2 Systemic Inflammatory Response Syndrome/genetics T-Lymphocytes | Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-kappaB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy. | Sacco, Keith Castagnoli, Riccardo Vakkilainen, Svetlana Liu, Can Delmonte, Ottavia M Oguz, Cihan Kaplan, Ian M Alehashemi, Sara Burbelo, Peter D Bhuyan, Farzana de Jesus, Adriana A Dobbs, Kerry Rosen, Lindsey B Cheng, Aristine Shaw, Elana Vakkilainen, Mikko S Pala, Francesca Lack, Justin Zhang, Yu Fink, Danielle L Oikonomou, Vasileios Snow, Andrew L Dalgard, Clifton L Chen, Jinguo Sellers, Brian A Montealegre Sanchez, Gina A Barron, Karyl Rey-Jurado, Emma Vial, Cecilia Poli, Maria Cecilia Licari, Amelia Montagna, Daniela Marseglia, Gian Luigi Licciardi, Francesco Ramenghi, Ugo Discepolo, Valentina Lo Vecchio, Andrea Guarino, Alfredo Eisenstein, Eli M Imberti, Luisa Sottini, Alessandra Biondi, Andrea Mato, Sayonara Gerstbacher, Dana Truong, Meng Stack, Michael A Magliocco, Mary Bosticardo, Marita Kawai, Tomoki Danielson, Jeffrey J Hulett, Tyler Askenazi, Manor Hu, Shaohui Cohen, Jeffrey I Su, Helen C Kuhns, Douglas B Lionakis, Michail S Snyder, Thomas M Holland, Steven M Goldbach-Mansky, Raphaela Tsang, John S Notarangelo, Luigi D eng ZIA AI001270/ImNIH/Intramural NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Nat Med. 2022 May;28(5):1050-1062. doi: 10.1038/s41591-022-01724-3. Epub 2022 Feb 17.I | 02/19/2022 | |
| Proteomics technologies for cancer liquid biopsies | Ding Z, et al. | 2022 | Mol Cancer | 21 | 1 | 53 | https://www.doi.org/10.1186/s12943-022-01526-8 | 35,168,611 | Early Detection of Cancer Humans Liquid Biopsy *Neoplasms/diagnosis/genetics Proteome/metabolism *Proteomics/methods Antibody arrays Aptamer Cancer liquid biopsy Mass spectrometry (MS) Proteomics Proximity extension assay (PEA) Reverse phase protein arrays (RPPA) declare no conflicts of interests and no competing interests of this work. | Alterations in DNAs could not reveal what happened in proteins. The accumulated alterations of DNAs would change the manifestation of proteins. Therefore, as is the case in cancer liquid biopsies, deep proteome profiling will likely provide invaluable and clinically relevant information in real-time throughout all stages of cancer progression. However, due to the great complexity of proteomes in liquid biopsy samples and the limitations of proteomic technologies compared to high-plex sequencing technologies, proteomic discoveries have yet lagged behind their counterpart, genomic technologies. Therefore, novel protein technologies are in urgent demand to fulfill the goals set out for biomarker discovery in cancer liquid biopsies.Notably, conventional and innovative technologies are being rapidly developed for proteomic analysis in cancer liquid biopsies. These advances have greatly facilitated early detection, diagnosis, prognosis, and monitoring of cancer evolution, adapted or adopted in response to therapeutic interventions. In this paper, we review the high-plex proteomics technologies that are capable of measuring at least hundreds of proteins simultaneously from liquid biopsy samples, ranging from traditional technologies based on mass spectrometry (MS) and antibody/antigen arrays to innovative technologies based on aptamer, proximity extension assay (PEA), and reverse phase protein arrays (RPPA). | Ding, Zhiyong Wang, Nan Ji, Ning Chen, Zhe-Sheng eng Research Support, Non-U.S. Gov't Review England Mol Cancer. 2022 Feb 15;21(1):53. doi: 10.1186/s12943-022-01526-8.I | 02/17/2022 | |
| Creatine kinase-(MB) and hepcidin as candidate biomarkers for early diagnosis of pulmonary tuberculosis: a proof-of-concept study in Lambarene, Gabon | Essone PN, et al. | 2022 | Infection | 50 | 4 | 897-905 | https://www.doi.org/10.1007/s15010-022-01760-8 | 35,133,607 | Biomarkers Creatine Kinase, MB Form Early Diagnosis Gabon Hepcidins Humans *Mycobacterium tuberculosis ROC Curve Sensitivity and Specificity *Tuberculosis/diagnosis *Tuberculosis, Pulmonary/diagnosis Creatine kinase-MB Diagnosis Hepcidin Tuberculosis | BACKGROUND: The present study aimed to evaluate the diagnostic utility of creatine kinase-MB (CK-MB), hepcidin (HEPC), phospholipase A2 group IIA (PLa2G2A), and myosin-binding protein C (MYBPC1) for tuberculosis (TB). These four biomarkers are differentially regulated between quiescent Mycobacterium tuberculosis (Mtb) infected individuals (non-progressors to TB disease) and Mtb-infected TB disease progressors 6 months before the onset of symptoms. METHODS: We enrolled samples from patients experiencing moderate-to-severe pulmonary infections diseases including 23 TB cases confirmed by smear microscopy and culture, and 34 TB-negative cases. For each participant, the serum levels of the four biomarkers were measured using ELISA. RESULTS: The levels of CK-MB and HEPC were significantly reduced in patients with active TB disease. CK-MB median level was 2045 pg/ml (1455-4000 pg/ml) in active TB cases and 3245 pg/ml (1645-4000 pg/ml) in non-TB pulmonary diseases. Using the receiver operating characteristic curve (ROC) analysis, HEPC and CK-MB had the Area Under the Curve (AUC) of 79% (95% CI 67-91%) and 81% (95% CI 69-93%), respectively. Both markers correlated with TB diagnosis as a single marker. PLa2G2A and MYBPC1 with AUCs of 48% (95% CI 36-65%) and 62% (95% CI 48-76%) did not performed well as single biomarkers. The three markers'model (CK-MB-HEPC-PLa2G2A) had the highest diagnostic accuracy at 82% (95% CI 56-82%) after cross-validation. CONCLUSION: CK-MB and HEPC levels were statistically different between confirmed TB cases and non-TB cases. This study yields promising results for the rapid diagnosis of TB disease using a single marker or three biomarkers model. | Essone, Paulin N Adegbite, Bayode R Mbadinga, Marien J M Mbouna, Armel V Lotola-Mougeni, Fabrice Alabi, Ayodele Edoa, Jean R Lell, Bertrand Alabi, Abraham S Adegnika, Ayola A Ramharter, Michael Siawaya, Joel F D Grobusch, Martin P Kremsner, Peter G Agnandji, Selidji T eng EDCTP-TMA-SF-1946-VARSAF/European and Developing Countries Clinical Trials Partnership/ Germany Infection. 2022 Aug;50(4):897-905. doi: 10.1007/s15010-022-01760-8. Epub 2022 Feb 8.I | 02/09/2022 | |
| Placental proteins with predicted roles in fetal development decrease in premature infants | Schreiner C, et al. | 2022 | Pediatr Res | 92 | 5 | 1316-1324 | https://www.doi.org/10.1038/s41390-022-01942-y | 35,132,128 | Female Humans Infant, Newborn Pregnancy Fetal Blood Fetal Development *Infant, Premature Placenta/metabolism *Pregnancy Proteins | BACKGROUND: Emerging evidence from animal experiments indicate that factors secreted by the placenta are critical for normal fetal organ development. Our objective was to characterize the umbilical vein and artery proteome in preterm infants and identify proteins that decrease in the neonatal circulation following delivery. METHODS: Cord blood at delivery and neonatal blood at 48-72 h of life was collected in 25 preterm infants. Plasma protein abundance was determined using the SomaLogic platform. RESULTS: When comparing protein levels of umbilical venous to arterial cord blood, 434 proteins were significantly higher indicating placental secretion into the fetal circulation. Moreover, when comparing neonatal blood to umbilical vein levels, 142 proteins were significantly lower. These proteins included Endoplasmic reticulum resident protein 29, CD59, Fibroblast growth factor 2 and Dynactin subunit 2, which are involved in brain development and prevention of brain damage as well as Fibroblast growth factor 1 which prevents lung fibrosis. CONCLUSIONS: The late second trimester human placenta secretes proteins into the fetal circulation which decrease following delivery. Many of these proteins are predicted to be important in the development of fetal organs. Further studies are needed to directly link placental proteins to organ development and poor outcomes in preterm infants. IMPACT: Prematurity remains a leading cause of morbidity and mortality requiring the development of novel treatments. Emerging evidence from animal studies suggest that factors secreted from the placenta may be critical in the development of the fetus. We report that the preterm human placenta secretes an array of proteins into the fetal circulation. Some of these proteins are predicted to be involved in the development of the brain and the lung. When born prematurely, infants are deprived of these placental proteins, which may contribute to their poor outcomes. | Schreiner, Cynthia Powell, Theresa L Palmer, Claire Jansson, Thomas eng R21 HD104914/HD/NICHD NIH HHS/ Pediatr Res. 2022 Nov;92(5):1316-1324. doi: 10.1038/s41390-022-01942-y. Epub 2022 Feb 7.I | 02/09/2022 | |
| Defining the effects of traffic-related air pollution on the human plasma proteome using an aptamer proteomic array: A dose-dependent increase in atherosclerosis-related proteins | Mookherjee N, et al. | 2022 | Environ Res | 209 | 112803 | https://www.doi.org/10.1016/j.envres.2022.112803 | 35,120,890 | *Air Pollutants/analysis/toxicity *Air Pollution/adverse effects/analysis *Atherosclerosis/chemically induced/etiology/metabolism Humans Proteome Proteomics Random Allocation Vehicle Emissions/analysis/toxicity Air pollution Atherosclerosis Biomarkers Diesel exhaust | BACKGROUND: Traffic-related air pollution (TRAP) is a critical risk factor and major contributor to respiratory and cardiovascular disease (CVD). The effects of TRAP beyond the lungs can be related to changes in circulatory proteins. However, such TRAP-mediated changes have not been defined in an unbiased manner using a controlled human model. OBJECTIVE: To detail global protein changes (the proteome) in plasma following exposure to inhaled diesel exhaust (DE), a paradigm of TRAP, using controlled human exposures. METHODS: In one protocol, ex-smokers and never-smokers were exposed to filtered air (FA) and DE (300 mug PM(2.5)/m(3)), on order-randomized days, for 2 h. In a second protocol, independent never-smoking participants were exposed to lower concentrations of DE (20, 50 or 150 mug PM(2.5)/m(3)) and FA, for 4 h, on order-randomized days. Each exposure was separated by 4 weeks of washout. Plasma samples obtained 24 h post-exposure from ex-smokers (n = 6) were first probed using Slow off-rate modified aptamer proteomic array. Plasma from never-smokers (n = 11) was used for independent assessment of proteins selected from the proteomics study by immunoblotting. RESULTS: Proteomics analyses revealed that DE significantly altered 342 proteins in plasma of ex-smokers (n = 6). The top 20 proteins therein were primarily associated with inflammation and CVD. Plasma from never-smokers (n = 11) was used for independent assessment of 6 proteins, amongst the top 10 proteins increased by DE in the proteomics study, for immunoblotting. The abundance of all six proteins (fractalkine, apolipoproteins (APOB and APOM), IL18R1, MIP-3 and MMP-12) was significantly increased by DE in plasma of these never-smokers. DE-mediated increase was shown to be concentration-dependent for fractalkine, APOB and MMP-12, all biomarkers of atherosclerosis, which correlated with plasma levels of IL-6, a subclinical marker of CVD, in independent participants. CONCLUSION: This investigation details changes in the human plasma proteome due to TRAP. We identify specific atherosclerosis-related proteins that increase concentration-dependently across a range of TRAP levels applicable worldwide. | Mookherjee, Neeloffer Ryu, Min Hyung Hemshekhar, Mahadevappa Orach, Juma Spicer, Victor Carlsten, Christopher eng Netherlands Environ Res. 2022 Jun;209:112803. doi: 10.1016/j.envres.2022.112803. Epub 2022 Feb 1.I | 02/06/2022 | ||
| Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology | Bjornsdottir G, et al. | 2022 | Nat Commun | 13 | 1 | 634 | https://www.doi.org/10.1038/s41467-022-28167-1 | 35,110,524 | 3' Untranslated Regions Bone and Bones/metabolism Genome-Wide Association Study Humans Intervertebral Disc/*metabolism Intervertebral Disc Degeneration/*genetics Intervertebral Disc Displacement/*genetics Sodium Sulfate Cotransporter/*genetics/*metabolism Sulfates/*metabolism Symporters/genetics/metabolism | Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (OR(IDD) = 0.92, P = 1.6 x 10(-39); OR(dorsalgia) = 0.92, P = 7.2 x 10(-15)) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 x 10(-11)); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes. | Bjornsdottir, Gyda Stefansdottir, Lilja Thorleifsson, Gudmar Sulem, Patrick Norland, Kristjan Ferkingstad, Egil Oddsson, Asmundur Zink, Florian Lund, Sigrun H Nawaz, Muhammad S Bragi Walters, G Skuladottir, Astros Th Gudjonsson, Sigurjon A Einarsson, Gudmundur Halldorsson, Gisli H Bjarnadottir, Valgerdur Sveinbjornsson, Gardar Helgadottir, Anna Styrkarsdottir, Unnur Gudmundsson, Larus J Pedersen, Ole B Hansen, Thomas Folkmann Werge, Thomas Banasik, Karina Troelsen, Anders Skou, Soren T Thorner, Lise Wegner Erikstrup, Christian Nielsen, Kaspar Rene Mikkelsen, Susan Jonsdottir, Ingileif Bjornsson, Aron Olafsson, Ingvar H Ulfarsson, Elfar Blondal, Josep Vikingsson, Arnor Brunak, Soren Ostrowski, Sisse R Ullum, Henrik Thorsteinsdottir, Unnur Stefansson, Hreinn Gudbjartsson, Daniel F Thorgeirsson, Thorgeir E Stefansson, Kari eng Research Support, Non-U.S. Gov't England Nat Commun. 2022 Feb 2;13(1):634. doi: 10.1038/s41467-022-28167-1.I | 02/04/2022 | |
| Linking Genetics and Proteomics: Gene-Protein Associations Built on Diversity | Schunkert H, et al. | 2022 | Circulation | 145 | 5 | 371-374 | https://www.doi.org/10.1161/CIRCULATIONAHA.121.058303 | 35,100,019 | Genome-Wide Association Study *Genomics Humans *Proteomics Editorials cardiovascular disease ethnic diversity genomics proteomics | Schunkert, Heribert Mayr, Manuel eng SP/17/10/33219/BHF_/British Heart Foundation/United Kingdom RG/16/14/32397/BHF_/British Heart Foundation/United Kingdom CH/16/3/32406/BHF_/British Heart Foundation/United Kingdom Comment Editorial Research Support, Non-U.S. Gov't Circulation. 2022 Feb;145(5):371-374. doi: 10.1161/CIRCULATIONAHA.121.058303. Epub 2022 Jan 31.I | 02/01/2022 | ||
| Aptamer-Based Screen of Neuropsychiatric Lupus Cerebrospinal Fluid Reveals Potential Biomarkers That Overlap With the Choroid Plexus Transcriptome | Vanarsa K, et al. | 2022 | Arthritis Rheumatol | 74 | 7 | 1223-1234 | https://www.doi.org/10.1002/art.42080 | 35,099,126 | *Biomarkers/cerebrospinal fluid Choroid Plexus/metabolism Complement C3/metabolism Humans Immunoglobulin M/metabolism Lipocalin-2/metabolism *Lupus Vasculitis, Central Nervous System/cerebrospinal fluid/diagnosis Macrophage Colony-Stimulating Factor/metabolism Proteomics Transcriptome | OBJECTIVE: As no gold-standard diagnostic test exists for neuropsychiatric systemic lupus erythematosus (NPSLE), we undertook this study to execute a broad screen of NPSLE cerebrospinal fluid (CSF) using an aptamer-based platform. METHODS: CSF was obtained from NPSLE patients and subjected to proteomic assay using the aptamer-based screen. Potential biomarkers were identified and validated in independent NPSLE cohorts in comparison to other neurologic diseases. RESULTS: Forty proteins out of the 1,129 screened were found to be elevated in NPSLE CSF. Based on enzyme-linked immunosorbent assay validation, CSF levels of angiostatin, alpha2-macroglobulin, DAN, fibronectin, hepatocellular carcinoma clone 1, IgM, lipocalin 2, macrophage colony-stimulating factor (M-CSF), and serine protease inhibitor G1 were significantly elevated in a predominantly White NPSLE cohort (n = 24), compared to patients with other neurologic diseases (n = 54), with CSF IgM (area under the curve [AUC] 0.95) and M-CSF (AUC 0.91) being the most discriminatory proteins. In a second Hong Kong-based NPSLE cohort, CSF IgM (AUC 0.78) and lipocalin 2 (AUC 0.85) were the most discriminatory proteins. Several CSF proteins exhibited high diagnostic specificity for NPSLE in both cohorts. Elevated CSF complement C3 was associated with an acute confusional state. Eleven molecules elevated in NPSLE CSF exhibited concordant elevation in the choroid plexus, suggesting shared origins. CONCLUSION: Lipocalin 2, M-CSF, IgM, and complement C3 emerge as promising CSF biomarkers of NPSLE with diagnostic potential. | Vanarsa, Kamala Sasidharan, Prashanth Duran, Valeria Gokaraju, Sirisha Nidhi, Malavika Titus, Anto Sam Crosslee Louis Sam Soomro, Sanam Stock, Ariel D Der, Evan Putterman, Chaim Greenberg, Benjamin Mok, Chi Chiu Hanly, John G Mohan, Chandra eng R01 AR074096/GF/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Arthritis Rheumatol. 2022 Jul;74(7):1223-1234. doi: 10.1002/art.42080. Epub 2022 May 18.I | 02/01/2022 | |
| Coding and regulatory variants are associated with serum protein levels and disease | Emilsson V, et al. | 2022 | Nat Commun | 13 | 1 | 481 | https://www.doi.org/10.1038/s41467-022-28081-6 | 35,079,000 | Aged Blood Proteins/*genetics Disease/classification/*genetics Exome/*genetics Female *Genetic Predisposition to Disease *Genotype Humans Iceland Male *Polymorphism, Single Nucleotide Proteome/*metabolism | Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. In the current study, 54,469 low-frequency and common exome-array variants were compared to 4782 protein measurements in the serum of 5343 individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that 2021 independent exome array variants are associated with serum levels of 1942 proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins' emerging role as biomarkers and potential causative agents of a wide range of diseases. | Emilsson, Valur Gudmundsdottir, Valborg Gudjonsson, Alexander Jonmundsson, Thorarinn Jonsson, Brynjolfur G Karim, Mohd A Ilkov, Marjan Staley, James R Gudmundsson, Elias F Launer, Lenore J Lindeman, Jan H Morton, Nicholas M Aspelund, Thor Lamb, John R Jennings, Lori L Gudnason, Vilmundur eng N01AG12100/AG/NIA NIH HHS/ 206194/WT_/Wellcome Trust/United Kingdom R01 AG065596/AG/NIA NIH HHS/ WT_/Wellcome Trust/United Kingdom HHSN271201200022C/DA/NIDA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. 2022 Jan 25;13(1):481. doi: 10.1038/s41467-022-28081-6.I | 01/27/2022 | |
| A genome-wide association study of serum proteins reveals shared loci with common diseases | Gudjonsson A, et al. | 2022 | Nat Commun | 13 | 1 | 480 | https://www.doi.org/10.1038/s41467-021-27850-z | 35,078,996 | Aged Aged, 80 and over Blood Proteins/*genetics Cohort Studies Disease/classification/*genetics Female *Genetic Predisposition to Disease *Genome, Human Genome-Wide Association Study/*methods Humans Iceland Male *Polymorphism, Single Nucleotide *Quantitative Trait Loci | With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein's genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease. | Gudjonsson, Alexander Gudmundsdottir, Valborg Axelsson, Gisli T Gudmundsson, Elias F Jonsson, Brynjolfur G Launer, Lenore J Lamb, John R Jennings, Lori L Aspelund, Thor Emilsson, Valur Gudnason, Vilmundur eng HHSN271201200022C/DA/NIDA NIH HHS/ N01AG12100/AG/NIA NIH HHS/ R01 AG065596/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. 2022 Jan 25;13(1):480. doi: 10.1038/s41467-021-27850-z.I | 01/27/2022 | |
| Using the Plasma Proteome for Risk Stratifying Patients with Pulmonary Arterial Hypertension | Rhodes CJ, et al. | 2022 | Am J Respir Crit Care Med | 205 | 9 | 1102-1111 | https://www.doi.org/10.1164/rccm.202105-1118OC | 35,081,018 | Area Under Curve Biomarkers Familial Primary Pulmonary Hypertension Humans Natriuretic Peptide, Brain Peptide Fragments Prognosis Proteome *Pulmonary Arterial Hypertension clinical outcomes | Rationale: NT-proBNP (N-terminal pro-brain natriuretic peptide), a biomarker of cardiac origin, is used to risk stratify patients with pulmonary arterial hypertension (PAH). Its limitations include poor sensitivity to early vascular pathology. Other biomarkers of vascular or systemic origin may also be useful in the management of PAH. Objectives: Identify prognostic proteins in PAH that complement NT-proBNP and clinical risk scores. Methods: An aptamer-based assay (SomaScan version 4) targeting 4,152 proteins was used to measure plasma proteins in patients with idiopathic, heritable, or drug-induced PAH from the UK National Cohort of PAH (n = 357) and the French EFORT (Evaluation of Prognostic Factors and Therapeutic Targets in PAH) study (n = 79). Prognostic proteins were identified in discovery-replication analyses of UK samples. Proteins independent of 6-minute-walk distance and NT-proBNP entered least absolute shrinkage and selection operator modeling, and the best combination in a single score was evaluated against clinical targets in EFORT. Measurements and Main Results: Thirty-one proteins robustly informed prognosis independent of NT-proBNP and 6-minute-walk distance in the UK cohort. A weighted combination score of six proteins was validated at baseline (5-yr mortality; area under the curve [AUC], 0.73; 95% confidence interval [CI], 0.63-0.85) and follow-up in EFORT (AUC, 0.84; 95% CI, 0.75-0.94; P = 9.96 x 10(-6)). The protein score risk stratified patients independent of established clinical targets and risk equations. The addition of the six-protein model score to NT-proBNP improved prediction of 5-year outcomes from AUC 0.762 (0.702-0.821) to 0.818 (0.767-0.869) by receiver operating characteristic analysis (P = 0.00426 for difference in AUC) in the UK replication and French samples combined. Conclusions: The plasma proteome informs prognosis beyond established factors in PAH and may provide a more sensitive measure of therapeutic response. | Rhodes, Christopher J Wharton, John Swietlik, Emilia M Harbaum, Lars Girerd, Barbara Coghlan, J Gerry Lordan, James Church, Colin Pepke-Zaba, Joanna Toshner, Mark Wort, Stephen J Kiely, David G Condliffe, Robin Lawrie, Allan Graf, Stefan Montani, David Boucly, Athenais Sitbon, Olivier Humbert, Marc Howard, Luke S Morrell, Nicholas W Wilkins, Martin R eng FS/15/59/31839/BHF_/British Heart Foundation/United Kingdom MR/K020919/1/MRC_/Medical Research Council/United Kingdom FS/13/48/30453/BHF_/British Heart Foundation/United Kingdom FS/18/52/33808/BHF_/British Heart Foundation/United Kingdom RE/18/4/34215/BHF_/British Heart Foundation/United Kingdom SP/12/12/29836/BHF_/British Heart Foundation/United Kingdom DH_/Department of Health/United Kingdom SP/18/10/33975/BHF_/British Heart Foundation/United Kingdom Research Support, Non-U.S. Gov't Am J Respir Crit Care Med. 2022 May 1;205(9):1102-1111. doi: 10.1164/rccm.202105-1118OC.I | 01/27/2022 | |
| Comparison of Proteomic Expression Profiles after Radiation Exposure across Four Different Species | Sproull M, et al. | 2022 | Radiat Res | 197 | 4 | 315-323 | https://www.doi.org/10.1667/RADE-21-00182.1 | 35,073,400 | Animals Biomarkers/metabolism Dose-Response Relationship, Radiation Histones Humans Mice Mice, Inbred C57BL *Proteomics *Radiation Exposure/adverse effects/analysis Swine Swine, Miniature | There is a need to identify biomarkers of radiation exposure for use in development of circulating biodosimeters for radiation exposure and for clinical use as markers of radiation injury. Most research approaches for biomarker discovery rely on a single animal model. The current study sought to take advantage of a novel aptamer-based proteomic assay which has been validated for use in many species to characterize changes to the blood proteome after total-body irradiation (TBI) across four different mammalian species including humans. Plasma was collected from C57BL6 mice, Sinclair minipigs, and Rhesus non-human primates (NHPs) receiving a single dose of TBI at a range of 3.3 Gy to 4.22 Gy at 24 h postirradiation. NHP and minipig models were irradiated using a 60Co source at a dose rate of 0.6 Gy/min, the C57BL6 mouse model using an X-ray source at a dose rate of 2.28 Gy/min and clinical samples from a photon source at 10 cGy/min. Plasma was collected from human patients receiving a single dose of 2 Gy TBI collected 6 h postirradiation. Plasma was screened using the aptamer-based SomaLogic SomaScan(R) proteomic assay technology to evaluate changes in the expression of 1,310 protein analytes. Confirmatory analysis of protein expression of biomarker HIST1H1C, was completed using plasma from C57BL6 mice receiving a 2, 3.5 or 8 Gy TBI collected at days 1, 3, and 7 postirradiation by singleplex ELISA. Summary of key pathways with altered expression after radiation exposure across all four mammalian species was determined using Ingenuity Pathway Analysis (IPA). Detectable values were obtained for all 1,310 proteins in all samples included in the SomaScan assay. A subset panel of protein biomarkers which demonstrated significant (p < 0.05) changes in expression of at least 1.3-fold after radiation exposure were characterized for each species. IPA of significantly altered proteins yielded a variety of top disease and biofunction pathways across species with the organismal injury and abnormalities pathway held in common for all four species. The HIST1H1C protein was shown to be radiation responsive within the human, NHP and murine species within the SomaScan dataset and was shown to demonstrate dose dependent upregulation at 2, 3.5 and 8 Gy at 24 h postirradiation in a separate murine cohort by ELISA. The SomaScan proteomics platform is a useful screening tool to evaluate changes in biomarker expression across multiple mammalian species. In our study, we were able to identify a novel biomarker of radiation exposure, HIST1H1C, and characterize panels of radiation responsive proteins and functional proteomic pathways altered by radiation exposure across murine, minipig, NHP and human species. Our study demonstrates the efficacy of using a multispecies approach for biomarker discovery. | Sproull, Mary Nishita, Denise Chang, Polly Moroni, Maria Citrin, Deborah Shankavaram, Uma Camphausen, Kevin eng Z99 CA999999/ImNIH/Intramural NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Radiat Res. 2022 Apr 1;197(4):315-323. doi: 10.1667/RADE-21-00182.1.I | 01/25/2022 | |
| Association of Circulating Proteins with Death or Lung Transplant in Patients with Idiopathic Pulmonary Fibrosis in the IPF-PRO Registry Cohort | Todd JL, et al. | 2022 | Lung | 200 | 1 | 18-Nov | https://www.doi.org/10.1007/s00408-021-00505-y | 35,066,606 | Cohort Studies Humans *Idiopathic Pulmonary Fibrosis *Lung Transplantation Proteomics Registries Biomarkers Interstitial lung diseases Observational study Proteomics RO, HM and SMP are employees of the Duke Clinical Research Institute, which was funded by Boehringer Ingelheim Pharmaceuticals, Inc to conduct this research. JR reports grants and personal fees from Boehringer Ingelheim and grants from Genentech, Galapagos, Syneos Health, Bellerophon Therapeutics, FibroGen, and the National Institutes of Health. JAL reports personal fees from Biogen, Boehringer Ingelheim, Galecto, Roche/Genentech and Veracyte. JAdA reports personal fees from Boehringer Ingelheim. MG reports personal fees, non-financial support, and other support from the France Foundation grants, non-financial support and other support from Boehringer Ingelheim and the Pulmonary Fibrosis Foundation and personal fees from Genentech. HH is on a speaker panel for Boehringer Ingelheim. IN reports personal fees from Boehringer Ingelheim, Genentech, and ImmuneWorks. JAB has no disclosures. KRF reports grants and personal fees from Boehringer Ingelheim and Roche/Genentech and personal fees from FibroGen, Sanofi, Genzyme, and Veracyte. TBL was an employee of Boehringer Ingelheim at the time this study was conducted. CH is an employee of Boehringer Ingelheim. | Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease with a variable clinical course. Biomarkers that predict patient outcomes are needed. We leveraged data from 300 patients in the multicenter IPF-PRO Registry to determine associations between circulating proteins and the composite outcome of respiratory death or lung transplant. Plasma collected at enrollment was analyzed using aptamer-based proteomics (1305 proteins). Over a median follow-up of 30.4 months, there were 76 respiratory deaths and 26 lung transplants. In unadjusted univariable analyses, 61 proteins were significantly associated with the outcome (hazard ratio > 2 or < 0.5, corrected p | Todd, Jamie L Neely, Megan L Overton, Robert Mulder, Hillary Roman, Jesse Lasky, Joseph A de Andrade, Joao A Gulati, Mridu Huang, Howard Leonard, Thomas B Hesslinger, Christian Noth, Imre Belperio, John A Flaherty, Kevin R Palmer, Scott M eng UL1 TR001863/TR/NCATS NIH HHS/ Multicenter Study Research Support, Non-U.S. Gov't Lung. 2022 Feb;200(1):11-18. doi: 10.1007/s00408-021-00505-y. Epub 2022 Jan 23.I | 01/24/2022 | |
| Proteins in the pathway from high red blood cell width distribution to all-cause mortality | Osawa Y, et al. | 2022 | EBioMedicine | 76 | 103816 | https://www.doi.org/10.1016/j.ebiom.2022.103816 | 35,065,420 | Adult Aged Aged, 80 and over Aging *Erythrocyte Indices *Erythrocytes Female Humans Middle Aged Prognosis Proteomics Risk Factors Young Adult Insulin-like growth factor-binding protein 2 Mortality Red blood cell distribution width | BACKGROUND: The pathophysiological mechanisms underlying the association between red blood cell distribution width (RDW) and all-cause mortality are unknown. We conducted a data-driven discovery investigation to identify plasma proteins that mediate the association between RDW and time to death in community-dwelling adults. METHODS: At baseline, 962 adults (women, 54.4%; age range, 21-98 years) participated in the InCHIANTI, Aging in the Chianti Area" study, and proteomics data were generated from their plasma specimens. Of these, 623 participants had proteomics data available at the 9-year follow-up. For each visit, a total of 1301 plasma proteins were measured using SOMAscan technology. Complete data on vital status were available up to the 15-year follow-up period. Protein-specific exponential distribution accelerated failure time, and linear regression analyses adjusted for possible covariates were used for mortality and mediation analyses, respectively (survival data analysis). FINDINGS: Baseline values of EGFR, GHR, NTRK3, SOD2, KLRF1, THBS2, TIMP1, IGFBP2, C9, APOB, and LRP1B mediated the association between baseline RDW and all-cause mortality. Changes in IGFBP2 and C7 over 9 years mediated the association between changes in RDW and 6-year all-cause mortality. INTERPRETATION: Cellular senescence may contribute to the association between RDW and mortality. FUNDING: This study was funded by grants from the National Institutes of Health (NIH) and the National Institute on Aging (NIA) contract and was supported by the Intramural Research Program of the NIA, NIH. The InCHIANTI study was supported as a 'targeted project' by the Italian Ministry of Health and in part by the U.S. NIA." | Osawa, Yusuke Tanaka, Toshiko Semba, Richard D Fantoni, Giovanna Moaddel, Ruin Candia, Julian Simonsick, Eleanor M Bandinelli, Stefania Ferrucci, Luigi eng R01 AG027012/AG/NIA NIH HHS/ R01 AG057723/AG/NIA NIH HHS/ R21 HL112662/HL/NHLBI NIH HHS/ R01 MD009164/MD/NIMHD NIH HHS/ R01 HL111271/HL/NHLBI NIH HHS/ Netherlands EBioMedicine. 2022 Feb;76:103816. doi: 10.1016/j.ebiom.2022.103816. Epub 2022 Jan 19.I | 01/23/2022 | ||
| Aptamers: Potential Diagnostic and Therapeutic Agents for Blood Diseases | Aljohani MM, et al. | 2022 | Molecules | 27 | 2 | https://www.doi.org/10.3390/molecules27020383 | 35,056,696 | *Aptamers, Nucleotide aptamers blood diseases diagnostic therapeutic | Aptamers are RNA/DNA oligonucleotide molecules that specifically bind to a targeted complementary molecule. As potential recognition elements with promising diagnostic and therapeutic applications, aptamers, such as monoclonal antibodies, could provide many treatment and diagnostic options for blood diseases. Aptamers present several superior features over antibodies, including a simple in vitro selection and production, ease of modification and conjugation, high stability, and low immunogenicity. Emerging as promising alternatives to antibodies, aptamers could overcome the present limitations of monoclonal antibody therapy to provide novel diagnostic, therapeutic, and preventive treatments for blood diseases. Researchers in several biomedical areas, such as biomarker detection, diagnosis, imaging, and targeted therapy, have widely investigated aptamers, and several aptamers have been developed over the past two decades. One of these is the pegaptanib sodium injection, an aptamer-based therapeutic that functions as an anti-angiogenic medicine, and it is the first aptamer approved by the U.S. Food and Drug Administration (FDA) for therapeutic use. Several other aptamers are now in clinical trials. In this review, we highlight the current state of aptamers in the clinical trial program and introduce some promising aptamers currently in pre-clinical development for blood diseases. | Aljohani, Maher M Cialla-May, Dana Popp, Jurgen Chinnappan, Raja Al-Kattan, Khaled Zourob, Mohammed eng Review Switzerland Molecules. 2022 Jan 7;27(2):383. doi: 10.3390/molecules27020383.I | 01/22/2022 | ||
| Recent Developments in Clinical Plasma Proteomics-Applied to Cardiovascular Research | Palstrom NB, et al. | 2022 | Biomedicines | 10 | 1 | https://www.doi.org/10.3390/biomedicines10010162 | 35,052,841 | affinity proteomics cardiovascular disease mass spectrometry-based proteomics plasma proteomics | The human plasma proteome mirrors the physiological state of the cardiovascular system, a fact that has been used to analyze plasma biomarkers in routine analysis for the diagnosis and monitoring of cardiovascular diseases for decades. These biomarkers address, however, only a very limited subset of cardiovascular diseases, such as acute myocardial infarct or acute deep vein thrombosis, and clinical plasma biomarkers for the diagnosis and stratification cardiovascular diseases that are growing in incidence, such as heart failure and abdominal aortic aneurysm, do not exist and are urgently needed. The discovery of novel biomarkers in plasma has been hindered by the complexity of the human plasma proteome that again transforms into an extreme analytical complexity when it comes to the discovery of novel plasma biomarkers. This complexity is, however, addressed by recent achievements in technologies for analyzing the human plasma proteome, thereby facilitating the possibility for novel biomarker discoveries. The aims of this article is to provide an overview of the recent achievements in technologies for proteomic analysis of the human plasma proteome and their applications in cardiovascular medicine. | Palstrom, Nicolai Bjodstrup Matthiesen, Rune Rasmussen, Lars Melholt Beck, Hans Christian eng Review Switzerland Biomedicines. 2022 Jan 12;10(1):162. doi: 10.3390/biomedicines10010162.I | 01/22/2022 | ||
| The amniotic fluid proteome changes with gestational age in normal pregnancy: a cross-sectional study | Bhatti G, et al. | 2022 | Sci Rep | 12 | 1 | 601 | https://www.doi.org/10.1038/s41598-021-04050-9 | 35,022,423 | Adult Amniotic Fluid/*metabolism Cross-Sectional Studies Female *Gestational Age Humans Pregnancy/*metabolism *Proteome Retrospective Studies Young Adult | The cell-free transcriptome in amniotic fluid (AF) has been shown to be informative of physiologic and pathologic processes in pregnancy; however, the change in AF proteome with gestational age has mostly been studied by targeted approaches. The objective of this study was to describe the gestational age-dependent changes in the AF proteome during normal pregnancy by using an omics platform. The abundance of 1310 proteins was measured on a high-throughput aptamer-based proteomics platform in AF samples collected from women during midtrimester (16-24 weeks of gestation, n = 15) and at term without labor (37-42 weeks of gestation, n = 13). Only pregnancies without obstetrical complications were included in the study. Almost 25% (320) of AF proteins significantly changed in abundance between the midtrimester and term gestation. Of these, 154 (48.1%) proteins increased, and 166 (51.9%) decreased in abundance at term compared to midtrimester. Tissue-specific signatures of the trachea, salivary glands, brain regions, and immune system were increased while those of the gestational tissues (uterus, placenta, and ovary), cardiac myocytes, and fetal liver were decreased at term compared to midtrimester. The changes in AF protein abundance were correlated with those previously reported in the cell-free AF transcriptome. Intersecting gestational age-modulated AF proteins and their corresponding mRNAs previously reported in the maternal blood identified neutrophil-related protein/mRNA pairs that were modulated in the same direction. The first study to utilize an aptamer-based assay to profile the AF proteome modulation with gestational age, it reveals that almost one-quarter of the proteins are modulated as gestation advances, which is more than twice the fraction of altered plasma proteins (~ 10%). The results reported herein have implications for future studies focused on discovering biomarkers to predict, monitor, and diagnose obstetrical diseases. | Bhatti, Gaurav Romero, Roberto Gomez-Lopez, Nardhy Chaiworapongsa, Tinnakorn Jung, Eunjung Gotsch, Francesca Pique-Regi, Roger Pacora, Percy Hsu, Chaur-Dong Kavdia, Mahendra Tarca, Adi L eng HHSN275201300006C/HD/NICHD NIH HHS/ Research Support, N.I.H., Intramural England Sci Rep. 2022 Jan 12;12(1):601. doi: 10.1038/s41598-021-04050-9.I | 01/14/2022 | |
| Epigenetic scores for the circulating proteome as tools for disease prediction | Gadd DA, et al. | 2022 | Elife | 11 | https://www.doi.org/10.7554/eLife.71802 | 35,023,833 | Adolescent Adult Aged Aged, 80 and over Aging Biomarkers Cardiovascular Diseases/*diagnosis DNA Methylation/*genetics Diabetes Mellitus/*diagnosis Epigenesis, Genetic Epigenomics/*methods Female Humans Life Style Male Middle Aged Neoplasms/*diagnosis Proteome/*genetics Risk Factors Scotland Young Adult biomarker epidemiology epigenetic genetics genomics global health human morbiditiy prediction proteomics CH, PV, SC, KE, AM, KS No competing interests declared, RH has received consultant fees from Illumina, RM has received speaker fees from Illumina and is an advisor to the Epigenetic Clock Development Foundation | Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNA methylation (DNAm) signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample (Generation Scotland; n = 9537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore-disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors, and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification. Although our genetic code does not change throughout our lives, our genes can be turned on and off as a result of epigenetics. Epigenetics can track how the environment and even certain behaviors add or remove small chemical markers to the DNA that makes up the genome. The type and location of these markers may affect whether genes are active or silent, this is, whether the protein coded for by that gene is being produced or not. One common epigenetic marker is known as DNA methylation. DNA methylation has been linked to the levels of a range of proteins in our cells and the risk people have of developing chronic diseases. Blood samples can be used to determine the epigenetic markers a person has on their genome and to study the abundance of many proteins. Gadd, Hillary, McCartney, Zaghlool et al. studied the relationships between DNA methylation and the abundance of 953 different proteins in blood samples from individuals in the German KORA cohort and the Scottish Lothian Birth Cohort 1936. They then used machine learning to analyze the relationship between epigenetic markers found in people's blood and the abundance of proteins, obtaining epigenetic scores or 'EpiScores' for each protein. They found 109 proteins for which DNA methylation patterns explained between at least 1% and up to 58% of the variation in protein levels. Integrating the 'EpiScores' with 14 years of medical records for more than 9000 individuals from the Generation Scotland study revealed 137 connections between EpiScores for proteins and a future diagnosis of common adverse health outcomes. These included diabetes, stroke, depression, Alzheimer's dementia, various cancers, and inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease. Age-related chronic diseases are a growing issue worldwide and place pressure on healthcare systems. They also severely reduce quality of life for individuals over many years. This work shows how epigenetic scores based on protein levels in the blood could predict a person's risk of several of these diseases. In the case of type 2 diabetes, the EpiScore results replicated previous research linking protein levels in the blood to future diagnosis of diabetes. Protein EpiScores could therefore allow researchers to identify people with the highest risk of disease, making it possible to intervene early and prevent these people from developing chronic conditions as they age. eng | Gadd, Danni A Hillary, Robert F McCartney, Daniel L Zaghlool, Shaza B Stevenson, Anna J Cheng, Yipeng Fawns-Ritchie, Chloe Nangle, Cliff Campbell, Archie Flaig, Robin Harris, Sarah E Walker, Rosie M Shi, Liu Tucker-Drob, Elliot M Gieger, Christian Peters, Annette Waldenberger, Melanie Graumann, Johannes McRae, Allan F Deary, Ian J Porteous, David J Hayward, Caroline Visscher, Peter M Cox, Simon R Evans, Kathryn L McIntosh, Andrew M Suhre, Karsten Marioni, Riccardo E eng BB/F019394/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom 216767/Z/19/Z/WT_/Wellcome Trust/United Kingdom 221890/Z/20/Z/WT_/Wellcome Trust/United Kingdom G0700704/MRC_/Medical Research Council/United Kingdom P2C HD042849/HD/NICHD NIH HHS/ MR/R024065/1/MRC_/Medical Research Council/United Kingdom MC_UU_00007/10/MRC_/Medical Research Council/United Kingdom WT_/Wellcome Trust/United Kingdom MR/L023784/2/MRC_/Medical Research Council/United Kingdom MR/M013111/1/MRC_/Medical Research Council/United Kingdom RF1 AG073593/AG/NIA NIH HHS/ 104036/Z/14/Z/WT_/Wellcome Trust/United Kingdom 220857/Z/20/Z/WT_/Wellcome Trust/United Kingdom 203771/Z/16/Z/WT_/Wellcome Trust/United Kingdom 108890/Z/15/Z/WT_/Wellcome Trust/United Kingdom DH_/Department of Health/United Kingdom R01 AG054628/AG/NIA NIH HHS/ P30 AG066614/AG/NIA NIH HHS/ G1001245/MRC_/Medical Research Council/United Kingdom G0701120/MRC_/Medical Research Council/United Kingdom MR/K026992/1/MRC_/Medical Research Council/United Kingdom CZD/16/6/CSO_/Chief Scientist Office/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Elife. 2022 Jan 13;11:e71802. doi: 10.7554/eLife.71802.I | 01/14/2022 | |||
| Acute serum protein and cytokine response of single dose of prednisone in adult volunteers | Roy R, et al. | 2022 | Steroids | 178 | 108953 | https://www.doi.org/10.1016/j.steroids.2021.108953 | 35,026,285 | Blood Proteins *Cytokines/genetics Glucocorticoids/therapeutic use Humans Prednisone/pharmacology *Receptors, Glucocorticoid/genetics/metabolism Tumor Necrosis Factor Ligand Superfamily Member 15 Volunteers Young Adult Corticosteroids Il-10 Il-8 Pharmacodynamic biomarkers Prednisone | Pharmacological glucocorticoids are the most prescribed anti-inflammatory medications, and are chemical variants of cortisol, the circadian and stress hormone. Both endogenous and pharmacological glucocorticoids bind the glucocorticoid receptor (NR3C1) with high affinity, and both then bind downstream gene promoter elements (GRE) to drive positive gene transcription of many proteins. Glucocorticoid/GR complexes also bind distinct negative gene promoter elements (nGRE) to inhibit expression of genes involved in NF-kappaB innate immunity signaling. We sought to define the acute response of a single dose of prednisone (0.2 mg/kg) in young adult volunteers, with blood samples taken at baseline, 2, 3, 4 and 6 h post-oral dose. To control for circadian morning cortisol hitting the same molecular pathways, a day of blood draws was done without oral prednisone (same time of day), one day prior to drug day. Serum samples were processed for steroid hormone profiles (mass spectrometry; 9 steroidal hormones), proteomics (SOMAscan aptamer panels, 1,305 proteins), and inflammatory markers (Meso Scale Discovery; 10 pro-inflammatory cytokines). The pharmacological effect of the prednisone dose was shown by significant declines of adrenal steroids by 3 h after dosing. IL-10 showed drug-related increase to 4 hrs, then decrease to 6 hrs. IL-8 showed drug-related decrease in serum by 4 h, consistent with direct negative action of GR/ligand on IL-8 gene promoter. Proteomics data showed beta-2 microglobulin, TNFSF15, TSH, CST3, NBL1 to show time-related decreases with prednisone, while CXCL13 showed increases, although these require validation. In summary, a single low dose of prednisone leads to broad suppression of the adrenal axis within 3 h, and down-regulation of inflammatory serum proteins by 6 h. | Roy, Runia Soldin, Steven J Stolze, Brian Barbieri, Marissa Tawalbeh, Shefa M Rouhana, Nicole Fronczek, Ann E Nagaraju, Kanneboyina van den Anker, John Dang, Utkarsh J Hoffman, Eric P eng U54 HD090254/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural Steroids. 2022 Feb;178:108953. doi: 10.1016/j.steroids.2021.108953. Epub 2022 Jan 10.I | 01/14/2022 | ||
| Influenza A Virus Uses PSMA2 for Downregulation of the NRF2-Mediated Oxidative Stress Response | Rashid MU, et al. | 2022 | J Virol | 96 | 5 | e0199021 | https://www.doi.org/10.1128/jvi.01990-21 | 35,019,712 | Down-Regulation *Host-Pathogen Interactions/genetics Humans Immune Evasion/genetics *Influenza A virus/genetics/immunology *Influenza, Human/immunology/virology NF-E2-Related Factor 2/genetics Oxidative Stress *Proteasome Endopeptidase Complex/genetics/metabolism Proteomics Reactive Oxygen Species/metabolism Virus Replication/genetics Nrf-2 Psma2 host protein influenza A virus proteasome | Influenza A virus (IAV), an obligatory intracellular parasite, uses host cellular molecules to complete its replication cycle and suppress immune responses. Proteasome subunit alpha type 2 (PSMA2) is a cellular protein highly expressed in IAV-infected human lung epithelial A549 cells. PSMA2 is part of the 20S proteasome complex that degrades or recycles defective proteins and involves proteolytic modification of many cellular regulatory proteins. However, the role of PSMA2 in IAV replication is not well understood. In this study, PSMA2 knockdown (KD) in A549 cells caused a significant reduction in extracellular progeny IAV, but intracellular viral protein translation and viral RNA transcription were not affected. This indicates that PSMA2 is a critical host factor for IAV maturation. To better understand the interplay between PSMA2 KD and IAV infection at the proteomic level, we used the SomaScan 1.3K version, which measures 1,307 proteins to analyze alterations induced by these treatments. We found seven cellular signaling pathways, including phospholipase C signaling, Pak signaling, and nuclear factor erythroid 2p45-related factor 2 (NRF2)-mediated oxidative stress response signaling, that were inhibited by IAV infection but significantly activated by PSMA2 KD. Further analysis of NRF2-mediated oxidative stress response signaling indicated IAV inhibits accumulation of reactive oxygen species (ROS), but ROS levels significantly increased during IAV infection in PSMA2 KD cells. However, IAV infection caused significantly higher NFR2 nuclear translocation that was inhibited in PSMA2 KD cells. This indicates that PSMA2 is required for NRF2-mediated ROS neutralization and that IAV uses PSMA2 to escape viral clearance via the NRF2-mediated cellular oxidative response. IMPORTANCE Influenza A virus (IAV) remains one of the most significant infectious agents, responsible for 3 million to 5 million illnesses each year and more than 50 million deaths during the 20th century. The cellular processes that promote and inhibit IAV infection and pathogenesis remain only partially understood. PSMA2 is a critical component of the 20S proteasome and ubiquitin-proteasome system, which is important in the replication of numerous viruses. This study examined host protein responses to IAV infection alone, PSMA2 knockdown alone, and IAV infection in the presence of PSMA2 knockdown and determined that interfering with PSMA2 function affected IAV maturation. These results help us better understand the importance of PSMA2 in IAV replication and may pave the way for designing additional IAV antivirals targeting PSMA2 or the host proteasome for the treatment of seasonal flu. | Rashid, Mahamud-Ur Gao, Ang Coombs, Kevin M eng MOP-106713/CIHR/Canada Research Support, Non-U.S. Gov't J Virol. 2022 Mar 9;96(5):e0199021. doi: 10.1128/jvi.01990-21. Epub 2022 Jan 12.I | 01/13/2022 | |
| Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration | Bagaria J, et al. | 2022 | Int J Mol Sci | 23 | 1 | https://www.doi.org/10.3390/ijms23010552 | 35,008,978 | Alleles Amino Acid Substitution Animals Brain/metabolism/pathology Disease Management Gene Expression Regulation Genetic Association Studies *Genetic Predisposition to Disease Genotype Heat-Shock Proteins/chemistry/*genetics/metabolism Humans Mitochondria/metabolism Muscle Spasticity/*diagnosis/*genetics/therapy Mutation Neurodegenerative Diseases/diagnosis/*etiology *Phenotype Protein Interaction Domains and Motifs Spinocerebellar Ataxias/*congenital/diagnosis/genetics/therapy Arsacs ataxia neurodegeneration sacsin | Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases. | Bagaria, Jaya Bagyinszky, Eva An, Seong Soo A eng 2021R1A6A1A03038996/National Research Foundation of Korea/ 2020R1A2B5B01002463/National Research Foundation/ Review Switzerland Int J Mol Sci. 2022 Jan 4;23(1):552. doi: 10.3390/ijms23010552.I | 01/12/2022 | ||
| Effects of colchicine on lipolysis and adipose tissue inflammation in adults with obesity and metabolic syndrome | Levine JA, et al. | 2022 | Obesity (Silver Spring) | 30 | 2 | 358-368 | https://www.doi.org/10.1002/oby.23341 | 34,978,374 | Adipose Tissue/metabolism Adult Biomarkers/metabolism Colchicine/metabolism/pharmacology/therapeutic use Humans Inflammation/metabolism Insulin/metabolism *Insulin Resistance Lipolysis *Metabolic Syndrome/metabolism Obesity/complications/drug therapy/metabolism | OBJECTIVE: The aim of this study was to examine whether colchicine's anti-inflammatory effects would improve measures of lipolysis and distribution of leukocyte populations in subcutaneous adipose tissue (SAT). METHODS: A secondary analysis was conducted for a double-blind, randomized, placebo-controlled pilot study in which 40 adults with obesity and metabolic syndrome (MetS) were randomized to colchicine 0.6 mg or placebo twice daily for 3 months. Non-insulin-suppressible (l(0) ), insulin-suppressible (l(2) ), and maximal (l(0) +l(2) ) lipolysis rates were calculated by minimal model analysis. Body composition was determined by dual-energy x-ray absorptiometry. SAT leukocyte populations were characterized by flow cytometry analysis from biopsied samples obtained before and after the intervention. RESULTS: Colchicine treatment significantly decreased l(2) and l(0) +l(2) versus placebo (p < 0.05). These changes were associated with a significant reduction in markers of systemic inflammation, including high-sensitivity C-reactive protein, resistin, and circulating monocytes and neutrophils (p < 0.01). Colchicine did not significantly alter SAT leukocyte population distributions (p > 0.05). CONCLUSIONS: In adults with obesity and MetS, colchicine appears to improve insulin regulation of lipolysis and reduce markers of systemic inflammation independent of an effect on local leukocyte distributions in SAT. Further studies are needed to better understand the mechanisms by which colchicine affects adipose tissue metabolic pathways in adults with obesity and MetS. | Levine, Jordan A Sarrafan-Chaharsoughi, Zahra Patel, Tushar P Brady, Sheila M Chivukula, K Karthik Miller, Emily Han, Jung Min Periwal, Vipul Wolska, Anna Remaley, Alan T Dagur, Pradeep K Biancotto, Angelique Babyak, Ashley Fantoni, Giovanna Yanovski, Jack A Demidowich, Andrew P eng Z99 HD999999/ImNIH/Intramural NIH HHS/ ZIA HD000641/ImNIH/Intramural NIH HHS/ Randomized Controlled Trial Research Support, N.I.H., Intramural Obesity (Silver Spring). 2022 Feb;30(2):358-368. doi: 10.1002/oby.23341. Epub 2022 Jan 3.I | 01/04/2022 | |
| Serum Proteomics Uncovers Biomarkers of Clinical Portal Hypertension in Children With Biliary Atresia | Osborn J, et al. | 2022 | Hepatol Commun | 6 | 5 | 995-1004 | https://www.doi.org/10.1002/hep4.1878 | 34,962,102 | *Biliary Atresia/complications Biomarkers Child Endothelial Cells Humans *Hypertension, Portal/diagnosis Infant Proteomics | Children with biliary atresia (BA) often develop portal hypertension (PHT) and its complications, which are associated with high morbidity and mortality. The goal of this study was to identify serum biomarkers of PHT by using large-scale proteomics. We applied the slow off-rate modified aptamer scan (SOMAscan) to measure 1,305 proteins in serum samples of children with BA with and without clinical evidence of PHT in validation and discovery cohorts enrolled in the Biliary Atresia Study of Infants and Children. Serum proteomics data was analyzed using logistic regression to identify protein(s) with an area under the receiver operating characteristic curve (AUROC) >/= 0.90. Immunostaining was used to characterize the cellular localization of the new biomarker proteins in liver tissues. We identified nine proteins in the discovery cohort (n = 40 subjects) and five proteins in the validation cohort (n = 80 subjects) that individually or in combination predicted clinical PHT with AUROCs >/= 0.90. Merging the two cohorts, we found that semaphorin 6B (SEMA6B) alone and three other protein combinations (SEMA6B+secreted frizzle protein 3 [SFRP3], SEMA6B+COMM domain containing 7 [COMMD7], and vascular cell adhesion molecule 1 [VCAM1]+BMX nonreceptor tyrosine kinase [BMX]) had AUROCs >/= 0.90 in both cohorts, with high positive- and negative-predictive values. Immunostaining of the new protein biomarkers showed increased expression in hepatic endothelial cells, cholangiocytes, and immune cells within portal triads in BA livers with clinical PHT compared to healthy livers. Conclusion: Large-scale proteomics identified SEMA6B, SFRP3, COMMD7, BMX, and VCAM1 as biomarkers highly associated with clinical PHT in BA. The expression of the biomarkers in hepatic epithelial, endothelial, and immune cells support their potential role in the pathophysiology of PHT. | Osborn, Julie Mourya, Reena Thanekar, Unmesha Su, Weizhe Fei, Lin Shivakumar, Pranavkumar Bezerra, Jorge A eng T32 DK007727/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Hepatol Commun. 2022 May;6(5):995-1004. doi: 10.1002/hep4.1878. Epub 2021 Dec 27.I | 12/29/2021 | |
| Proteomic analysis of serum in workers exposed to diesel engine exhaust | Rahman ML, et al. | 2022 | Environ Mol Mutagen | 63 | 1 | 18-28 | https://www.doi.org/10.1002/em.22469 | 34,894,159 | *Air Pollutants, Occupational/analysis/toxicity Carbon/analysis/metabolism Cross-Sectional Studies Group IB Phospholipases A2/metabolism Humans Inflammation/metabolism *Occupational Exposure/adverse effects/analysis Proteomics RNA-Binding Proteins/analysis Vehicle Emissions/analysis/toxicity SOMAscan carcinogenesis diesel engine exhaust elemental carbon lung cancer | Diesel engine exhaust (DEE) is classified as a Group 1 human carcinogen. Using a targeted proteomics approach, we aimed to identify proteins associated with DEE and characterize these markers to understand the mechanisms of DEE-induced carcinogenicity. In this cross-sectional molecular epidemiology study, we measured elemental carbon (EC) using a personal air monitor and quantified 1317 targeted proteins in the serum using the SOMAScan assay (SOMALogic) among 19 diesel exposed factory workers and 19 unexposed controls. We used linear regressions to identify proteins associated with DEE and examined their exposure-response relationship across levels of EC using linear trend tests. We further examined pathway enrichment of DEE-related proteins using MetaCore. Occupational exposure to DEE was associated with altered levels of 22 serum proteins (permutation p < .01). Of these, 13 proteins (CXCL11, HAPLN1, FLT4, CD40LG, PES1, IGHE.IGK..IGL, TNFSF9, PGD, NAGK, CCL25, CCL4L1, PDXK, and PLA2G1B) showed an exposure-response relationship with EC (p trend < .01), with serum levels of all but PLA2G1B declining with increasing air levels of EC. For instance, C-X-C Motif Chemokine Ligand 11 (CXCL11) showed the most significant association with DEE (beta = -0.25; permutation p = .00004), where mean serum levels were 4121.1, 2356.7, and 2298.8 relative fluorescent units among the unexposed, lower exposed (median, range : 56.9, 40.2-62.1 mug/m(3) EC), and higher exposed (median, range of EC: 72.9, 66.9-107.7 mug/m(3) EC) groups, respectively (p trend = .0005). Pathway analysis suggested that these proteins are enriched in pathways related to inflammation and immune regulation. Our study suggests that DEE exposure is associated with altered serum proteins, which play a role in inflammation and immune regulation. | Rahman, Mohammad L Bassig, Bryan A Dai, Yufei Hu, Wei Wong, Jason Y Y Blechter, Batel Hosgood, H Dean Ren, Danzhi Duan, Huawei Niu, Yong Xu, Jun Fu, Wei Meliefste, Kees Zhou, Baosen Yang, Jufang Ye, Meng Jia, Xiaowei Meng, Tao Bin, Ping Silverman, Debra T Vermeulen, Roel Rothman, Nathaniel Zheng, Yuxin Lan, Qing eng Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Environ Mol Mutagen. 2022 Jan;63(1):18-28. doi: 10.1002/em.22469. Epub 2021 Dec 28.I | 12/12/2021 | |
| Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease | Katz DH, et al. | 2022 | Circulation | 145 | 5 | 357-370 | https://www.doi.org/10.1161/CIRCULATIONAHA.121.055117 | 34,814,699 | Adult Blacks Cardiovascular Diseases/*epidemiology/*genetics Female Genome-Wide Association Study/*methods Humans Male Proteome/*metabolism cardiovascular disease genetics proteomics race and ethnicity | BACKGROUND: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. METHODS: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count >/=5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). RESULTS: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8x10(-11). These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, beta=0.61+/-0.05, P=3.27x10(-30)) and MMP-3 (beta=-0.60+/-0.05, P=1.67x10(-32)), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, beta=0.34+/-0.04, P=1.34x10(-17)) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. CONCLUSIONS: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function. | Katz, Daniel H Tahir, Usman A Bick, Alexander G Pampana, Akhil Ngo, Debby Benson, Mark D Yu, Zhi Robbins, Jeremy M Chen, Zsu-Zsu Cruz, Daniel E Deng, Shuliang Farrell, Laurie Sinha, Sumita Schmaier, Alec A Shen, Dongxiao Gao, Yan Hall, Michael E Correa, Adolfo Tracy, Russell P Durda, Peter Taylor, Kent D Liu, Yongmei Johnson, W Craig Guo, Xiuqing Yao, Jie Ida Chen, Yii-Der Manichaikul, Ani W Jain, Deepti Bouchard, Claude Sarzynski, Mark A Rich, Stephen S Rotter, Jerome I Wang, Thomas J Wilson, James G Natarajan, Pradeep Gerszten, Robert E (Trans-Omics for Precision Medicine) eng R01 NR019628/NR/NINR NIH HHS/ DP5 OD029586/OD/NIH HHS/ R01 DK081572/DK/NIDDK NIH HHS/ R01 HL142711/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ T32 HL007374/HL/NHLBI NIH HHS/ F32 HL150992/HL/NHLBI NIH HHS/ K08 HL145095/HL/NHLBI NIH HHS/ U01 DK062413/DK/NIDDK NIH HHS/ KL2 TR002542/TR/NCATS NIH HHS/ K08 HL141601/HL/NHLBI NIH HHS/ RF1 AG063507/AG/NIA NIH HHS/ K23 DK127073/DK/NIDDK NIH HHS/ R01 HL146462/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circulation. 2022 Feb;145(5):357-370. doi: 10.1161/CIRCULATIONAHA.121.055117. Epub 2021 Nov 24.I | 11/25/2021 | |
| Liquid biomarkers for fibrotic NASH - progress in a complex field | Schuppan D, et al. | 2022 | J Hepatol | 76 | 1 | 7-May | https://www.doi.org/10.1016/j.jhep.2021.11.005 | 34,801,249 | Biomarkers Fibrosis Humans *Non-alcoholic Fatty Liver Disease/diagnosis Companion biomarker Nafld fibrogenesis liver biopsy liver fibrosis prediction serum marker arrangement or affiliation with any organization that may have a direct influence on their work. Please refer to the accompanying ICMJE disclosure forms for further details. | Schuppan, Detlef Myneni, Sudharani Surabattula, Rambabu eng Comment Editorial Research Support, Non-U.S. Gov't Netherlands J Hepatol. 2022 Jan;76(1):5-7. doi: 10.1016/j.jhep.2021.11.005. Epub 2021 Nov 17.I | 11/22/2021 | ||
| Identification of blood-based biomarkers for diagnosis and prognosis of Parkinson's disease: A systematic review of proteomics studies | Chelliah SS, et al. | 2022 | Ageing Res Rev | 73 | 101514 | https://www.doi.org/10.1016/j.arr.2021.101514 | 34,798,300 | Biomarkers Dopaminergic Neurons Humans *Parkinson Disease/diagnosis Prognosis Proteomics Apolipoprotein A-I Apolipoproteins Blood-based biomarkers Parkinson's disease Systematic review | Parkinson's Disease (PD), a neurodegenerative disorder, is characterised by the loss of motor function and dopamine neurons. Therapeutic avenues remain a challenge due to lack of accuracy in early diagnosis, monitoring of disease progression and limited therapeutic options. Proteomic platforms have been utilised to discover biomarkers for numerous diseases, a tool that may benefit the diagnosis and monitoring of disease progression in PD patients. Therefore, this systematic review focuses on analysing blood-based candidate biomarkers (CB) identified via proteomics platforms for PD. This study systematically reviewed articles across six databases (EMBASE, Cochrane, Ovid Medline, Scopus, Science Direct and PubMed) published between 2010 and 2020. Of the 504 articles identified, 12 controlled-PD studies were selected for further analysis. A total of 115 candidate biomarkers (CB) were identified across selected 12-controlled studies, of which 23 CB were found to be replicable in more than two cohorts. Using the PANTHER Go-Slim classification system and STRING network, the gene function and protein interactions between biomarkers were analysed. Our analysis highlights Apolipoprotein A-I (ApoA-I), which is essential in lipid metabolism, oxidative stress, and neuroprotection demonstrates high replicability across five cohorts with consistent downregulation across four cohorts. Since ApoA-I was highly replicable across blood fractions, proteomic platforms and continents, its relationship with cholesterol, statin and oxidative stress as PD biomarker, its role in the pathogenesis of PD is discussed in this paper. The present study identified ApoA-I as a potential biomarker via proteomics analysis of PD for the early diagnosis and prediction of disease progression. | Chelliah, Shalini Sundramurthi Bhuvanendran, Saatheeyavaane Magalingam, Kasthuri Bai Kamarudin, Muhamad Noor Alfarizal Radhakrishnan, Ammu Kutty eng Research Support, Non-U.S. Gov't Review Systematic Review England Ageing Res Rev. 2022 Jan;73:101514. doi: 10.1016/j.arr.2021.101514. Epub 2021 Nov 16.I | 11/20/2021 | ||
| Proteome-wide associations with short- and long-term weight loss and regain after Roux-en-Y gastric bypass surgery | Yousri NA, et al. | 2022 | Obesity (Silver Spring) | 30 | 1 | 129-141 | https://www.doi.org/10.1002/oby.23303 | 34,796,696 | Body Mass Index Follow-Up Studies *Gastric Bypass/methods Humans *Obesity, Morbid/complications/surgery Proteome Retrospective Studies Treatment Outcome Weight Loss | OBJECTIVE: Gastric bypass surgery results in long-term weight loss. Small studies have examined protein changes during rapid weight loss (up to 1 or 2 years post surgery). This study tested whether short-term changes were maintained after 12 years. METHODS: A 12-year follow-up, protein-wide association study of 1,297 SomaLogic aptamer-based plasma proteins compared short- (2-year) and long-term (12-year) protein changes in 234 individuals who had gastric bypass surgery with 144 nonintervened individuals with severe obesity. RESULTS: There were 51 replicated 12-year protein changes that differed between the surgery and nonsurgery groups. Adjusting for change in BMI, only 12 proteins remained significant, suggesting that BMI change was the primary reason for most protein changes and not non-BMI-related surgical effects. Protein changes were related to BMI changes during both weight-loss and weight-regain periods. The significant proteins were associated primarily with lipid, uric acid, or resting energy expenditure clinical variables and metabolic pathways. Eight protein changes were associated with 12-year diabetes remission, including apolipoprotein M, sex hormone binding globulin, and adiponectin (p < 3.5 x 10(-5) ). CONCLUSIONS: This study showed that most short-term postsurgical changes in proteins were maintained at 12 years. Systemic protection pathways, including inflammation, complement, lipid, and adipocyte pathways, were related to the long-term benefits of gastric bypass surgery. | Yousri, Noha A Engelke, Rudolf Sarwath, Hina McKinlay, Rodrick D Simper, Steven C Adams, Ted D Schmidt, Frank Suhre, Karsten Hunt, Steven C eng M01 RR000064/RR/NCRR NIH HHS/ R01 DK055006/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Obesity (Silver Spring). 2022 Jan;30(1):129-141. doi: 10.1002/oby.23303. Epub 2021 Nov 18.I | 11/20/2021 | |
| Clinically Relevant Circulating Protein Biomarkers for Type 1 Diabetes: Evidence From a Two-Sample Mendelian Randomization Study | Yazdanpanah N, et al. | 2022 | Diabetes Care | 45 | 1 | 169-177 | https://www.doi.org/10.2337/dc21-1049 | 34,758,976 | Biomarkers *Diabetes Mellitus, Type 1/genetics *Epstein-Barr Virus Infections Genome-Wide Association Study/methods Herpesvirus 4, Human Humans Mendelian Randomization Analysis/methods Polymorphism, Single Nucleotide | OBJECTIVE: To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR). RESEARCH DESIGN AND METHODS: We used a large-scale two-sample MR study, using cis genetic determinants (protein quantitative trait loci [pQTL]) of up to 1,611 circulating proteins from five large genome-wide association studies, to screen for causal associations of these proteins with type 1 diabetes risk in 9,684 case subjects with type 1 diabetes and 15,743 control subjects. Further, pleiotropy-robust MR methods were used in sensitivity analyses using both cis and trans-pQTL. RESULTS: We found that a genetically predicted SD increase in signal regulatory protein gamma (SIRPG) level was associated with increased risk of type 1 diabetes risk (MR odds ratio [OR] 1.66 [95% 1.36-2.03]; P = 7.1 x 10-7). The risk of type 1 diabetes increased almost twofold per genetically predicted standard deviation (SD) increase in interleukin-27 Epstein-Barr virus-induced 3 (IL27-EBI3) protein levels (MR OR 1.97 [95% CI 1.48-2.62]; P = 3.7 x 10-6). However, an SD increase in chymotrypsinogen B1 (CTRB1) was associated with decreased risk of type 1 diabetes (MR OR 0.84 [95% CI 0.77-0.90]; P = 6.1 x 10-6). Sensitivity analyses using MR methods testing for pleiotropy while including trans-pQTL showed similar results. While the MR-Egger suggested no pleotropic effect (P value MR-Egger intercept = 0.31), there was evidence of pleiotropy in MR-PRESSO (P value global test = 0.006). CONCLUSIONS: We identified three novel circulating protein biomarkers associated with type 1 diabetes risk using an MR approach. These biomarkers are promising targets for development of drugs and/or of screening tools for early prediction of type 1 diabetes. | Yazdanpanah, Nahid Yazdanpanah, Mojgan Wang, Ye Forgetta, Vincenzo Pollak, Michael Polychronakos, Constantin Richards, J Brent Manousaki, Despoina eng Research Support, Non-U.S. Gov't Diabetes Care. 2022 Jan 1;45(1):169-177. doi: 10.2337/dc21-1049.I | 11/12/2021 | |
| ADAMTSL2 protein and a soluble biomarker signature identify at-risk non-alcoholic steatohepatitis and fibrosis in adults with NAFLD | Corey KE, et al. | 2022 | J Hepatol | 76 | 1 | 25-33 | https://www.doi.org/10.1016/j.jhep.2021.09.026 | 34,600,973 | ADAMTS Proteins/*analysis Adult Area Under Curve Biomarkers/analysis Biopsy/methods/statistics & numerical data Case-Control Studies Cohort Studies Female Humans Liver Cirrhosis/blood/*diagnosis/pathology Logistic Models Male Massachusetts Middle Aged Non-alcoholic Fatty Liver Disease/*diagnosis/pathology Prospective Studies ROC Curve Adamtsl2 biomarker fibrosis non-alcoholic fatty liver disease non-alcoholic steatohepatitis proteomics of Novartis. KEC serves on the scientific advisory board for Novo Nordisk and BMS and has received grant funding from Boehringer-Ingelheim, BMS and Novartis. All other authors have no conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details. | BACKGROUND & AIMS: Identifying fibrosis in non-alcoholic fatty liver disease (NAFLD) is essential to predict liver-related outcomes and guide treatment decisions. A protein-based signature of fibrosis could serve as a valuable, non-invasive diagnostic tool. This study sought to identify circulating proteins associated with fibrosis in NAFLD. METHODS: We used aptamer-based proteomics to measure 4,783 proteins in 2 cohorts (Cohort A and B). Targeted, quantitative assays coupling aptamer-based protein pull down and mass spectrometry (SPMS) validated the profiling results in a bariatric and NAFLD cohort (Cohort C and D, respectively). Generalized linear modeling-logistic regression assessed the ability of candidate proteins to classify fibrosis. RESULTS: From the multiplex profiling, 16 proteins differed significantly by fibrosis in cohorts A (n = 62) and B (n = 98). Quantitative and robust SPMS assays were developed for 8 proteins and validated in Cohorts C (n = 71) and D (n = 84). The A disintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2) protein accurately distinguished non-alcoholic fatty liver (NAFL)/non-alcoholic steatohepatitis (NASH) with fibrosis stage 0-1 (F0-1) from at-risk NASH with fibrosis stage 2-4, with AUROCs of 0.83 and 0.86 in Cohorts C and D, respectively, and from NASH with significant fibrosis (F2-3), with AUROCs of 0.80 and 0.83 in Cohorts C and D, respectively. An 8-protein panel distinguished NAFL/NASH F0-1 from at-risk NASH (AUROCs 0.90 and 0.87 in Cohort C and D, respectively) and NASH F2-3 (AUROCs 0.89 and 0.83 in Cohorts C and D, respectively). The 8-protein panel and ADAMTSL2 protein had superior performance to the NAFLD fibrosis score and fibrosis-4 score. CONCLUSION: The ADAMTSL2 protein and an 8-protein soluble biomarker panel are highly associated with at-risk NASH and significant fibrosis; they exhibited superior diagnostic performance compared to standard of care fibrosis scores. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease worldwide. Diagnosing NAFLD and identifying fibrosis (scarring of the liver) currently requires a liver biopsy. Our study identified novel proteins found in the blood which may identify fibrosis without the need for a liver biopsy. | Corey, Kathleen E Pitts, Rebecca Lai, Michelle Loureiro, Joseph Masia, Ricard Osganian, Stephanie A Gustafson, Jenna L Hutter, Matthew M Gee, Denise W Meireles, Ozanan R Witkowski, Elan R Richards, Shola M Jacob, Jaison Finkel, Nancy Ngo, Debby Wang, Thomas J Gerszten, Robert E Ukomadu, Chinweike Jennings, Lori L eng P30 DK040561/DK/NIDDK NIH HHS/ R03 DK113349/DK/NIDDK NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ R01 DK114144/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Netherlands J Hepatol. 2022 Jan;76(1):25-33. doi: 10.1016/j.jhep.2021.09.026. Epub 2021 Oct 1.I | 10/04/2021 | |
| The Plasma Proteome Fingerprint Associated with Circulating Carotenoids and Retinol in Older Adults | Yamaguchi Y, et al. | 2022 | J Nutr | 152 | 1 | 40-48 | https://www.doi.org/10.1093/jn/nxab340 | 34,550,359 | Carotenoids Lutein *Proteome Proteomics *Vitamin A Zeaxanthins beta Carotene carotene carotenoid cryptoxanthin lycopene protein retinol zeaxanthin | BACKGROUND: Although diets rich in carotenoids are associated with reduced risks of cardiovascular disease, age-related macular degeneration, disability, and other adverse aging outcomes, the underlying biological mechanisms are not fully elucidated. OBJECTIVES: To characterize the plasma proteome fingerprint associated with circulating carotenoid and retinol concentrations in older adults. METHODS: In 728 adults >/=65 y participating in the Invecchiare in Chianti (InCHIANTI) Study, plasma alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, and lycopene were measured using HPLC. The SOMAscan assay was used to measure 1301 plasma proteins. Multivariable linear regression models were used to examine the relationship of individual carotenoids and retinol with plasma proteins. A false discovery rate approach was used to deal with multiple comparisons using a q-value < 0.05. RESULTS: Plasma beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, and lycopene were associated with 85, 39, 4, 2, and 5 plasma proteins, respectively, in multivariable linear regression models adjusting for potential confounders (q < 0.05). No proteins were associated with alpha-carotene or retinol. Two or more carotenoids were positively associated with ferritin, 6-phosphogluconate dehydrogenase (decarboxylating), hepcidin, thrombospondin-2, and choline/ethanolamine kinase. The proteins associated with circulating carotenoids were related to energy metabolism, sirtuin signaling, inflammation and oxidative stress, iron metabolism, proteostasis, innate immunity, and longevity. CONCLUSIONS: The plasma proteomic fingerprint associated with elevated circulating carotenoids in older adults provides insight into the mechanisms underlying the protective role of carotenoids on health. | Yamaguchi, Yuko Zampino, Marta Tanaka, Toshiko Bandinelli, Stefania Moaddel, Ruin Fantoni, Giovanna Candia, Julian Ferrucci, Luigi Semba, Richard D eng R01 AG057723/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Nutr. 2022 Jan 11;152(1):40-48. doi: 10.1093/jn/nxab340.I | 09/23/2021 | |
| Pediatric and adult dilated cardiomyopathy are distinguished by distinct biomarker profiles | Gropler MRF, et al. | 2022 | Pediatr Res | 92 | 1 | 206-215 | https://www.doi.org/10.1038/s41390-021-01698-x | 34,404,929 | Biomarkers *Cardiomyopathy, Dilated/diagnosis Humans Phenotype Prospective Studies | BACKGROUND: Emerging evidence suggests that pediatric and adult dilated cardiomyopathy (DCM) represent distinct diseases. Few diagnostic tools exist for pediatric cardiologists to assess clinical status and prognosis. We hypothesized that pediatric DCM would have a unique biomarker profile compared to adult DCM and controls. METHODS: We utilized a DNA aptamer array (SOMAScan) to compare biomarker profiles between pediatric and adult DCM. We simultaneously measured 1310 plasma proteins and peptides from 39 healthy children (mean age 3 years, interquartile range (IQR) 1-14), 39 ambulatory subjects with pediatric DCM (mean age 2.7 years, IQR 1-13), and 40 ambulatory adults with DCM (mean age 53 years, IQR 46-63). RESULTS: Pediatric and adult DCM patients displayed distinct biomarker profiles, despite similar clinical characteristics. We identified 20 plasma peptides and proteins that were increased in pediatric DCM compared to age- and sex-matched controls. Unbiased multidimensionality reduction analysis suggested previously unrecognized heterogeneity among pediatric DCM subjects. Biomarker profile analysis identified four subgroups of pediatric DCM with distinguishing clinical characteristics. CONCLUSIONS: These findings support the emerging concept that pediatric and adult DCM are distinct disease entities, signify the need to develop pediatric-specific biomarkers for disease prognostication, and challenge the paradigm that pediatric DCM should be viewed as a single disease. IMPACT: Pediatric and adult DCM patients displayed distinct biomarker profiles, despite similar clinical characteristics and outcomes. Our findings suggest that pediatric DCM may be a heterogeneous disease with various sub-phenotypes, including differing biomarker profiles and clinical findings. These data provide prerequisite information for future prospective studies that validate the identified pediatric DCM biomarkers, address their diagnostic accuracy and prognostic significance, and explore the full extent of heterogeneity amongst pediatric DCM patients. | Gropler, Melanie R F Lipshultz, Steven E Wilkinson, James D Towbin, Jeffrey A Colan, Steven D Canter, Charles E Lavine, Kory J Simpson, Kathleen E eng R01 HL151438/HL/NHLBI NIH HHS/ UL1 TR000448/TR/NCATS NIH HHS/ R01 HL138466/HL/NHLBI NIH HHS/ R01 HL139714/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Pediatr Res. 2022 Jul;92(1):206-215. doi: 10.1038/s41390-021-01698-x. Epub 2021 Aug 17.I | 08/19/2021 | |
| Plasma proteins, cognitive decline, and 20-year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies | Lindbohm JV, et al. | 2022 | Alzheimers Dement | 18 | 4 | 612-624 | https://www.doi.org/10.1002/alz.12419 | 34,338,426 | *Alzheimer Disease *Atherosclerosis/epidemiology Blood Proteins *Cognitive Dysfunction/epidemiology *Dementia/epidemiology Humans Prospective Studies tau Proteins cognitive decline cohort study dementia longitudinal study proteomics the hypothesis and study design and SomaLogic, Inc. provided expertise in plasma proteins and funded the SOMAscan assays. Joni V. Lindbohm and Pyry N. Sipila have received personal lecture fees from the University of Helsinki. Nina Mars reports no conflicts of interest. Keenan A. Walker reports personal lecture fee from the Boston University Medical Center and holds the Programming Chair at the National Academy of Neuropsychology. Eric J. Brunner reports Osaka University research capacity building grant paid to employer. Archana Singh-Manoux reports no conflicts of interest. Gill Livingston reports no conflicts of interest. Kalle Saksela reports no conflicts of interest. Jane E. Ferrie reports no conflicts of interest. Ruth C. Lovering reports personal lecture fees from the University College London, funding from a COST action grant, and is a member of the executive committee for the International Society of Biocuration (a voluntary role and no payment has been or will be made). Stephen A. Williams is employee of SomaLogic Inc., which has a commercial interest in the results and co-inventor on multiple patents for specific proteomic models of disease. None of these patents relate to dementia (the topic of the manuscript). Aroon D. Hingorani reports no conflicts of interest. Rebecca F. Gottesman reports personal lecture fees for speaking at University of Michigan grand rounds, University of Alabama McKnight lecture, and the American College of Cardiology conference. Rebecca F. Gottesman is the secretary for the American Neurological Association. Henrik Zetterberg reports that he has served on the scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, and CogRx has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Henrik Zetterberg is also the chair of the Alzheimer's Association Global Biomarker Standardization Consortium and the Alzheimer's Association Biolfluid-Based Biomarker Professional Interest Area. Mika Kivimaki reports no conflicts of interest. | INTRODUCTION: Plasma proteins affect biological processes and are common drug targets but their role in the development of Alzheimer's disease and related dementias remains unclear. We examined associations between 4953 plasma proteins and cognitive decline and risk of dementia in two cohort studies with 20-year follow-ups. METHODS: In the Whitehall II prospective cohort study proteins were measured using SOMAscan technology. Cognitive performance was tested five times over 20 years. Linkage to electronic health records identified incident dementia. The results were replicated in the Atherosclerosis Risk in Communities (ARIC) study. RESULTS: Fifteen non-amyloid/non-tau-related proteins were associated with cognitive decline and dementia, were consistently identified in both cohorts, and were not explained by known dementia risk factors. Levels of six of the proteins are modifiable by currently approved medications for other conditions. DISCUSSION: This study identified several plasma proteins in dementia-free people that are associated with long-term risk of cognitive decline and dementia. | Lindbohm, Joni V Mars, Nina Walker, Keenan A Singh-Manoux, Archana Livingston, Gill Brunner, Eric J Sipila, Pyry N Saksela, Kalle Ferrie, Jane E Lovering, Ruth C Williams, Stephen A Hingorani, Aroon D Gottesman, Rebecca F Zetterberg, Henrik Kivimaki, Mika eng RG/16/11/32334/BHF_/British Heart Foundation/United Kingdom UL1 RR025005/RR/NCRR NIH HHS/ U01 HL096917/HL/NHLBI NIH HHS/ 221854/Z/20/Z/WT_/Wellcome Trust/United Kingdom R01 HL086694/HL/NHLBI NIH HHS/ U01 HL096902/HL/NHLBI NIH HHS/ U01 HG004402/HG/NHGRI NIH HHS/ MR/R024227/1/MRC_/Medical Research Council/United Kingdom RG/13/2/30098/BHF_/British Heart Foundation/United Kingdom HHSN268201700001I/HL/NHLBI NIH HHS/ HHSN268201700004I/HL/NHLBI NIH HHS/ U01 HL096814/HL/NHLBI NIH HHS/ R56 AG056477/AG/NIA NIH HHS/ MR/S011676/1/MRC_/Medical Research Council/United Kingdom R01 HL087641/HL/NHLBI NIH HHS/ HHSN268201700003I/HL/NHLBI NIH HHS/ R01 AG056477/AG/NIA NIH HHS/ U01 HL096812/HL/NHLBI NIH HHS/ K23 AG064122/AG/NIA NIH HHS/ HHSN268201700002C/HL/NHLBI NIH HHS/ RF1 AG062553/AG/NIA NIH HHS/ HHSN268201700005C/HL/NHLBI NIH HHS/ HHSN268201700001C/HL/NHLBI NIH HHS/ HHSN268201700003C/HL/NHLBI NIH HHS/ U01 HL096899/HL/NHLBI NIH HHS/ HHSN268201700004C/HL/NHLBI NIH HHS/ WT_/Wellcome Trust/United Kingdom K24 AG052573/AG/NIA NIH HHS/ HHSN268201700002I/HL/NHLBI NIH HHS/ HHSN268201700005I/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Alzheimers Dement. 2022 Apr;18(4):612-624. doi: 10.1002/alz.12419. Epub 2021 Aug 2.I | 08/03/2021 | |
| Identification and Evaluation of Serum Protein Biomarkers That Differentiate Psoriatic Arthritis From Rheumatoid Arthritis | Mc Ardle A, et al. | 2022 | Arthritis Rheumatol | 74 | 1 | 81-91 | https://www.doi.org/10.1002/art.41899 | 34,114,357 | Adult Arthritis, Psoriatic/*blood/*diagnosis Arthritis, Rheumatoid/*blood/*diagnosis Biomarkers/blood Blood Proteins/*analysis Cross-Sectional Studies Diagnosis, Differential Female Humans Male Middle Aged | OBJECTIVE: To identify serum protein biomarkers that might distinguish patients with early inflammatory arthritis (IA) with psoriatic arthritis (PsA) from those with rheumatoid arthritis (RA) and may be used to support appropriate early intervention. METHODS: The serum proteome of patients with PsA and patients with RA was interrogated using nano-liquid chromatography mass spectrometry (nano-LC-MS/MS) (n = 64 patients), an aptamer-based assay (SomaScan) targeting 1,129 proteins (n = 36 patients), and a multiplexed antibody assay (Luminex) for 48 proteins (n = 64 patients). Multiple reaction monitoring (MRM) assays were developed to evaluate the performance of putative markers using the discovery cohort (n = 60 patients) and subsequently an independent cohort of PsA and RA patients (n = 167). RESULTS: Multivariate machine learning analysis of the protein discovery data from the 3 platforms revealed that it was possible to differentiate PsA patients from RA patients with an area under the curve (AUC) of 0.94 for nano-LC-MS/MS, 0.69 for bead-based immunoassay measurements, and 0.73 for aptamer-based analysis. Subsequently, in the separate verification and evaluation studies, random forest models revealed that a subset of proteins measured by MRM could differentiate PsA and RA patients with AUCs of 0.79 and 0.85, respectively. CONCLUSION: We present a serum protein biomarker panel that can separate patients with early-onset IA with PsA from those with RA. With continued evaluation and refinement using additional and larger patient cohorts, including those with other arthropathies, we suggest that the panel identified here could contribute to improved clinical decision making. | Mc Ardle, Angela Kwasnik, Anna Szentpetery, Agnes Hernandez, Belinda Parnell, Andrew de Jager, Wilco de Roock, Sytze FitzGerald, Oliver Pennington, Stephen R eng 305266/FP7 Health/ Research Support, Non-U.S. Gov't Arthritis Rheumatol. 2022 Jan;74(1):81-91. doi: 10.1002/art.41899. Epub 2021 Nov 23.I | 06/12/2021 | |
| An Approach to Biomarker Discovery of Cannabis Use Utilizing Proteomic, Metabolomic, and Lipidomic Analyses | Hinckley JD, et al. | 2022 | Cannabis Cannabinoid Res | 7 | 1 | 65-77 | https://www.doi.org/10.1089/can.2020.0002 | 33,998,853 | Adult Analgesics Biomarkers Cannabinoid Receptor Agonists *Cannabis Chromatography, Liquid/methods Dronabinol/analysis Female *Hallucinogens Humans Lipidomics Lipids Male Proteomics Substance Abuse Detection/methods Tandem Mass Spectrometry Myc proto-oncogene cannabis markers | Introduction: Relatively little is known about the molecular pathways influenced by cannabis use in humans. We used a multi-omics approach to examine protein, metabolomic, and lipid markers in plasma differentiating between cannabis users and nonusers to understand markers associated with cannabis use. Methods: Eight discordant twin pairs and four concordant twin pairs for cannabis use completed a blood draw, urine and plasma toxicology testing, and provided information about their past 30-day cannabis use and other substance use patterns. The 24 twins were all non-Hispanic whites. Sixty-six percent were female. Median age was 30 years. Fifteen participants reported that they had used cannabis in the last 30 days, including eight participants that used every day or almost every day (29-30 of 30 days). Of these 15 participants, plasma 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH) and total tetrahydrocannabinol (THC) concentrations were detectable in 12 participants. Among the eight heavy users" the amount of total THC (sum of THC and its metabolites) and plasma THC-COOH concentrations varied widely, with ranges of 13.1-1713 ng/mL and 2.7-284 ng/mL, respectively. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay measured plasma THC-COOH, THC, and other cannabinoids and metabolites. Plasma THC-COOH was used as the primary measure. Expression levels of 1305 proteins were measured using SOMAScan assay, and 34 lipid mediators and 314 metabolites were measured with LC-MS/MS. Analyses examined associations between markers and THC-COOH levels with and without taking genetic relatedness into account. Results: Thirteen proteins, three metabolites, and two lipids were identified as associated with THC-COOH levels. Myc proto-oncogene was identified as associated with THC-COOH levels in both molecular insight and potential marker analyses. Five pathways (interleukin-6 production, T lymphocyte regulation, apoptosis, kinase signaling pathways, and nuclear factor kappa-light-chain-enhancer of activated B cells) were linked with molecules identified in these analyses. Conclusions: THC-COOH levels are associated with immune system-related pathways. This study presents a feasible approach to identify additional molecular markers associated with THC-COOH levels." | Hinckley, Jesse D Saba, Laura Raymond, Kristen Bartels, Karsten Klawitter, Jost Christians, Uwe Hopfer, Christian eng P30 DA044223/DA/NIDA NIH HHS/ K24 DA032555/DA/NIDA NIH HHS/ Research Support, N.I.H., Extramural Twin Study Cannabis Cannabinoid Res. 2022 Feb;7(1):65-77. doi: 10.1089/can.2020.0002. Epub 2020 Jun 19.I | 05/18/2021 | |
| Proteomic signatures predict preeclampsia in individual cohorts but not across cohorts - implications for clinical biomarker studies | Ghaemi MS, et al. | 2022 | J Matern Fetal Neonatal Med | 35 | 25 | 5621-5628 | https://www.doi.org/10.1080/14767058.2021.1888915 | 33,653,202 | Female Humans Pregnancy *Proteomics/methods *Pre-Eclampsia/diagnosis Proteome/metabolism Biomarkers Blood Proteins Biomarker gestational age preeclampsia proteomics | BACKGROUND: Early identification of pregnant women at risk for preeclampsia (PE) is important, as it will enable targeted interventions ahead of clinical manifestations. The quantitative analyses of plasma proteins feature prominently among molecular approaches used for risk prediction. However, derivation of protein signatures of sufficient predictive power has been challenging. The recent availability of platforms simultaneously assessing over 1000 plasma proteins offers broad examinations of the plasma proteome, which may enable the extraction of proteomic signatures with improved prognostic performance in prenatal care. OBJECTIVE: The primary aim of this study was to examine the generalizability of proteomic signatures predictive of PE in two cohorts of pregnant women whose plasma proteome was interrogated with the same highly multiplexed platform. Establishing generalizability, or lack thereof, is critical to devise strategies facilitating the development of clinically useful predictive tests. A second aim was to examine the generalizability of protein signatures predictive of gestational age (GA) in uncomplicated pregnancies in the same cohorts to contrast physiological and pathological pregnancy outcomes. STUDY DESIGN: Serial blood samples were collected during the first, second, and third trimesters in 18 women who developed PE and 18 women with uncomplicated pregnancies (Stanford cohort). The second cohort (Detroit), used for comparative analysis, consisted of 76 women with PE and 90 women with uncomplicated pregnancies. Multivariate analyses were applied to infer predictive and cohort-specific proteomic models, which were then tested in the alternate cohort. Gene ontology (GO) analysis was performed to identify biological processes that were over-represented among top-ranked proteins associated with PE. RESULTS: The model derived in the Stanford cohort was highly significant (p = 3.9E-15) and predictive (AUC = 0.96), but failed validation in the Detroit cohort (p = 9.7E-01, AUC = 0.50). Similarly, the model derived in the Detroit cohort was highly significant (p = 1.0E-21, AUC = 0.73), but failed validation in the Stanford cohort (p = 7.3E-02, AUC = 0.60). By contrast, proteomic models predicting GA were readily validated across the Stanford (p = 1.1E-454, R = 0.92) and Detroit cohorts (p = 1.1.E-92, R = 0.92) indicating that the proteomic assay performed well enough to infer a generalizable model across studied cohorts, which makes it less likely that technical aspects of the assay, including batch effects, accounted for observed differences. CONCLUSIONS: Results point to a broader issue relevant for proteomic and other omic discovery studies in patient cohorts suffering from a clinical syndrome, such as PE, driven by heterogeneous pathophysiologies. While novel technologies including highly multiplex proteomic arrays and adapted computational algorithms allow for novel discoveries for a particular study cohort, they may not readily generalize across cohorts. A likely reason is that the prevalence of pathophysiologic processes leading up to the same" clinical syndrome can be distributed differently in different and smaller-sized cohorts. Signatures derived in individual cohorts may simply capture different facets of the spectrum of pathophysiologic processes driving a syndrome. Our findings have important implications for the design of omic studies of a syndrome like PE. They highlight the need for performing such studies in diverse and well-phenotyped patient populations that are large enough to characterize subsets of patients with shared pathophysiologies to then derive subset-specific signatures of sufficient predictive power." | Ghaemi, Mohammad S Tarca, Adi L Romero, Roberto Stanley, Natalie Fallahzadeh, Ramin Tanada, Athena Culos, Anthony Ando, Kazuo Han, Xiaoyuan Blumenfeld, Yair J Druzin, Maurice L El-Sayed, Yasser Y Gibbs, Ronald S Winn, Virginia D Contrepois, Kevin Ling, Xuefeng B Wong, Ronald J Shaw, Gary M Stevenson, David K Gaudilliere, Brice Aghaeepour, Nima Angst, Martin S eng R01 HL139844/HL/NHLBI NIH HHS/ R35 GM138353/GM/NIGMS NIH HHS/ England J Matern Fetal Neonatal Med. 2022 Dec;35(25):5621-5628. doi: 10.1080/14767058.2021.1888915. Epub 2021 Mar 2.I | 03/04/2021 | |
| Prospects for the application of aptamer based assay platforms in pathogen detection | Banu K, et al. | 2022 | Biocybernetics and Biomedical Engineering | 42 | 3 | 934-949 | https://www.doi.org/10.1016/j.bbe.2022.07.005 | Aptamer SELEX Biosensor Microfluidics Flow-cytometry | Aptamer-based diagnostics platforms for animal, human, plant and environmental pathogens are gaining importance as they are rapid, user-friendly, sensitive and selective. However, most of the aptamer-based platforms have not yet become commercially available. The increasing number of publications signifies the applications of aptamer-based platform and their potential. Herein, the present review is to describe, a brief overview of the development of various aptamer-based platforms and their applicability for the sensitive detection of pathogens. In this review, several aptamer-based platforms such as Enzyme linked immunosorbent assay (ELISA)-like assay, Apta blot, Apta Polymerase Chain Reaction (PCR), Apta array, Aptamer-based Lateral Flow Assays (LFA), Aptamer based fluorescence assay, Flowcytometry-based assay, Apta affinity chromatography, microfluidics-based platforms, and various aptasensor have been discussed. Most of the platforms are highlighted will encourage researchers to focus on developing pathogen detection platform for various applications. | Banu, Kauser Mondal, Bhairab Rai, Bhawana Monica, N. Hanumegowda, Raju | |||
| Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population | Belkadi A, et al. | 2022 | Cell Genomics | epub ahead of print | 100218 | https://www.doi.org/10.1016/j.xgen.2022.100218 | human gene knockouts metabolomics proteomics whole-genome sequencing consanguineous population drug target validation, drug target identification | Summary Natural human knockouts of genes associated with desirable outcomes, such as PCSK9 with low levels of LDL-cholesterol, can lead to the discovery of new drug targets and treatments. Rare loss-of-function variants are more likely to be found in the homozygous state in consanguineous populations, and deep molecular phenotyping of blood samples from homozygous carriers can help to discriminate between silent and functional variants. Here, we combined whole-genome sequencing with proteomics and metabolomics for 2,935 individuals from the Qatar Biobank (QBB) to evaluate the power of this approach for finding genes of clinical and pharmaceutical interest. As proof-of-concept, we identified a homozygous carrier of a very rare PCSK9 variant with extremely low circulating PCSK9 levels and low LDL. Our study demonstrates that the chances of finding such variants are about 168 times higher in QBB compared with GnomAD and emphasizes the potential of consanguineous populations for drug discovery. | Belkadi, Aziz Thareja, Gaurav Abbaszadeh, Fatemeh Badii, Ramin Fauman, Eric Albagha, Omar M. E. Suhre, Karsten | ||||
| Proteome-Wide Analysis Using SOMAscan Identifies and Validates Epidermal Growth Factor as a Disease Marker of Collagenous Gastritis | Curci D, et al. | 2022 | Gastro Hep Advances | 1 | 5 | 689-702 | https://www.doi.org/10.1016/j.gastha.2022.04.016 | Collagenous Gastritis Proteomics Biomarker Epidermal Growth Factor | Collagenous gastritis (CG) is a rare disorder characterized by increased subepithelial collagen deposition and inflammatory infiltrates. The mechanisms involved in CG pathogenesis are poorly understood, and no CG-associated biomarkers have been identified. This proteomics study identified serum biomarkers and pathogenic pathways to provide new knowledge about the pathobiology of CG, a disease reported in less than 100 patients. | Curci, Debora Dillon, Simon T. Gu, Xuesong Winter, Harland Libermann, Towia A. | |||
| Prioritization of drug targets for neurodegenerative diseases by integrating genetic and proteomic data from brain and blood | Ge Y-J, et al. | 2022 | Biological Psychiatry | epub ahead of print | https://www.doi.org/10.1016/j.biopsych.2022.11.002 | drug discovery genetics Mendelian randomization neurodegenerative disease omics proteomics | Background Neurodegenerative diseases are among the most prevalent and devastating neurological disorders, with few effective prevention and treatment strategies. We aimed to integrate genetic and proteomic data to prioritize drug targets for neurodegenerative diseases. Methods We screened human proteomes through Mendelian randomization to identify causal mediators of Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), frontotemporal dementia, and Lewy body dementia. For instruments, we used brain and blood protein quantitative trait loci (pQTLs) identified from one GWAS with 376 individuals and another with 3,301, respectively. Causal associations were subsequently validated by sensitivity analyses and colocalization. The safety and druggability of identified targets were also evaluated. Results Our analyses showed targeting BIN1, GRN, and RET levels in blood, as well as ACE, ICA1L, MAP1S, SLC20A2, and TOM1L2 levels in brain might reduce AD risk, while ICA1L, SLC20A2, and TOM1L2 were not recommended as prioritized drugs due to the identified potential side-effects. Brain CD38, DGKQ, GPNMB, and SEC23IP were candidate targets for PD. Among them, GPNMB was the most promising target for PD with their causal relationship evidenced by studies on both brain and blood tissues. Interventions targeting FCRL3, LMAN2, MAPK3 in blood and DHRS11, FAM120B, SHMT1, TSFM in brain might affect MS risk. The risk of ALS might be reduced by medications targeting DHRS11, PSMB3, SARM1, and SCFD1 in brain. Conclusions Our study prioritized 22 proteins as targets for neurodegenerative diseases and provided preliminary evidence for drug development. Further studies are warranted to validate these targets. | Ge, Yi-Jun Ou, Ya-Nan Deng, Yue-Ting Wu, Bang-Sheng Yang, Liu Zhang, Ya-Ru Chen, Shi-Dong Huang, Yu-Yuan Dong, Qiang Tan, Lan Yu, Jin-Tai | |||||
| Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing diseases | Lindbohm JV, et al. | 2022 | Nature Aging | 2 | 10 | 956-972 | https://www.doi.org/10.1038/s43587-022-00293-x | Immune system and blood–brain barrier dysfunction are implicated in the development of Alzheimer’s and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827_immune system- and blood–brain barrier-related biomarkers and identified 127_potential causal risk factors for dementia-causing diseases. Pathway analyses linked these biomarkers to amyloid-_, tau and _-synuclein pathways and to autoimmunity-related processes. A phenome-wide analysis using Mendelian randomization-based polygenic risk score in the FinnGen study (n_=_339,233) for the biomarkers indicated shared genetic background for dementias and autoimmune diseases. This association was further supported by human leukocyte antigen analyses. In inverse-probability-weighted analyses that simulate randomized controlled drug trials in observational data, anti-inflammatory methotrexate treatment reduced the incidence of Alzheimer’s disease in high-risk individuals (hazard ratio compared with no treatment, 0.64, 95% confidence interval 0.49–0.88, P_=_0.005). These converging results from different lines of human research suggest that autoimmunity is a modifiable component in dementia-causing diseases. | Lindbohm, Joni V. Mars, Nina Sipilä, Pyry N. Singh-Manoux, Archana Runz, Heiko Livingston, Gill Seshadri, Sudha Xavier, Ramnik Hingorani, Aroon D. Ripatti, Samuli Kivimäki, Mika | ||||
| Limited proteolysis–mass spectrometry reveals aging-associated changes in cerebrospinal fluid protein abundances and structures | Shuken SR, et al. | 2022 | Nature Aging | 2 | 5 | 379-388 | https://www.doi.org/10.1038/s43587-022-00196-x | Cerebrospinal fluid (CSF) proteins and their structures have been implicated in aging and neurodegenerative diseases. In the present study, we used limited proteolysis–mass spectrometry (LiP–MS) to screen for new aging-associated changes in the CSF proteome using a modified analysis. We found 38 protein groups that change in abundance with aging, predominantly immunoglobulins of the IgM subclass. We discovered six high-confidence candidates that underwent structural changes with aging, of which Kng1, Itih2, Lp-PLA2 and 14-3-3 proteins have binding partners or chemical forms known previously to change in the brains of patients with Alzheimer’s disease. Orthogonal validation by western blotting identified that the LiP–MS hit Cd5l forms a covalent complex with IgM in mouse and human CSF, the abundance of which increases with aging. In human CSF, SOMAmer probe signals for all six LiP–MS hits were associated with cognitive function and/or biomarkers of neurodegeneration, especially 14-3-3 proteins YWHAB and YWHAZ. Together, our findings show that LiP–MS can uncover age-related structural changes in CSF with relevance to neurodegeneration. | Shuken, Steven R. Rutledge, Jarod Iram, Tal Losada, Patricia Moran Wilson, Edward N. Andreasson, Katrin I. Leib, Ryan D. Wyss-Coray, Tony | ||||
| Differential Proteomics of Cardiovascular Risk and Coronary Artery Disease in Humans | Ferrannini E, et al. | 2021 | Front Cardiovasc Med | 8 | 790289 | https://www.doi.org/10.3389/fcvm.2021.790289 | 35,187,107 | atrial myosin regulatory light chain 2 cardiovascular risk factors coronary artery disease protein shisa-3 homolog proteomics Sankyo outside the submitted work. SW is an employee and shareholder of SomaLogic Inc., Boulder, Colorado, USA. AMag reports personal fees from Bayer, Fresenius, and Novartis outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | BACKGROUND: Proteomics of atypical phenotypes may help unravel cardiovascular disease mechanisms. AIM: We aimed to prospectively screen the proteome of four types of individuals: with or without coronary artery disease (CAD), each with or without multiple risk factors. Associations with individual risk factors and circulating biomarkers were also tested to provide a functional context to the protein hits. MATERIALS AND METHODS: The CAPIRE study (ClinicalTrials.gov Identifier: NCT02157662) is a cross-sectional study aimed at identifying possible new mechanisms promoting or protecting against atherothrombosis. Quantification (by aptamer technology), ranking (using partial least squares), and correlations (by multivariate regression) of ~5000 plasma proteins were performed in consecutive individuals aged 45-75 years, without previous cardiovascular disease, undergoing computed tomography angiography for suspected CAD, showing either >5/16 atherosclerotic segments (CAD(+)) or completely clean arteries (CAD(-)) and either /=3 risk factors (RF(-)) (based on history, blood pressure, glycemia, lipids, and smoking). RESULTS: Of 544 individuals, 39% were atypical (93 CAD(+)/RF(-); 120 CAD(-)/RF(+)) and 61% typical (102 CAD(+)/RF(+); 229 CAD(-)/RF(-)). In the comparison with CAD(+)/RF(-) adjusted for sex and age, CAD(-)/RF(+) was associated with increased atrial myosin regulatory light chain 2 (MYO) and C-C motif chemokine-22 (C-C-22), and reduced protein shisa-3 homolog (PS-3) and platelet-activating factor acetylhydrolase (PAF-AH). Extending the analysis to the entire cohort, an additional 8 proteins were independently associated with CAD or RF; by logistic regression, the 12-protein panel alone discriminated the four groups with AUC(ROC)'s of 0.72-0.81 (overall p = 1.0e(-38)). Among them, insulin-like growth factor binding protein-3 is positively associated with RF, lower BMI, and HDL-cholesterol, renin with CAD higher glycated hemoglobin HbA(1c), and smoking. CONCLUSIONS: In a CCTA-based cohort, four proteins, involved in opposing vascular processes (healing vs. adverse remodeling), are specifically associated with low CAD burden in high CV-risk individuals (high MYO and C-C-22) and high CAD burden in low-risk subjects (high PS-3 and PAF-AH), in interaction with BMI, smoking, diabetes, HDL-cholesterol, and HbA(1c). These findings could contribute to a deeper understanding of the atherosclerotic process beyond traditional risk profile assessment and potentially constitute new treatment targets. | Ferrannini, Ele Manca, Maria Laura Ferrannini, Giulia Andreotti, Felicita Andreini, Daniele Latini, Roberto Magnoni, Marco Williams, Stephen A Maseri, Attilio Maggioni, Aldo P eng Switzerland Front Cardiovasc Med. 2022 Feb 4;8:790289. doi: 10.3389/fcvm.2021.790289. eCollection 2021.I | 02/22/2022 | ||
| Integrated Multi-Omics for Novel Aging Biomarkers and Antiaging Targets | Wu L, et al. | 2021 | Biomolecules | 12 | 1 | https://www.doi.org/10.3390/biom12010039 | 35,053,186 | Aging/genetics Biomarkers *Genomics/methods Humans Metabolomics/methods *Proteomics/methods aging aging biomarkers aging clock antiaging targets multi-omics | Aging is closely related to the occurrence of human diseases; however, its exact biological mechanism is unclear. Advancements in high-throughput technology provide new opportunities for omics research to understand the pathological process of various complex human diseases. However, single-omics technologies only provide limited insights into the biological mechanisms of diseases. DNA, RNA, protein, metabolites, and microorganisms usually play complementary roles and perform certain biological functions together. In this review, we summarize multi-omics methods based on the most relevant biomarkers in single-omics to better understand molecular functions and disease causes. The integration of multi-omics technologies can systematically reveal the interactions among aging molecules from a multidimensional perspective. Our review provides new insights regarding the discovery of aging biomarkers, mechanism of aging, and identification of novel antiaging targets. Overall, data from genomics, transcriptomics, proteomics, metabolomics, integromics, microbiomics, and systems biology contribute to the identification of new candidate biomarkers for aging and novel targets for antiaging interventions. | Wu, Lei Xie, Xinqiang Liang, Tingting Ma, Jun Yang, Lingshuang Yang, Juan Li, Longyan Xi, Yu Li, Haixin Zhang, Jumei Chen, Xuefeng Ding, Yu Wu, Qingping eng Research Support, Non-U.S. Gov't Review Switzerland Biomolecules. 2021 Dec 28;12(1):39. doi: 10.3390/biom12010039.I | 01/22/2022 | ||
| Multi-omic analysis in injured humans: Patterns align with outcomes and treatment responses | Wu J, et al. | 2021 | Cell Rep Med | 2 | 12 | 100478 | https://www.doi.org/10.1016/j.xcrm.2021.100478 | 35,028,617 | Brain Injuries, Traumatic/*genetics/*therapy Cluster Analysis Cohort Studies *Genomics Humans Metabolome Plasma Proteome/metabolism Time Factors Treatment Outcome PAMPer trial endotype host response metabolomics multi-omics outcome proteomics systemic storm thawed plasma trauma Avita Medical and Spectral MD. M.D.N. holds an equity stake in Haima Therapeutics. He has received research support and/or honoraria from Haemonetics, Instrumentation Laboratories, and Janssen Pharmaceuticals. T.R.B. is a stakeholder in Immunetrics. Other authors declare no conflict of interests. | Trauma is a leading cause of death and morbidity worldwide. Here, we present the analysis of a longitudinal multi-omic dataset comprising clinical, cytokine, endotheliopathy biomarker, lipidome, metabolome, and proteome data from severely injured humans. A systemic storm" pattern with release of 1,061 markers, together with a pattern suggestive of the "massive consumption" of 892 constitutive circulating markers, is identified in the acute phase post-trauma. Data integration reveals two human injury response endotypes, which align with clinical trajectory. Prehospital thawed plasma rescues only endotype 2 patients with traumatic brain injury (30-day mortality: 30.3 versus 75.0%; p = 0.0015). Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) was identified as the most predictive circulating biomarker to identify endotype 2-traumatic brain injury (TBI) patients. These response patterns refine the paradigm for human injury, while the datasets provide a resource for the study of critical illness, trauma, and human stress responses." | Wu, Junru Vodovotz, Yoram Abdelhamid, Sultan Guyette, Francis X Yaffe, Michael B Gruen, Danielle S Cyr, Anthony Okonkwo, David O Kar, Upendra K Krishnamoorthi, Neha Voinchet, Robert G Billiar, Isabel M Yazer, Mark H Namas, Rami A Daley, Brian J Miller, Richard S Harbrecht, Brian G Claridge, Jeffrey A Phelan, Herbert A Zuckerbraun, Brian S Johansson, Par I Stensballe, Jakob Morrissey, James H Tracy, Russell P Wisniewski, Stephen R Neal, Matthew D Sperry, Jason L Billiar, Timothy R eng T32 GM008516/GM/NIGMS NIH HHS/ UM1 HL120877/HL/NHLBI NIH HHS/ R35 GM119526/GM/NIGMS NIH HHS/ R35 GM127027/GM/NIGMS NIH HHS/ R01 HL141080/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Cell Rep Med. 2021 Dec 21;2(12):100478. doi: 10.1016/j.xcrm.2021.100478. eCollection 2021 Dec 21.I | 01/15/2022 | |
| Blood Levels of the SMOC1 Hepatokine Are Not Causally Linked with Type 2 Diabetes: A Bidirectional Mendelian Randomization Study | Ghodsian N, et al. | 2021 | Nutrients | 13 | 12 | https://www.doi.org/10.3390/nu13124208 | 34,959,760 | Blood Glucose/metabolism Body Mass Index Case-Control Studies Diabetes Mellitus, Type 2/blood/*genetics Fasting/blood Gene Expression/physiology Genome-Wide Association Study Glycated Hemoglobin A/metabolism Humans Insulin/blood Insulin Resistance/genetics Liver/metabolism Mendelian Randomization Analysis Non-alcoholic Fatty Liver Disease/blood/*genetics Osteonectin/*blood Polymorphism, Single Nucleotide Risk Factors Waist-Hip Ratio Mendelian randomization Smoc1 hepatokine type 2 diabetes research contracts from Pfizer, Ionis Pharmaceuticals and Silence Therapeutics. | Hepatokines are liver-derived proteins that may influence metabolic pathways such as insulin sensitivity. Recently, Sparc-related modular calcium-binding protein 1 (SMOC1) was identified as glucose-responsive hepatokine that is dysregulated in the setting of non-alcoholic fatty liver disease (NAFLD). While SMOC1 may influence glucose-insulin homeostasis in rodents, it is unknown if SMOC1 is influenced by NAFLD in humans. It is also unknown if SMOC1 is causally associated with metabolic and disease traits in humans. Therefore, we aimed to determine the effect of NAFLD on SMOC1 gene expression in the liver and aimed to explore the potential causal associations of SMOC1 levels with NAFLD, T2D, and glycemic traits in humans. Using an RNA sequencing dataset from a cohort of 216 patients with NAFLD, we assessed SMOC1 expression levels across the NAFLD spectrum. We performed a series of bidirectional inverse-variance weighted Mendelian randomization (MR) analyses on blood SMOC1 levels using two sources of genome-wide association studies (GWAS) (Fenland study, n = 10,708 and INTERVAL study, n = 3301). We utilized GWAS summary statistics for NAFLD in 8434 cases and 770,180 controls, as well as publicly available GWAS for type 2 diabetes (T2D), body mass index (BMI), waist-to-hip ratio (WHR), fasting blood insulin (FBI), fasting blood glucose (FBG), homeostatic Model Assessment of Insulin Resistance (HOMA-B and HOMA-IR), and hemoglobin A1c (HbA1C). We found that SMOC1 expression showed no significant differences across NAFLD stages. We also identified that the top single-nucleotide polymorphism associated with blood SMOC1 levels, was associated with SMOC1 gene expression in the liver, but not in other tissues. Using MR, we did not find any evidence that genetically predicted NAFLD, T2D, and glycemic traits influenced SMOC1 levels. We also did not find evidence that blood SMOC1 levels were causally associated with T2D, NAFLD, and glycemic traits. In conclusion, the hepatokine SMOC1 does not appear to be modulated by the presence of NAFLD and may not regulate glucose-insulin homeostasis in humans. Results of this study suggest that blood factors regulating metabolism in rodents may not always translate to human biology. | Ghodsian, Nooshin Gagnon, Eloi Bourgault, Jerome Gobeil, Emilie Manikpurage, Hasanga D Perrot, Nicolas Girard, Arnaud Mitchell, Patricia L Arsenault, Benoit J eng Switzerland Nutrients. 2021 Nov 24;13(12):4208. doi: 10.3390/nu13124208.I | 12/29/2021 | ||
| Large-scale plasma proteomics can reveal distinct endotypes in chronic obstructive pulmonary disease and severe asthma | Suzuki M, et al. | 2021 | Clin Transl Allergy | 11 | 10 | e12091 | https://www.doi.org/10.1002/clt2.12091 | 34,962,717 | Bpco Copd Epoc asma severa asthme severe endotipos endotypen endotypes exosomas exosome exosomen exosomes proteomic proteomics proteomica proteomique schweres Asthma severe asthma ______ ______ _______ ____ Masaru Suzuki has received lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, and GlaxoSmithKline. Satoshi Konno has received grants from AstraZeneca, Boehringer Ingelheim, KYORIN Pharmaceutical, Novartis, and Japan Allergy Foundation during the conduct of the study, and has received lecture fees from AstraZeneca and Boehringer Ingelheim. Masaharu Nishimura has received grants from AstraZeneca, Boehringer Ingelheim, KYORIN Pharmaceutical, and MSD during the conduct of the study. John J. Cole, Hironi Makita, and Hiroki Kimura have no relevant conflicts of interest. | BACKGROUND: Chronic airway diseases including chronic obstructive pulmonary disease (COPD) and asthma are heterogenous in nature and endotypes within are underpinned by complex biology. This study aimed to investigate the utility of proteomic profiling of plasma combined with bioinformatic mining, and to define molecular endotypes and expand our knowledge of the underlying biology in chronic respiratory diseases. METHODS: The plasma proteome was evaluated using an aptamer-based affinity proteomics platform (SOMAscan(R)), representing 1238 proteins in 34 subjects with stable COPD and 51 subjects with stable but severe asthma. For each disease, we evaluated a range of clinical/demographic characteristics including bronchodilator reversibility, blood eosinophilia levels, and smoking history. We applied modified bioinformatic approaches used in the evaluation of RNA transcriptomics. RESULTS: Subjects with COPD and severe asthma were distinguished from each other by 365 different protein abundancies, with differential pathway networks and upstream modulators. Furthermore, molecular endotypes within each disease could be defined. The protein groups that defined these endotypes had both known and novel biology including groups significantly enriched in exosomal markers derived from immune/inflammatory cells. Finally, we observed associations to clinical characteristics that previously have been under-explored. CONCLUSION: This investigational study evaluating the plasma proteome in clinically-phenotyped subjects with chronic airway diseases provides support that such a method can be used to define molecular endotypes and pathobiological mechanisms that underpins these endotypes. It provided new concepts about the complexity of molecular pathways that define these diseases. In the longer term, such information will help to refine treatment options for defined groups. | Suzuki, Masaru Cole, John J Konno, Satoshi Makita, Hironi Kimura, Hiroki Nishimura, Masaharu Maciewicz, Rose A eng KYORIN Pharmaceutical/ Pfizer/ Boehringer Ingelheim/ Ministry of Health, Labor, and Welfare, Japan/ AstraZeneca/ Japan Allergy Foundation/ 17390239/Ministry of Education, Science, Culture and Sports of Japan/ 2139053/Ministry of Education, Science, Culture and Sports of Japan/ 24249049/Ministry of Education, Science, Culture and Sports of Japan/ England Clin Transl Allergy. 2021 Dec;11(10):e12091. doi: 10.1002/clt2.12091.I | 12/29/2021 | |
| Discovery of Novel Proteomic Biomarkers for the Prediction of Kidney Recovery from Dialysis-Dependent AKI Patients | Daniels JR, et al. | 2021 | Kidney360 | 2 | 11 | 1716-1727 | https://www.doi.org/10.34067/kid.0002642021 | 34,913,041 | *Acute Kidney Injury/diagnosis Biomarkers/urine Humans Kidney/metabolism *Proteomics Renal Dialysis/methods | BACKGROUND: AKI requiring dialysis (AKI-D) is associated with prolonged hospitalization, mortality, and progressive CKD among survivors. Previous studies have examined only select urine or serum biomarkers for predicting kidney recovery from AKI. METHODS: Serum samples collected on day 8 of randomized RRT from 72 patients enrolled in the Veteran's Affairs/National Institutes of Health Acute Renal Failure Trial Network study were analyzed by the SOMAscan proteomic platform to profile 1305 proteins in each sample. Of these patients, 38 recovered kidney function and dialysis was discontinued, whereas another 34 patients remained on dialysis by day 28. RESULTS: Differential serum levels of 119 proteins, with 53 higher and 66 lower, were detected in samples from patients who discontinued dialysis, compared with patients who remained on dialysis by day 28. Patients were classified into tertiles on the basis of SOMAscan protein measurements for the 25 proteins most differentially expressed. The association of serum levels of each protein with kidney recovery was further evaluated using logistic regression analysis. Higher serum levels of CXCL11, CXCL2/CXCL3, CD86, Wnt-7a, BTK, c-Myc, TIMP-3, CCL5, ghrelin, PDGF-C, survivin, CA2, IL-9, EGF, and neuregulin-1, and lower levels of soluble CXCL16, IL1RL1, stanniocalcin-1, IL-6, and FGF23 when classified in tertiles were significantly associated with better kidney recovery. This significant association persisted for each of these proteins after adjusting for potential confounding risk factors including age, sex, cardiovascular SOFA score, congestive heart failure, diabetes, modality of intensive dialysis treatment, cause of AKI, baseline serum creatinine, day 8 urine volume, and estimated 60-day mortality risk. CONCLUSIONS: These results suggest concerted changes between survival-related proteins and immune-regulatory chemokines in regulating angiogenesis, endothelial and epithelial remodeling, and kidney cell regeneration, illustrating potential mechanisms of kidney recovery. Thus, this study identifies potential novel predictive biomarkers of kidney recovery in patients with AKI-D. | Daniels, Jaclyn R Ma, Jennie Z Cao, Zhijun Beger, Richard D Sun, Jinchun Schnackenberg, Laura Pence, Lisa Choudhury, Devasmita Palevsky, Paul M Portilla, Didier Yu, Li-Rong eng FD999999/ImFDA/Intramural FDA HHS/ R01 DK075976/DK/NIDDK NIH HHS/ R01 DK122624/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Kidney360. 2021 Nov 25;2(11):1716-1727. doi: 10.34067/kid.0002642021.I | 12/17/2021 | |
| An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging | Sayed N, et al. | 2021 | Nat Aging | 1 | 598-615 | https://www.doi.org/10.1038/s43587-021-00082-y | 34,888,528 | While many diseases of aging have been linked to the immunological system, immune metrics capable of identifying the most at-risk individuals are lacking. From the blood immunome of 1,001 individuals aged 8-96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The strongest contributor to iAge was the chemokine CXCL9, which was involved in cardiac aging, adverse cardiac remodeling and poor vascular function. Furthermore, aging endothelial cells in human and mice show loss of function, cellular senescence and hallmark phenotypes of arterial stiffness, all of which are reversed by silencing CXCL9. In conclusion, we identify a key role of CXCL9 in age-related chronic inflammation and derive a metric for multimorbidity that can be utilized for the early detection of age-related clinical phenotypes. | Sayed, Nazish Huang, Yingxiang Nguyen, Khiem Krejciova-Rajaniemi, Zuzana Grawe, Anissa P Gao, Tianxiang Tibshirani, Robert Hastie, Trevor Alpert, Ayelet Cui, Lu Kuznetsova, Tatiana Rosenberg-Hasson, Yael Ostan, Rita Monti, Daniela Lehallier, Benoit Shen-Orr, Shai S Maecker, Holden T Dekker, Cornelia L Wyss-Coray, Tony Franceschi, Claudio Jojic, Vladimir Haddad, Francois Montoya, Jose G Wu, Joseph C Davis, Mark M Furman, David eng P30 AG059307/AG/NIA NIH HHS/ P30 AG066515/AG/NIA NIH HHS/ U19 AI057229/AI/NIAID NIH HHS/ U19 AI090019/AI/NIAID NIH HHS/ P50 AG047366/AG/NIA NIH HHS/ P30 DK116074/DK/NIDDK NIH HHS/ UL1 TR003142/TR/NCATS NIH HHS/ UL1 RR025744/RR/NCRR NIH HHS/ K01 HL135455/HL/NHLBI NIH HHS/ Nat Aging. 2021 Jul;1:598-615. doi: 10.1038/s43587-021-00082-y. Epub 2021 Jul 12.I | 12/11/2021 | |||
| Exercise plasma boosts memory and dampens brain inflammation via clusterin | De Miguel Z, et al. | 2021 | Nature | 600 | 7,889 | 494-499 | https://www.doi.org/10.1038/s41586-021-04183-x | 34,880,498 | *Alzheimer Disease/metabolism Animals Clusterin/genetics/metabolism *Encephalitis Endothelial Cells/metabolism Humans Mice Proteomics | Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration(1). The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus(2-4), yet little is known about the factors and mechanisms that mediate these effects. Here we show that 'runner plasma', collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer's disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise. | De Miguel, Zurine Khoury, Nathalie Betley, Michael J Lehallier, Benoit Willoughby, Drew Olsson, Niclas Yang, Andrew C Hahn, Oliver Lu, Nannan Vest, Ryan T Bonanno, Liana N Yerra, Lakshmi Zhang, Lichao Saw, Nay Lui Fairchild, J Kaci Lee, Davis Zhang, Hui McAlpine, Patrick L Contrepois, Kevin Shamloo, Mehrdad Elias, Joshua E Rando, Thomas A Wyss-Coray, Tony eng R01 AG071783/AG/NIA NIH HHS/ P30 AG066515/AG/NIA NIH HHS/ F32 AG067652/AG/NIA NIH HHS/ R01 AG047820/AG/NIA NIH HHS/ P01 AG036695/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Nature. 2021 Dec;600(7889):494-499. doi: 10.1038/s41586-021-04183-x. Epub 2021 Dec 8.I | 12/10/2021 | |
| Proteomic Approaches to Defining Remission and the Risk of Relapse in Rheumatoid Arthritis | O'Neil LJ, et al. | 2021 | Front Immunol | 12 | 729681 | https://www.doi.org/10.3389/fimmu.2021.729681 | 34,867,950 | Adult Aged Antirheumatic Agents/therapeutic use Arthritis, Rheumatoid/*blood/*classification/drug therapy Biomarkers/blood Blood Proteins/*analysis Female Humans Male Middle Aged Proteomics Recurrence Remission Induction disease activity outcomes research rheumatoid arthritis treatment commercial or financial relationships that could be construed as a potential conflict of interest. | OBJECTIVES: Patients with Rheumatoid Arthritis (RA) are increasingly achieving stable disease remission, yet the mechanisms that govern ongoing clinical disease and subsequent risk of future flare are not well understood. We sought to identify serum proteomic alterations that dictate clinically important features of stable RA, and couple broad-based proteomics with machine learning to predict future flare. METHODS: We studied baseline serum samples from a cohort of stable RA patients (RETRO, n = 130) in clinical remission (DAS28<2.6) and quantified 1307 serum proteins using the SOMAscan platform. Unsupervised hierarchical clustering and supervised classification were applied to identify proteomic-driven clusters and model biomarkers that were associated with future disease flare after 12 months of follow-up and RA medication withdrawal. Network analysis was used to define pathways that were enriched in proteomic datasets. RESULTS: We defined 4 proteomic clusters, with one cluster (Cluster 4) displaying a lower mean DAS28 score (p = 0.03), with DAS28 associating with humoral immune responses and complement activation. Clustering did not clearly predict future risk of flare, however an XGboost machine learning algorithm classified patients who relapsed with an AUC (area under the receiver operating characteristic curve) of 0.80 using only baseline serum proteomics. CONCLUSIONS: The serum proteome provides a rich dataset to understand stable RA and its clinical heterogeneity. Combining proteomics and machine learning may enable prediction of future RA disease flare in patients with RA who aim to withdrawal therapy. | O'Neil, Liam J Hu, Pingzhao Liu, Qian Islam, Md Mohaiminul Spicer, Victor Rech, Juergen Hueber, Axel Anaparti, Vidyanand Smolik, Irene El-Gabalawy, Hani S Schett, Georg Wilkins, John A eng Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't Switzerland Front Immunol. 2021 Nov 18;12:729681. doi: 10.3389/fimmu.2021.729681. eCollection 2021.I | 12/07/2021 | ||
| Large-scale integration of the plasma proteome with genetics and disease | Ferkingstad E, et al. | 2021 | Nat Genet | 53 | 12 | 1712-1721 | https://www.doi.org/10.1038/s41588-021-00978-w | 34,857,953 | Biomarkers/blood Blood Proteins/*genetics/metabolism Disease/*genetics Female Gene Frequency Genetic Variation Genome-Wide Association Study Humans Male Middle Aged Proteome/*genetics Quantitative Trait Loci | The plasma proteome can help bridge the gap between the genome and diseases. Here we describe genome-wide association studies (GWASs) of plasma protein levels measured with 4,907 aptamers in 35,559 Icelanders. We found 18,084 associations between sequence variants and levels of proteins in plasma (protein quantitative trait loci; pQTL), of which 19% were with rare variants (minor allele frequency (MAF) < 1%). We tested plasma protein levels for association with 373 diseases and other traits and identified 257,490 associations. We integrated pQTL and genetic associations with diseases and other traits and found that 12% of 45,334 lead associations in the GWAS Catalog are with variants in high linkage disequilibrium with pQTL. We identified 938 genes encoding potential drug targets with variants that influence levels of possible biomarkers. Combining proteomics, genomics and transcriptomics, we provide a valuable resource that can be used to improve understanding of disease pathogenesis and to assist with drug discovery and development. | Ferkingstad, Egil Sulem, Patrick Atlason, Bjarni A Sveinbjornsson, Gardar Magnusson, Magnus I Styrmisdottir, Edda L Gunnarsdottir, Kristbjorg Helgason, Agnar Oddsson, Asmundur Halldorsson, Bjarni V Jensson, Brynjar O Zink, Florian Halldorsson, Gisli H Masson, Gisli Arnadottir, Gudny A Katrinardottir, Hildigunnur Juliusson, Kristinn Magnusson, Magnus K Magnusson, Olafur Th Fridriksdottir, Run Saevarsdottir, Saedis Gudjonsson, Sigurjon A Stacey, Simon N Rognvaldsson, Solvi Eiriksdottir, Thjodbjorg Olafsdottir, Thorunn A Steinthorsdottir, Valgerdur Tragante, Vinicius Ulfarsson, Magnus O Stefansson, Hreinn Jonsdottir, Ingileif Holm, Hilma Rafnar, Thorunn Melsted, Pall Saemundsdottir, Jona Norddahl, Gudmundur L Lund, Sigrun H Gudbjartsson, Daniel F Thorsteinsdottir, Unnur Stefansson, Kari eng Nat Genet. 2021 Dec;53(12):1712-1721. doi: 10.1038/s41588-021-00978-w. Epub 2021 Dec 2.I | 12/04/2021 | |
| High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control | Dreyfuss JM, et al. | 2021 | Nat Commun | 12 | 1 | 6951 | https://www.doi.org/10.1038/s41467-021-27289-2 | 34,845,204 | Animals Biomarkers/blood Blood Glucose/metabolism Body Mass Index Carrier Proteins/blood/genetics Diabetes Mellitus, Type 2/*blood/genetics/pathology/surgery Dipeptidases/blood/genetics Fasting/physiology *Gastric Bypass Gene Expression Regulation Glycated Hemoglobin A/genetics/metabolism Hepatocytes/metabolism/pathology Human Growth Hormone/blood/genetics Humans Insulin-Like Growth Factor Binding Protein 1/blood/genetics Insulin-Like Growth Factor Binding Protein 2/blood/genetics Liver/*metabolism/pathology *Metabolome Obesity/*blood/genetics/pathology/surgery Primary Cell Culture *Proteome Rats Retrospective Studies | To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR's mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling.Trial Registration: Clinicaltrials.gov NCT01073020. | Dreyfuss, Jonathan M Yuchi, Yixing Dong, Xuehong Efthymiou, Vissarion Pan, Hui Simonson, Donald C Vernon, Ashley Halperin, Florencia Aryal, Pratik Konkar, Anish Sebastian, Yinong Higgs, Brandon W Grimsby, Joseph Rondinone, Cristina M Kasif, Simon Kahn, Barbara B Foster, Kathleen Seeley, Randy Goldfine, Allison Djordjilovic, Vera Patti, Mary Elizabeth eng RC1 DK086918/DK/NIDDK NIH HHS/ P01 DK117821/DK/NIDDK NIH HHS/ U01 DK114156/DK/NIDDK NIH HHS/ P30 DK036836/DK/NIDDK NIH HHS/ P30 DK057521/DK/NIDDK NIH HHS/ R56 DK095451/DK/NIDDK NIH HHS/ R01 DK043051/DK/NIDDK NIH HHS/ Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. 2021 Nov 29;12(1):6951. doi: 10.1038/s41467-021-27289-2.I | 12/01/2021 | |
| Heat Shock-Related Protein Responses and Inflammatory Protein Changes Are Associated with Mild Prolonged Hypoglycemia | Moin ASM, et al. | 2021 | Cells | 10 | 11 | https://www.doi.org/10.3390/cells10113109 | 34,831,332 | Adult Biomarkers/metabolism Case-Control Studies Diabetes Mellitus, Type 2/blood/metabolism Dinoprost/analogs & derivatives/metabolism Female Heat-Shock Proteins/blood *Heat-Shock Response Humans Hypoglycemia/blood/*metabolism Inflammation/*metabolism Male Middle Aged Oxidative Stress Protein Interaction Mapping Proteins/*metabolism Ubiquitin-Conjugating Enzymes/metabolism heat shock proteins hypoglycemia inflammatory proteins type 2 diabetes | Mild hypoglycemia is common in clinical practice. Severe hypoglycemia results in heat shock protein and associate co-chaperone changes. Whether mild prolonged hypoglycemia elicits a similar response with inflammatory and oxidative-stress responses compared with a severe hypoglycemic event is unclear; therefore, this pilot exploratory study was undertaken. We performed a case-control induced hypoglycemia clamp study, maintaining blood glucose at 2.8 mmol/L (50 mg/dL) for 1 h in 17 subjects (T2D (n = 10); controls (n = 7)). Blood sampling was performed at baseline, hypoglycemia, and 24 h; slow off-rate modified aptamer (SOMA)-scan plasma protein analysis of HSP-related proteins, inflammatory stress markers, and oxidative stress markers was performed. In total, 16 HSPs were analyzed. At baseline, TLR4:MD-2 complex was elevated (p = 0.01), whilst HSPA8 was lower (p < 0.05) in T2D. At hypoglycemia, UBE2N, STIP1, and UBE2L3 increased (all p < 0.05), whilst TLR4:MD-2 and HSPA8 decreased (p < 0.05) in T2D versus baseline. In follow-up after hypoglycemia, HSPs normalized to baseline by 24 h, except UBE2L3 (p < 0.05), which was decreased in controls versus baseline. Correlation of altered inflammatory markers with HSPs revealed the following: at baseline, TLR4:MD-2 correlated with CXCL10 (p < 0.01) and SIGLEC1 (p < 0.05) in controls; HSPA8 negatively correlated with IL5 (p < 0.05) in T2D. A negative correlation between urinary isoprostane 8-iso PGF2alpha, a marker of oxidative stress, and HSPA1A was seen at 24 h in T2D only (p < 0.05). In conclusion, the HSP changes seen for mild prolonged hypoglycemia were similar to those previously reported for a severe event. However, mild prolonged hypoglycemia appeared to elicit an increased inflammatory response that was associated with heat shock and related proteins. | Moin, Abu Saleh Md Nandakumar, Manjula Kahal, Hassan Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Clinical Trial Switzerland Cells. 2021 Nov 10;10(11):3109. doi: 10.3390/cells10113109.I | 11/28/2021 | ||
| The Use of 'Omics for Diagnosing and Predicting Progression of Chronic Kidney Disease: A Scoping Review | Govender MA, et al. | 2021 | Front Genet | 12 | 682929 | https://www.doi.org/10.3389/fgene.2021.682929 | 34,819,944 | Sub-Saharan Africa biomarkers chronic kidney disease diabetes diagnosis early detection hypertension 'omics commercial or financial relationships that could be construed as a potential conflict of interest. | Globally, chronic kidney disease (CKD) contributes substantial morbidity and mortality. Recently, various 'omics platforms have provided insight into the molecular basis of kidney dysfunction. This scoping review is a synthesis of the current literature on the use of different 'omics platforms to identify biomarkers that could be used to detect early-stage CKD, predict disease progression, and identify pathways leading to CKD. This review includes 123 articles published from January 2007 to May 2021, following a structured selection process. The most common type of 'omic platform was proteomics, appearing in 55 of the studies and two of these included a metabolomics component. Most studies (n = 91) reported on CKD associated with diabetes mellitus. Thirteen studies that provided information on the biomarkers associated with CKD and explored potential pathways involved in CKD are discussed. The biomarkers that are associated with risk or early detection of CKD are SNPs in the MYH9/APOL1 and UMOD genes, the proteomic CKD273 biomarker panel and metabolite pantothenic acid. Pantothenic acid and the CKD273 biomarker panel were also involved in predicting CKD progression. Retinoic acid pathway genes, UMOD, and pantothenic acid provided insight into potential pathways leading to CKD. The biomarkers were mainly used to detect CKD and predict progression in high-income, European ancestry populations, highlighting the need for representative 'omics research in other populations with disparate socio-economic strata, including Africans, since disease etiologies may differ across ethnic groups. To assess the transferability of findings, it is essential to do research in diverse populations. | Govender, Melanie A Brandenburg, Jean-Tristan Fabian, June Ramsay, Michele eng Review Switzerland Front Genet. 2021 Nov 8;12:682929. doi: 10.3389/fgene.2021.682929. eCollection 2021.I | 11/26/2021 | ||
| Synergistic insights into human health from aptamer- and antibody-based proteomic profiling | Pietzner M, et al. | 2021 | Nat Commun | 12 | 1 | 6822 | https://www.doi.org/10.1038/s41467-021-27164-0 | 34,819,519 | Adult Alzheimer Disease/genetics Antibodies/metabolism Aptamers, Peptide/metabolism Cohort Studies Female Humans Male Membrane Glycoproteins/genetics Middle Aged Phenotype Protein Interaction Mapping Protein Interaction Maps/genetics Proteome/*genetics/metabolism Proteomics/*methods *Quantitative Trait Loci Receptors, Immunologic/genetics | Affinity-based proteomics has enabled scalable quantification of thousands of protein targets in blood enhancing biomarker discovery, understanding of disease mechanisms, and genetic evaluation of drug targets in humans through protein quantitative trait loci (pQTLs). Here, we integrate two partly complementary techniques-the aptamer-based SomaScan((R)) v4 assay and the antibody-based Olink assays-to systematically assess phenotypic consequences of hundreds of pQTLs discovered for 871 protein targets across both platforms. We create a genetically anchored cross-platform proteome-phenome network comprising 547 protein-phenotype connections, 36.3% of which were only seen with one of the two platforms suggesting that both techniques capture distinct aspects of protein biology. We further highlight discordance of genetically predicted effect directions between assays, such as for PILRA and Alzheimer's disease. Our results showcase the synergistic nature of these technologies to better understand and identify disease mechanisms and provide a benchmark for future cross-platform discoveries. | Pietzner, Maik Wheeler, Eleanor Carrasco-Zanini, Julia Kerrison, Nicola D Oerton, Erin Koprulu, Mine Luan, Jian'an Hingorani, Aroon D Williams, Steve A Wareham, Nicholas J Langenberg, Claudia eng MC_UU_00006/1/MRC_/Medical Research Council/United Kingdom MC_PC_13046/MRC_/Medical Research Council/United Kingdom AA/18/6/34223/BHF_/British Heart Foundation/United Kingdom WT_/Wellcome Trust/United Kingdom MC_UU_12015/1/MRC_/Medical Research Council/United Kingdom MR/V033867/1/MRC_/Medical Research Council/United Kingdom Observational Study Research Support, Non-U.S. Gov't England Nat Commun. 2021 Nov 24;12(1):6822. doi: 10.1038/s41467-021-27164-0.I | 11/26/2021 | |
| Proteomics and Risk of Atrial Fibrillation in Older Adults (From the Atherosclerosis Risk in Communities [ARIC] Study) | Norby FL, et al. | 2021 | Am J Cardiol | 161 | 42-50 | https://www.doi.org/10.1016/j.amjcard.2021.08.064 | 34,794,617 | Atherosclerosis/*blood/complications/epidemiology Atrial Fibrillation/*blood/complications/epidemiology Biomarkers/blood Female Follow-Up Studies Humans Incidence Male Middle Aged Natriuretic Peptide, Brain/*blood Peptide Fragments/*blood Protein Precursors Proteomics/*methods Risk Assessment/*methods Risk Factors Time Factors United States/epidemiology | Plasma proteomic profiling may aid in the discovery of novel biomarkers upstream of the development of atrial fibrillation (AF). We used data from the Atherosclerosis Risk in Communities study to examine the relation between large-scale proteomics and incident AF in a cohort of older-aged adults in the United States. We quantified 4,877 plasma proteins in Atherosclerosis Risk in Communities participants at visit 5 (2011-2013) using an aptamer-based proteomic profiling platform. We used Cox proportional hazards models to assess the association between protein levels and incident AF, and explored relation of selected protein biomarkers using annotated pathway analysis. Our study included 4,668 AF-free participants (mean age 75 +/- 5 years; 59% female; 20% Black race) with proteomic measures. A total of 585 participants developed AF over a mean follow-up of 5.7 +/- 1.7 years. After adjustment for clinical factors associated with AF, N-terminal pro-B-type natriuretic peptide (NT-proBNP) was associated with the risk of incident AF (hazard ratio, 1.82; 95% CI, 1.68 to 1.98; p, 2.91 x 10(-45) per doubling of NT-proBNP). In addition, 36 other proteins were also significantly associated with incident AF after Bonferroni correction. We further adjusted for medication use and estimated glomerular filtration rate and found 17 proteins, including angiopoietin-2 and transgelin, that remained significantly associated with incident AF. Pathway analyses implicated the inhibition of matrix metalloproteases as the top canonical pathway in AF pathogenesis. In conclusion, using a large-scale proteomic platform, we identified both novel and established proteins associated with incident AF and explored mechanistic pathways of AF development. | Norby, Faye L Tang, Weihong Pankow, James S Lutsey, Pamela L Alonso, Alvaro Steffan, Brian Chen, Lin Y Zhang, Michael Shippee, Nathan D Ballantyne, Christie M Boerwinkle, Eric Coresh, Josef Folsom, Aaron R eng 16EIA26410001/AHA/American Heart Association-American Stroke Association/ HHSN268201700002C/HL/NHLBI NIH HHS/ HHSN268201700001I/HL/NHLBI NIH HHS/ HHSN268201700004C/HL/NHLBI NIH HHS/ HHSN268201700003I/HL/NHLBI NIH HHS/ R01 HL126637/HL/NHLBI NIH HHS/ K24 HL148521/HL/NHLBI NIH HHS/ HHSN268201700004I/HL/NHLBI NIH HHS/ HHSN268201700005C/HL/NHLBI NIH HHS/ HHSN268201700001C/HL/NHLBI NIH HHS/ HHSN268201700003C/HL/NHLBI NIH HHS/ R01 HL141288/HL/NHLBI NIH HHS/ HHSN268201700002I/HL/NHLBI NIH HHS/ HHSN268201700005I/HL/NHLBI NIH HHS/ Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Cardiol. 2021 Dec 15;161:42-50. doi: 10.1016/j.amjcard.2021.08.064.I | 11/20/2021 | ||
| The Proteomic Signature of Recombinant Growth Hormone in Recreational Athletes | Esefeld M, et al. | 2021 | J Endocr Soc | 5 | 12 | bvab156 | https://www.doi.org/10.1210/jendso/bvab156 | 34,765,854 | antidoping glucose metabolism human growth hormone proteomics | OBJECTIVE: Administration of human growth hormone (hGH) is prohibited in competitive sport and its detection in an athlete's sample triggers an adverse analytical finding. However, the biological processes that are modulated by recombinant hGH are not well characterized and associated blood serum proteins may constitute new biomarkers for hGH misuse. METHODS: Thirty-five recreational athletes were enrolled in a study to investigate the time- and dose-dependent response of serum protein levels to recombinant hGH administration. Participants were randomly assigned to 4 groups, receiving 1 of 3 different doses of recombinant hGH or a placebo. Bio samples were collected at 22 time points over a period of 13 weeks, starting 4 weeks before treatment, during 3 weeks of treatment, and at 6 weeks' follow-up. A total of 749 serum samples were analyzed for 1305 protein markers using the SOMAscan proteomics platform. RESULTS: We identified 66 proteins that significantly associated with recombinant hGH administration and dosage, including well known hGH targets, such as IGF1, but also previously unknown hGH-related proteins (eg, protease inhibitors, WFIKKN1, and chemokines, CCL2). Network analysis revealed changes in specific biological pathways, mainly related to the immune system and glucose metabolism. CONCLUSION: Our analysis suggests that hGH administration affects biological processes more strongly than previously acknowledged. Some of the proteins were dysregulated even after hGH treatment and could potentially be developed into biomarkers for hGH misuse. Moreover, our findings suggest new roles for hGH-associated proteins in the etiology of hGH-related diseases and may indicate new risks that may be associated with hGH misuse. | Esefeld, Max Pastor, Antoni de la Torre, Rafael Barroso, Osquel Aikin, Reid Sarwath, Hina Engelke, Rudolf Schmidt, Frank Suhre, Karsten eng J Endocr Soc. 2021 Nov 2;5(12):bvab156. doi: 10.1210/jendso/bvab156. eCollection 2021 Dec 1.I | 11/13/2021 | |
| Cross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations | Helms L, et al. | 2021 | JCI Insight | 6 | 24 | https://www.doi.org/10.1172/jci.insight.154882 | 34,767,537 | Acute Kidney Injury/etiology/*urine Adult Aged Angiotensin-Converting Enzyme 2/genetics Animals Apoptosis Bowman Capsule/cytology/virology COVID-19/complications/*urine Chlorocebus aethiops Female Gene Knockout Techniques Hospital Mortality Hospitalization Humans Kidney/metabolism/pathology/*virology Kidney Tubules, Proximal/metabolism/pathology/*virology Male Middle Aged Organoids/metabolism/*virology Podocytes/virology Polycystic Kidney Diseases Protein Kinase D2/genetics Proteome Receptors, Coronavirus/genetics Reproducibility of Results SARS-CoV-2/*pathogenicity Transcriptome Vero Cells Viral Tropism Virus Replication Covid-19 Genetic diseases Molecular pathology Nephrology iPS cells human kidney organoid differentiation and modeling of disease in this system (patent applications US 63/253,797 15/756,846 62/213,740 62/672,470 62/739,637 and PCT/US2019/032754). | Kidneys are critical target organs of COVID-19, but susceptibility and responses to infection remain poorly understood. Here, we combine SARS-CoV-2 variants with genome-edited kidney organoids and clinical data to investigate tropism, mechanism, and therapeutics. SARS-CoV-2 specifically infects organoid proximal tubules among diverse cell types. Infections produce replicating virus, apoptosis, and disrupted cell morphology, features of which are revealed in the context of polycystic kidney disease. Cross-validation of gene expression patterns in organoids reflects proteomic signatures of COVID-19 in the urine of critically ill patients indicating interferon pathway upregulation. SARS-CoV-2 viral variants alpha, beta, gamma, kappa, and delta exhibit comparable levels of infection in organoids. Infection is ameliorated in ACE2-/- organoids and blocked via treatment with de novo-designed spike binder peptides. Collectively, these studies clarify the impact of kidney infection in COVID-19 as reflected in organoids and clinical populations, enabling assessment of viral fitness and emerging therapies. | Helms, Louisa Marchiano, Silvia Stanaway, Ian B Hsiang, Tien-Ying Juliar, Benjamin A Saini, Shally Zhao, Yan Ting Khanna, Akshita Menon, Rajasree Alakwaa, Fadhl Mikacenic, Carmen Morrell, Eric D Wurfel, Mark M Kretzler, Matthias Harder, Jennifer L Murry, Charles E Himmelfarb, Jonathan Ruohola-Baker, Hannele Bhatraju, Pavan K Gale, Michael Jr Freedman, Benjamin S eng R21 AI158788/AI/NIAID NIH HHS/ P51 OD010425/OD/NIH HHS/ K23 DK116967/DK/NIDDK NIH HHS/ UH3 TR002158/TR/NCATS NIH HHS/ T90 DE021984/DE/NIDCR NIH HHS/ R24 HD000836/HD/NICHD NIH HHS/ F31 DK130550/DK/NIDDK NIH HHS/ U01 AI151698/AI/NIAID NIH HHS/ TL1 TR002318/TR/NCATS NIH HHS/ UC2 DK126006/DK/NIDDK NIH HHS/ UG3 TR003288/TR/NCATS NIH HHS/ UG3 TR002158/TR/NCATS NIH HHS/ K23 HL144916/HL/NHLBI NIH HHS/ R01 DK117914/DK/NIDDK NIH HHS/ R01 DK130386/DK/NIDDK NIH HHS/ R01 DK124063/DK/NIDDK NIH HHS/ U01 DK127553/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. JCI Insight. 2021 Dec 22;6(24):e154882. doi: 10.1172/jci.insight.154882.I | 11/13/2021 | ||
| A brain proteomic signature of incipient Alzheimer's disease in young APOE epsilon4 carriers identifies novel drug targets | Roberts JA, et al. | 2021 | Sci Adv | 7 | 46 | eabi8178 | https://www.doi.org/10.1126/sciadv.abi8178 | 34,757,788 | Aptamer-based proteomics revealed differentially abundant proteins in Alzheimer's disease (AD) brains in the Baltimore Longitudinal Study of Aging and Religious Orders Study (mean age, 89 +/- 9 years). A subset of these proteins was also differentially abundant in the brains of young APOE epsilon4 carriers relative to noncarriers (mean age, 39 +/- 6 years). Several of these proteins represent targets of approved and experimental drugs for other indications and were validated using orthogonal methods in independent human brain tissue samples as well as in transgenic AD models. Using cell culture-based phenotypic assays, we showed that drugs targeting the cytokine transducer STAT3 and the Src family tyrosine kinases, YES1 and FYN, rescued molecular phenotypes relevant to AD pathogenesis. Our findings may accelerate the development of effective interventions targeting the earliest molecular triggers of AD. | Roberts, Jackson A Varma, Vijay R An, Yang Varma, Sudhir Candia, Julian Fantoni, Giovanna Tiwari, Vinod Anerillas, Carlos Williamson, Andrew Saito, Atsushi Loeffler, Tina Schilcher, Irene Moaddel, Ruin Khadeer, Mohammed Lovett, Jacqueline Tanaka, Toshiko Pletnikova, Olga Troncoso, Juan C Bennett, David A Albert, Marilyn S Yu, Kaiwen Niu, Mingming Haroutunian, Vahram Zhang, Bin Peng, Junmin Croteau, Deborah L Resnick, Susan M Gorospe, Myriam Bohr, Vilhelm A Ferrucci, Luigi Thambisetty, Madhav eng P30 AG072975/AG/NIA NIH HHS/ P30 AG066507/AG/NIA NIH HHS/ RF1 AG057440/AG/NIA NIH HHS/ U01 AG046170/AG/NIA NIH HHS/ R01 AG053987/AG/NIA NIH HHS/ P30 AG010161/AG/NIA NIH HHS/ R01 AG015819/AG/NIA NIH HHS/ Sci Adv. 2021 Nov 12;7(46):eabi8178. doi: 10.1126/sciadv.abi8178. Epub 2021 Nov 10.I | 11/11/2021 | ||
| Ultrasensitive detection of blood biomarkers of Alzheimer's and Parkinson's diseases: a systematic review | Singh K, et al. | 2021 | Biomark Med | 15 | 17 | 1693-1708 | https://www.doi.org/10.2217/bmm-2021-0219 | 34,743,546 | Alzheimer Disease/*blood/*diagnosis Biomarkers/*blood Case-Control Studies Humans Longitudinal Studies Parkinson Disease/*blood/*diagnosis Publication Bias Publications Risk Alzheimer's disease Meso Scale Discovery Parkinson's disease Simoa SOMAscan biomarkers meta-analysis systematic review | Purpose: Neurodegenerative disorders are a global health burden with costly and invasive diagnoses relying on brain imaging technology or CSF-based biomarkers. Therefore, considerable efforts to identify blood-biomarkers for Alzheimer's (AD) and Parkinson's diseases (PD) are ongoing. Objectives: This review evaluates the blood biomarkers for AD and PD for their diagnostic value. Methods: This study systematically reviewed articles published between July 1984 and February 2021. Among 1266 papers, we selected 42 studies for a systematic review and 23 studies for meta-analysis. Results & conclusion: Our analysis highlights P-tau181, T-tau and Nfl as promising blood biomarkers for AD diagnosis. Nfl levels were consistently raised in 16 AD and three PD cohorts. P-tau181 and T-tau were also significantly increased in 12 and eight AD cohorts, respectively. | Singh, Kailash Cheung, Bernard My Xu, Aimin eng Meta-Analysis Research Support, Non-U.S. Gov't Systematic Review England Biomark Med. 2021 Dec;15(17):1693-1708. doi: 10.2217/bmm-2021-0219. Epub 2021 Nov 8.I | 11/09/2021 | |
| Dysregulated expression levels of APH1B in peripheral blood are associated with brain atrophy and amyloid-beta deposition in Alzheimer's disease | Park YH, et al. | 2021 | Alzheimers Res Ther | 13 | 1 | 183 | https://www.doi.org/10.1186/s13195-021-00919-z | 34,732,252 | *Alzheimer Disease/diagnostic imaging/genetics/pathology *Amyloid beta-Protein Precursor/metabolism Atrophy/pathology Brain/diagnostic imaging/pathology *Endopeptidases/genetics Genetic Predisposition to Disease Genome-Wide Association Study Humans *Membrane Proteins/genetics Transcriptome Alzheimer's disease Blood Expression Expression quantitative trait locus Imaging Transcriptome board. | BACKGROUND: The interaction between the brain and periphery might play a crucial role in the development of Alzheimer's disease (AD). METHODS: Using blood transcriptomic profile data from two independent AD cohorts, we performed expression quantitative trait locus (cis-eQTL) analysis of 29 significant genetic loci from a recent large-scale genome-wide association study to investigate the effects of the AD genetic variants on gene expression levels and identify their potential target genes. We then performed differential gene expression analysis of identified AD target genes and linear regression analysis to evaluate the association of differentially expressed genes with neuroimaging biomarkers. RESULTS: A cis-eQTL analysis identified and replicated significant associations in seven genes (APH1B, BIN1, FCER1G, GATS, MS4A6A, RABEP1, TRIM4). APH1B expression levels in the blood increased in AD and were associated with entorhinal cortical thickness and global cortical amyloid-beta deposition. CONCLUSION: An integrative analysis of genetics, blood-based transcriptomic profiles, and imaging biomarkers suggests that APH1B expression levels in the blood might play a role in the pathogenesis of AD. | Park, Young Ho Pyun, Jung-Min Hodges, Angela Jang, Jae-Won Bice, Paula J Kim, SangYun Saykin, Andrew J Nho, Kwangsik eng U01 AG072177/AG/NIA NIH HHS/ R01 LM011360/LM/NLM NIH HHS/ U01 AG068057/AG/NIA NIH HHS/ DH_/Department of Health/United Kingdom U01 AG024904/AG/NIA NIH HHS/ R03 AG054936/AG/NIA NIH HHS/ UL1 TR001108/TR/NCATS NIH HHS/ R01 LM012535/LM/NLM NIH HHS/ P50 GM115318/GM/NIGMS NIH HHS/ K01 AG049050/AG/NIA NIH HHS/ CIHR/Canada Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Alzheimers Res Ther. 2021 Nov 3;13(1):183. doi: 10.1186/s13195-021-00919-z.I | 11/05/2021 | |
| Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis | Sivakumar P, et al. | 2021 | Respir Res | 22 | 1 | 273 | https://www.doi.org/10.1186/s12931-021-01860-3 | 34,689,792 | Biomarkers/blood Blood Proteins/*analysis Case-Control Studies *Gene Expression Profiling Humans Idiopathic Pulmonary Fibrosis/*blood/diagnosis/*genetics Lung/*chemistry *Proteome *Proteomics *Transcriptome Biomarkers Chemokines Extracellular matrix Idiopathic pulmonary fibrosis Mast cells | BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a significant unmet medical need. Development of transformational therapies for IPF is challenging in part to due to lack of robust predictive biomarkers of prognosis and treatment response. Importantly, circulating biomarkers of IPF are limited and none are in clinical use. METHODS: We previously reported dysregulated pathways and new disease biomarkers in advanced IPF through RNA sequencing of lung tissues from a cohort of transplant-stage IPF patients (n = 36) in comparison to normal healthy donors (n = 19) and patients with acute lung injury (n = 11). Here we performed proteomic profiling of matching plasma samples from these cohorts through the Somascan-1300 SomaLogics platform. RESULTS: Comparative analyses of lung transcriptomic and plasma proteomic signatures identified a set of 34 differentially expressed analytes (fold change (FC) >/= +/- 1.5, false discovery ratio (FDR) | Sivakumar, Pitchumani Ammar, Ron Thompson, John Ryan Luo, Yi Streltsov, Denis Porteous, Mary McCoubrey, Carly Cantu, Edward 3rd Beers, Michael F Jarai, Gabor Christie, Jason D eng I01 BX001176/BX/BLRD VA/ R01 HL145408/HL/NHLBI NIH HHS/ U01 HL152970/HL/NHLBI NIH HHS/ England Respir Res. 2021 Oct 24;22(1):273. doi: 10.1186/s12931-021-01860-3.I | 10/26/2021 | |
| Advances and Utility of the Human Plasma Proteome | Deutsch EW, et al. | 2021 | J Proteome Res | 20 | 12 | 5241-5263 | https://www.doi.org/10.1021/acs.jproteome.1c00657 | 34,672,606 | Aging/genetics COVID-19/genetics Databases, Protein Hemostasis/genetics Humans Mass Spectrometry *Proteome/genetics Proteomics/*trends DNA aptamers (Somascan) Human Plasma Proteome Project Human Proteome Project PeptideAtlas blood plasma proteomics proximity extension assays (PEA by Olink) interest(s): Krishnan K. Palaniappan is an employee of Freenome. Philipp E. Geyer is an employee of OmicEra Diagnostics GmbH. All other authors declare no competing financial interest. | The study of proteins circulating in blood offers tremendous opportunities to diagnose, stratify, or possibly prevent diseases. With recent technological advances and the urgent need to understand the effects of COVID-19, the proteomic analysis of blood-derived serum and plasma has become even more important for studying human biology and pathophysiology. Here we provide views and perspectives about technological developments and possible clinical applications that use mass-spectrometry(MS)- or affinity-based methods. We discuss examples where plasma proteomics contributed valuable insights into SARS-CoV-2 infections, aging, and hemostasis and the opportunities offered by combining proteomics with genetic data. As a contribution to the Human Proteome Organization (HUPO) Human Plasma Proteome Project (HPPP), we present the Human Plasma PeptideAtlas build 2021-07 that comprises 4395 canonical and 1482 additional nonredundant human proteins detected in 240 MS-based experiments. In addition, we report the new Human Extracellular Vesicle PeptideAtlas 2021-06, which comprises five studies and 2757 canonical proteins detected in extracellular vesicles circulating in blood, of which 74% (2047) are in common with the plasma PeptideAtlas. Our overview summarizes the recent advances, impactful applications, and ongoing challenges for translating plasma proteomics into utility for precision medicine. | Deutsch, Eric W Omenn, Gilbert S Sun, Zhi Maes, Michal Pernemalm, Maria Palaniappan, Krishnan K Letunica, Natasha Vandenbrouck, Yves Brun, Virginie Tao, Sheng-Ce Yu, Xiaobo Geyer, Philipp E Ignjatovic, Vera Moritz, Robert L Schwenk, Jochen M eng R24 GM127667/GM/NIGMS NIH HHS/ U19 AG023122/AG/NIA NIH HHS/ U24 CA210967/CA/NCI NIH HHS/ R01 GM087221/GM/NIGMS NIH HHS/ P30 ES017885/ES/NIEHS NIH HHS/ S10 OD026936/OD/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review J Proteome Res. 2021 Dec 3;20(12):5241-5263. doi: 10.1021/acs.jproteome.1c00657. Epub 2021 Oct 21.I | 10/22/2021 | |
| Mapping the proteo-genomic convergence of human diseases | Pietzner M, et al. | 2021 | Science | 374 | 6,569 | eabj1541 | https://www.doi.org/10.1126/science.abj1541 | 34,648,354 | Aging Alternative Splicing Blood Proteins/*genetics/metabolism COVID-19/genetics Connective Tissue Diseases/genetics Disease/etiology/*genetics Drug Development Female Gallstones/genetics Genetic Association Studies Genetic Variation *Genome, Human Genome-Wide Association Study *Genomics Humans Internet Male Phenotype Proteins/*genetics/metabolism *Proteome Quantitative Trait Loci Sex Characteristics | Characterization of the genetic regulation of proteins is essential for understanding disease etiology and developing therapies. We identified 10,674 genetic associations for 3892 plasma proteins to create a cis-anchored gene-protein-disease map of 1859 connections that highlights strong cross-disease biological convergence. This proteo-genomic map provides a framework to connect etiologically related diseases, to provide biological context for new or emerging disorders, and to integrate different biological domains to establish mechanisms for known gene-disease links. Our results identify proteo-genomic connections within and between diseases and establish the value of cis-protein variants for annotation of likely causal disease genes at loci identified in genome-wide association studies, thereby addressing a major barrier to experimental validation and clinical translation of genetic discoveries. | Pietzner, Maik Wheeler, Eleanor Carrasco-Zanini, Julia Cortes, Adrian Koprulu, Mine Worheide, Maria A Oerton, Erin Cook, James Stewart, Isobel D Kerrison, Nicola D Luan, Jian'an Raffler, Johannes Arnold, Matthias Arlt, Wiebke O'Rahilly, Stephen Kastenmuller, Gabi Gamazon, Eric R Hingorani, Aroon D Scott, Robert A Wareham, Nicholas J Langenberg, Claudia eng MC_UU_00006/1/MRC_/Medical Research Council/United Kingdom R01 HG011138/HG/NHGRI NIH HHS/ RF1 AG059093/AG/NIA NIH HHS/ U01 AG061359/AG/NIA NIH HHS/ RF1 AG057452/AG/NIA NIH HHS/ MR/V033867/1/MRC_/Medical Research Council/United Kingdom R35 HG010718/HG/NHGRI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Science. 2021 Nov 12;374(6569):eabj1541. doi: 10.1126/science.abj1541. Epub 2021 Nov 12.I | 10/15/2021 | |
| Plasma P-selectin is an early marker of thromboembolism in COVID-19 | Fenyves BG, et al. | 2021 | Am J Hematol | 96 | 12 | E468-E471 | https://www.doi.org/10.1002/ajh.26372 | 34,622,480 | Aged Biomarkers/blood COVID-19/*blood/complications/diagnosis Female Humans Male P-Selectin/*blood Prospective Studies SARS-CoV-2/isolation & purification Thromboembolism/*blood/diagnosis/etiology | Fenyves, Bank G Mehta, Arnav Kays, Kyle R Beakes, Caroline Margolin, Justin Goldberg, Marcia B Hacohen, Nir Filbin, Michael R eng UL1 TR 002541-01/NH/NIH HHS/ David P. Ryan, MD Endowed Chair in Cancer Research/ UL1 TR002541/TR/NCATS NIH HHS/ Rosztoczy Foundation/ Massachusetts General Hospital/ U19 AI082630/AI/NIAID NIH HHS/ U19 AI082630/NH/NIH HHS/ American Lung Association/ T32 CA071345/CA/NCI NIH HHS/ Letter Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Hematol. 2021 Dec 1;96(12):E468-E471. doi: 10.1002/ajh.26372. Epub 2021 Oct 16.I | 10/09/2021 | ||
| Vitamin D association with the renin angiotensin system in polycystic ovary syndrome | Butler AE, et al. | 2021 | J Steroid Biochem Mol Biol | 214 | 105965 | https://www.doi.org/10.1016/j.jsbmb.2021.105965 | 34,619,249 | Adult Angiotensin-Converting Enzyme 2/*blood Angiotensinogen/*blood Blood Pressure Female Humans Polycystic Ovary Syndrome/*blood/physiopathology Renin/*blood Renin-Angiotensin System Vitamin D/blood Vitamin D Deficiency/*blood/physiopathology Vitamins/blood Young Adult ACE2 protein Angiotensinogen Polycystic ovary syndrome Renin Vitamin D | Vitamin D deficiency is a negative endocrine renin-angiotensin system (RAS) modulator and PCOS women are often vitamin D deficient, leading to RAS overactivation in PCOS. A cross-sectional study was performed in 99 PCOS and 68 control women who presented sequentially. Circulating plasma levels of RAS proteins (Angiotensin-converting enzyme 2 (ACE2), renin and angiotensinogen) were measured by Slow Off-rate Modified Aptamer (SOMA)-scan and 25-hydroxyvitamin D [25(OH)D] was measured by tandem mass spectroscopy. The RAS system was found to be overactivated in the PCOS women compared to non-PCOS control women with increased renin and decreased angiotensinogen (p < 0.05); 25-hydroxyvitamin D was also significantly lower in the PCOS group (p < 0.0001). In PCOS women, plasma renin was increased in vitamin D deficient and insufficient groups compared with the vitamin D sufficient group (p < 0.005), but did not differ across non-PCOS control subgroups. In non-PCOS controls, plasma ACE2 decreased from vitamin D insufficiency to deficiency (p < 0.05). Angiotensinogen was not different across the vitamin D sufficiency, insufficiency and deficiency strata for either PCOS or non-PCOS controls. These data show that RAS activation through increased plasma renin levels was seen in vitamin D insufficient and deficient PCOS subjects compared to non-PCOS control women. In addition, decreased plasma ACE2 levels were seen in vitamin D deficiency in non-PCOS controls, which may predispose these vitamin D deficient subjects to increased cardiovascular risk and susceptibility to infectious agents such as COVID-19 where this is a risk factor. | Butler, Alexandra E Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L eng England J Steroid Biochem Mol Biol. 2021 Nov;214:105965. doi: 10.1016/j.jsbmb.2021.105965. Epub 2021 Oct 5.I | 10/08/2021 | ||
| Proteomic Biomarker Analysis of Serum from Japanese Field Mice (Apodemus Speciosus) Collected within the Fukushima Difficult-to-return Zone | Sproull M, et al. | 2021 | Health Phys | 121 | 6 | 564-573 | https://www.doi.org/10.1097/HP.0000000000001467 | 34,618,712 | Animals Cesium Radioisotopes/analysis *Fukushima Nuclear Accident Japan Mice Murinae Proteomics Radiation Dosage *Radiation Monitoring | The environmental impact of the Fukushima Daiichi nuclear power plant accident is a source of ongoing concern as there is uncertainty regarding the effects of chronic radiation exposure on local plant and animal life from Fukushima-derived radionuclides. In the current study, changes in proteomic biomarker expression due to chronic environmentally-derived radiation exposures was examined in wild field mice. Serum from 10 wild field mice (Apodemus speciosus) native to the Fukushima difficult-to-return zone and from eight wild field mice native to the Soma area (control) were collected. External dose estimations were completed using measurements of ambient radiation levels and calculating 137Cs concentrations in soil. Internal dose was estimated by counting whole mice using an HPGe detector. Age of the mice was estimated using molar wear. Serum was screened using the aptamer-based SOMAscan proteomic assay technology for changes in expression of 1,310 protein analytes. A subset panel of protein biomarkers that demonstrated significant changes in expression between control and exposed mice was determined and analyzed using Ingenuity Pathway Analysis (IPA). Control animals had a calculated lifetime dose range from 0.001 to 0.007 Gy, and exposed animals had a calculated lifetime dose range from 0.01 to 0.64 Gy. No discernable effect of dose rate was seen as relative dose rate correlated with dose for all samples. Detectable values were obtained for all 1,310 proteins included in the SOMAscan assay. Subset panels of proteins demonstrating significant (p < 0.05) changes in expression with either an upregulated or downregulated 1.5-fold change over control were identified for both the sample cohort inclusive of all exposed samples and the sample cohort restricted to samples from animals receiving low" dose exposures. These panels of proteins from exposed animals were analyzed using IPA, which highlighted changes in key biological pathways related to injury, respiratory, renal, urological, and gastrointestinal disease, and cancer. Significant changes in expression of proteomic biomarkers were seen in the serum of wild field mice that received environmental exposure to Fukushima-derived radionuclides. Our findings demonstrate novel biomarkers of radiation exposure in wildlife within the Fukushima difficult-to-return zone." | Sproull, Mary Hayes, Joshua Ishiniwa, Hiroko Nanba, Kenji Shankavaram, Uma Camphausen, Kevin Johnson, Thomas E eng T42 OH009229/OH/NIOSH CDC HHS/ T42OH009229/ACL/ACL HHS/ ZIA SC010373/ImNIH/Intramural NIH HHS/ ZID BC010990/ImNIH/Intramural NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Health Phys. 2021 Dec 1;121(6):564-573. doi: 10.1097/HP.0000000000001467.I | 10/08/2021 | |
| Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals | Shi L, et al. | 2021 | Alzheimers Dement (Amst) | 13 | 1 | e12240 | https://www.doi.org/10.1002/dad2.12240 | 34,604,499 | mediation neurodegeneration plasma proteomics sex-related difference vascular damage SOBP2021). R.E.M. is an advisor to the Epigenetic Clock Development Foundation and has received a speaker fee from Illumina. A.C. is member of Edinburgh MVM Research Ethics Committee. J.M.W is involved in European Stroke Organisation Guideline on Covert Small Vessel Disease 2021 and European Stroke Organisation Chair of Conference Planning Group 2021 and 2022. D.S. helped to set up CAPE study. A.M. received speaker fees from Janssen and Illumina. S.L. is an employee of Janssen Medical UK and Co-founder of Akrivia Health Ltd. He is also named as an inventor on biomarker intellectual property protected by Proteome Sciences and Kings College London unrelated to the current study and within the past 5 years has advised for Optum labs, Merck, SomaLogic, and been the recipient of funding from AstraZeneca and other companies via the IMI funding scheme. N.B. is a member of Mehta Family Centre for Engineering in Medicine, Kanpur, India as well as the editorial board of Stem Cells. A.N.H. is the main PI of a project funded by J&J, and another projects funded by GSK, all unrelated to this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | INTRODUCTION: This study aims to first discover plasma proteomic biomarkers relating to neurodegeneration (N) and vascular (V) damage in cognitively normal individuals and second to discover proteins mediating sex-related difference in N and V pathology. METHODS: Five thousand and thirty-two plasma proteins were measured in 1061 cognitively normal individuals (628 females and 433 males), nearly 90% of whom had magnetic resonance imaging measures of hippocampal volume (as N) and white matter hyperintensities (as V). RESULTS: Differential protein expression analysis and co-expression network analysis revealed different proteins and modules associated with N and V, respectively. Furthermore, causal mediation analysis revealed four proteins mediated sex-related difference in N and one protein mediated such difference in V damage. DISCUSSION: Once validated, the identified proteins could help to select cognitively normal individuals with N and V pathology for Alzheimer's disease clinical trials and provide targets for further mechanistic studies on brain sex differences, leading to sex-specific therapeutic strategies. | Shi, Liu Buchanan, Colin R Cox, Simon R Hillary, Robert F Marioni, Riccardo E Campbell, Archie Hayward, Caroline Stolicyn, Aleks Whalley, Heather C Harris, Mathew A Waymont, Jennifer Waiter, Gordon Backhouse, Ellen Wardlaw, Joanna M Steele, Douglas Mcintosh, Andrew Lovestone, Simon Buckley, Noel J Nevado-Holgado, Alejo J eng MR/S010351/1/MRC_/Medical Research Council/United Kingdom R01 AG054628/AG/NIA NIH HHS/ U19 AG063744/AG/NIA NIH HHS/ MC_PC_17209/MRC_/Medical Research Council/United Kingdom MC_UU_00007/10/MRC_/Medical Research Council/United Kingdom RF1 AG057452/AG/NIA NIH HHS/ WT_/Wellcome Trust/United Kingdom Alzheimers Dement (Amst). 2021 Sep 27;13(1):e12240. doi: 10.1002/dad2.12240. eCollection 2021.I | 10/05/2021 | |
| Influence of renin-angiotensin-aldosterone system inhibitors on plasma levels of angiotensin-converting enzyme 2 | Zimmermann T, et al. | 2021 | ESC Heart Fail | 8 | 2 | 1717-1721 | https://www.doi.org/10.1002/ehf2.13249 | 34,596,976 | Aged Angiotensin Receptor Antagonists *Angiotensin-Converting Enzyme 2 Angiotensin-Converting Enzyme Inhibitors *covid-19 Female Humans Male Proteomics Renin-Angiotensin System SARS-CoV-2 Ace Ace2 Arb Covid-19 Plasma levels Raas SARS-CoV-2 Gesellschaft Basel. Dr. Walter reports research grants from the Swiss Heart Foundation (FF19097 and F18111) and the Swiss Academy of Medical Sciences and Bangerter Foundation. Dr. Mueller has received research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the European Union, the Cardiovascular Research Foundation Basel, the University Hospital Basel, Abbott, Astra Zeneca, Beckman Coulter, Biomerieux, BRAHMS, Critical Diagnostics, Roche, Siemens, Singulex, and Sphingotec, as well as speaker/consulting honoraria from Abbott, Alere, Astra Zeneca, Bayer, Biomerieux, Boehringer Ingelheim, BMS, BRAHMS, Cardiorentis, Novartis, Roche, Sanofi, Siemens, and Singulex. All other authors declare that they have no conflict of interest with this study. All authors critically reviewed the manuscript and approved the final version for submission. The sponsors had no role in the design and conduct of the study collection, management, analysis, and interpretation of the data preparation or approval of the manuscript. | AIMS: Concern has been raised that treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the expression of angiotensin-converting enzyme 2 (ACE2), which acts as the entry receptor for SARS-CoV-2, and lead to an increased risk of death from SARS-CoV-2. We aimed to address this concern by evaluating the in vivo relationship of treatment with ACE inhibitors and angiotensin receptor blockers (ARB) with circulating plasma concentrations of ACE2 in a large cohort of patients with established cardiovascular disease (n = 1864) or cardiovascular risk factors (n = 2144) but without a history of heart failure. METHODS AND RESULTS: Angiotensin-converting enzyme 2 was measured in 4008 patients (median age 68, 33% women, 31% on ACE-inhibitors, 31% on ARB) using the SOMAscan proteomic platform (SomaLogic Inc, Colorado, USA). Plasma concentration of ACE2 was comparable in 1250 patients on ACE inhibitors (mean 5.99) versus patients without ACE inhibitors (mean 5.98, P = 0.54). Similarly, plasma concentration of ACE2 was comparable in 1260 patients on ARB (mean 5.99) versus patients without ARB (mean 5.98, P = 0.50). Plasma concentration of ACE2 was comparable in 2474 patients on either ACE inhibitors or ARB (mean 5.99) versus patients without ACE inhibitors or ARB (mean 5.98, P = 0.31). Multivariable quantile regression model analysis confirmed the lack of association between treatment with ACE inhibitors or ARB and ACE2 concentrations. Body mass index showed the only positive association with ACE2 plasma concentration (effect 0.015, 95% confidence interval 0.002 to 0.028, P = 0.024). CONCLUSIONS: In a large cohort of patients with established cardiovascular disease or cardiovascular risk factors but without heart failure, ACE inhibitors and ARB were not associated with higher plasma concentrations of ACE2. | Zimmermann, Tobias Walter, Joan Elias Lopez-Ayala, Pedro Strebel, Ivo Amrein, Melissa Koechlin, Michael Honegger, Ursina Mueller, Christian eng Research Support, Non-U.S. Gov't England ESC Heart Fail. 2021 Apr;8(2):1717-1721. doi: 10.1002/ehf2.13249. Epub 2021 Feb 19.I | 10/02/2021 | |
| Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases | Yu Z, et al. | 2021 | J Am Soc Nephrol | 32 | 12 | 3161-73 | https://www.doi.org/10.1681/ASN.2020111599 | 34,548,389 | chronic kidney disease end stage kidney disease epidemiology and outcomes genetics and development glomerular filtration rate kidney disease | BACKGROUND: Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (eGFR). The relationship between polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. METHODS: We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS (n=765,348) and UK Biobank GWAS (90% of the cohort; n=451,508), followed by best-parameter selection using the remaining 10% of UK Biobank data (n=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (n=8866) with incident CKD, ESKD, kidney failure, and AKI. We also examined associations between the PRS and 4877 plasma proteins measured at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. RESULTS: The developed PRS showed a significant association with all outcomes. Hazard ratios per 1 SD lower PRS ranged from 1.06 (95% CI, 1.01 to 1.11) to 1.33 (95% CI, 1.28 to 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin C, collagen alpha-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for five proteins, including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. CONCLUSIONS: A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR. | Yu, Zhi Jin, Jin Tin, Adrienne Kottgen, Anna Yu, Bing Chen, Jingsha Surapaneni, Aditya Zhou, Linda Ballantyne, Christie M Hoogeveen, Ron C Arking, Dan E Chatterjee, Nilanjan Grams, Morgan E Coresh, Josef eng MC_PC_17228/MRC_/Medical Research Council/United Kingdom R01 HG010480/HG/NHGRI NIH HHS/ U01 HL096917/HL/NHLBI NIH HHS/ K24 HL155861/HL/NHLBI NIH HHS/ U01 DK106981/DK/NIDDK NIH HHS/ R01 DK124399/DK/NIDDK NIH HHS/ R01 HL134320/HL/NHLBI NIH HHS/ MC_QA137853/MRC_/Medical Research Council/United Kingdom J Am Soc Nephrol. 2021 Sep 21;32(12):3161-73. doi: 10.1681/ASN.2020111599.I | 09/23/2021 | |
| Towards Building a Quantitative Proteomics Toolbox in Precision Medicine: A Mini-Review | Correa Rojo A, et al. | 2021 | Front Physiol | 12 | 723510 | https://www.doi.org/10.3389/fphys.2021.723510 | 34,512,391 | bioinformatics biomarker discovery clinical diagnostics precision medicine protein quantitative trait loci quantitative proteomics targeted techniques commercial or financial relationships that could be construed as a potential conflict of interest. | Precision medicine as a framework for disease diagnosis, treatment, and prevention at the molecular level has entered clinical practice. From the start, genetics has been an indispensable tool to understand and stratify the biology of chronic and complex diseases in precision medicine. However, with the advances in biomedical and omics technologies, quantitative proteomics is emerging as a powerful technology complementing genetics. Quantitative proteomics provide insight about the dynamic behaviour of proteins as they represent intermediate phenotypes. They provide direct biological insights into physiological patterns, while genetics accounting for baseline characteristics. Additionally, it opens a wide range of applications in clinical diagnostics, treatment stratification, and drug discovery. In this mini-review, we discuss the current status of quantitative proteomics in precision medicine including the available technologies and common methods to analyze quantitative proteomics data. Furthermore, we highlight the current challenges to put quantitative proteomics into clinical settings and provide a perspective to integrate proteomics data with genomics data for future applications in precision medicine. | Correa Rojo, Alejandro Heylen, Dries Aerts, Jan Thas, Olivier Hooyberghs, Jef Ertaylan, Gokhan Valkenborg, Dirk eng Review Switzerland Front Physiol. 2021 Aug 26;12:723510. doi: 10.3389/fphys.2021.723510. eCollection 2021.I | 09/14/2021 | ||
| Slow Off-Rate Modified Aptamer (SOMAmer) Proteomic Analysis of Patient-Derived Malignant Glioma Identifies Distinct Cellular Proteomes | Thanasupawat T, et al. | 2021 | Int J Mol Sci | 22 | 17 | https://www.doi.org/10.3390/ijms22179566 | 34,502,484 | Aptamers, Nucleotide/*chemistry Brain Neoplasms/*metabolism/pathology Glioma/*metabolism/pathology Humans Neoplasm Proteins/*metabolism Proteome/*metabolism *Proteomics Tumor Cells, Cultured SOMAmers glioblastoma glioma patient cell isolates proteomic clusters | Malignant gliomas derive from brain glial cells and represent >75% of primary brain tumors. This includes anaplastic astrocytoma (grade III; AS), the most common and fatal glioblastoma multiforme (grade IV; GBM), and oligodendroglioma (ODG). We have generated patient-derived AS, GBM, and ODG cell models to study disease mechanisms and test patient-centered therapeutic strategies. We have used an aptamer-based high-throughput SOMAscan((R)) 1.3K assay to determine the proteomic profiles of 1307 different analytes. SOMAscan((R)) proteomes of AS and GBM self-organized into closely adjacent proteomes which were clearly distinct from ODG proteomes. GBM self-organized into four proteomic clusters of which SOMAscan((R)) cluster 4 proteome predicted a highly inter-connected proteomic network. Several up- and down-regulated proteins relevant to glioma were successfully validated in GBM cell isolates across different SOMAscan((R)) clusters and in corresponding GBM tissues. Slow off-rate modified aptamer proteomics is an attractive analytical tool for rapid proteomic stratification of different malignant gliomas and identified cluster-specific SOMAscan((R)) signatures and functionalities in patient GBM cells. | Thanasupawat, Thatchawan Glogowska, Aleksandra Pascoe, Christopher Krishnan, Sai Nivedita Munir, Maliha Begum, Farhana Beiko, Jason Krcek, Jerry Del Bigio, Marc R Pitz, Marshall Shen, Yaoqing Spicer, Victor Coombs, Kevin M Wilkins, John Hombach-Klonisch, Sabine Klonisch, Thomas eng Switzerland Int J Mol Sci. 2021 Sep 3;22(17):9566. doi: 10.3390/ijms22179566.I | 09/11/2021 | ||
| Evolving A RIG-I Antagonist: A Modified DNA Aptamer Mimics Viral RNA | Ren X, et al. | 2021 | J Mol Biol | 433 | 21 | 167227 | https://www.doi.org/10.1016/j.jmb.2021.167227 | 34,487,794 | Antigens, Viral/*chemistry/metabolism Aptamers, Nucleotide/*chemistry/metabolism Binding Sites Cloning, Molecular Crystallography, X-Ray DEAD Box Protein 58/*chemistry/genetics/metabolism Escherichia coli/genetics/metabolism Gene Expression Genetic Vectors/chemistry/metabolism Humans Immunologic Factors/*chemistry/metabolism Kinetics Models, Molecular Molecular Mimicry Mutation Nucleic Acid Conformation Protein Binding Protein Conformation, alpha-Helical Protein Conformation, beta-Strand Protein Interaction Domains and Motifs RNA, Viral/*chemistry/metabolism Receptors, Immunologic/*chemistry/genetics/metabolism Recombinant Proteins/chemistry/genetics/metabolism SELEX Aptamer Technique DNA structure in-vitro innate immunity molecular recognition nucleic acid folding | Vertebrate organisms express a diversity of protein receptors that recognize and respond to the presence of pathogenic molecules, functioning as an early warning system for infection. As a result of mutation or dysregulated metabolism, these same innate immune receptors can be inappropriately activated, leading to inflammation and disease. One of the most important receptors for detection and response to RNA viruses is called RIG-I, and dysregulation of this protein is linked with a variety of disease states. Despite its central role in inflammatory responses, antagonists for RIG-I are underdeveloped. In this study, we use invitro selection from a pool of modified DNA aptamers to create a high affinity RIG-I antagonist. A high resolution crystal structure of the complex reveals molecular mimicry between the aptamer and the 5'-triphosphate terminus of viral ligands, which bind to the same amino acids within the CTD recognition platform of the RIG-I receptor. Our study suggests a powerful, generalizable strategy for generating immunomodulatory drugs and mechanistic tool compounds. | Ren, Xiaoming Gelinas, Amy D Linehan, Melissa Iwasaki, Akiko Wang, Wenshuai Janjic, Nebojsa Pyle, Anna Marie eng Research Support, Non-U.S. Gov't Netherlands J Mol Biol. 2021 Oct 15;433(21):167227. doi: 10.1016/j.jmb.2021.167227. Epub 2021 Sep 3.I | 09/07/2021 | |
| Radicava/Edaravone Findings in Biomarkers From Amyotrophic Lateral Sclerosis (REFINE-ALS): Protocol and Study Design | Berry J, et al. | 2021 | Neurol Clin Pract | 11 | 4 | e472-e479 | https://www.doi.org/10.1212/CPJ.0000000000000968 | 34,476,128 | OBJECTIVES: To identify putative biomarkers that may serve as quantifiable, biological, nonclinical measures of the pharmacodynamic effect of edaravone in amyotrophic lateral sclerosis (ALS) and to report real-world treatment outcomes. METHODS: This is a prospective, observational, longitudinal, multicenter (up to 40 sites) US study (Clinicaltrials.gov; NCT04259255) with at least 200 patients with ALS who will receive edaravone for 24 weeks (6 cycles; Food and Drug Administration-approved regimen). All participants must either be treatment naive for edaravone or be more than 1 month without receiving any edaravone dose before screening. Biomarker quantification and other assessments will be performed at baseline (before cycle 1) and during cycles 1, 3, and 6. Selected biomarkers of oxidative stress, inflammation, neuronal injury and death, and muscle injury, as well as biomarker discovery panels (EpiSwitch and SOMAscan), will be evaluated and, when feasible, compared with biobanked samples. Clinical efficacy assessments will include the ALS Functional Rating Scale-Revised, King's clinical staging, ALS Assessment Questionnaire-40, Appel ALS Score (Rating Scale), slow vital capacity, hand-held dynamometry and grip strength, and time to specified states of disease progression or death. DNA samples will also be collected for potential genomic evaluation. The predicted rates of progression and survival, and their potential correlations with biomarkers, will be evaluated. Adverse events related to the study will be reported. RESULTS: The study is estimated to be completed in 2022 with an interim analysis planned. CONCLUSIONS: Findings may help to further the understanding of the pharmacodynamic effect of edaravone, including changes in biomarkers, in response to treatment. | Berry, James Brooks, Benjamin Genge, Angela Heiman-Patterson, Terry Appel, Stanley Benatar, Michael Bowser, Robert Cudkowicz, Merit Gooch, Clifton Shefner, Jeremy Westra, Jurjen Agnese, Wendy Merrill, Charlotte Nelson, Sally Apple, Stephen eng Neurol Clin Pract. 2021 Aug;11(4):e472-e479. doi: 10.1212/CPJ.0000000000000968.I | 09/04/2021 | ||
| Serum Proteomics of Older Patients Undergoing Major Cardiac Surgery: Identification of Biomarkers Associated With Postoperative Delirium | Rhee J, et al. | 2021 | Front Aging Neurosci | 13 | 699763 | https://www.doi.org/10.3389/fnagi.2021.699763 | 34,456,709 | Il-6 Pde3a SOMAscan Timp-1 TruCulture cardiopulmonary bypass postoperative delirium proteomics commercial or financial relationships that could be construed as a potential conflict of interest. | BACKGROUND: Postoperative delirium (POD) is an acute altered mental state commonly encountered after cardiac surgery. The pathophysiological mechanisms underlying POD remain unclear. We aimed to identify circulating proteins significantly altered after major cardiac surgery with cardiopulmonary bypass (CPB). We also aimed to enable inferences on associations with POD. METHODS: Serum and whole blood samples were collected before CPB (n = 16 patients; n = 8 with POD) and again from the same patients on postoperative day 1. All patients were clinically evaluated for POD on postoperative days 1-3. An aptamer-based proteomics platform (SOMAscan) was used to quantify serum protein abundance in patients with POD compared with non-POD controls. We also performed a lipopolysaccharide (LPS)-based in vitro functional analysis (TruCulture) on whole blood samples from patients with POD and non-POD controls to approximate surgical stress. Cytokine levels were determined using a Luminex immunoassay. RESULTS: Cardiac surgery with CPB resulted in a significant (p(adj) < 0.01) change in 48.8% (637 out of 1,305) of proteins detected by SOMAscan. Gene set enrichment showed that the most impacted biological processes involved myeloid cell activation. Specifically, activation and degranulation of neutrophils were the top five highest-scoring processes. Pathway analyses with the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that metabolic enzymes, particularly those of glycolysis, were elevated in serum concentration after surgery. Several proteins were significantly increased postoperatively in patients diagnosed with POD relative to the non-POD controls, with interleukin-6 (IL-6) showing the greatest fold-change. LPS stimulation of whole blood samples confirmed these findings. Linear regression analysis showed a highly significant correlation between Confusion Assessment Method (CAM) scores and CPB-mediated changes in cGMP-inhibited 3',5'-cyclic phosphodiesterase A (PDE3A). CONCLUSIONS: Cardiac surgery with CPB resulted in inflammasome changes accompanied by unexpected increases in metabolic pathways. In exploratory analyses, we found that POD was associated with changes in the expression level of various proteins, most notably IL-6 and PDE3A. This study and ongoing protein biomarker studies will likely help quantify risk or confirm the diagnosis for POD and increase understanding of its pathophysiological mechanisms. | Rhee, James Kuznetsov, Alexandra McKay, Tina Lyons, Margaret Houstis, Nicholas Mekkonen, Jennifer Ethridge, Breanna Ibala, Reine Hahm, Eunice Gitlin, Jacob Guseh, J Sawalla Kitchen, Robert Rosenzweig, Anthony Shaefi, Shahzad Flaczyk, Adam Qu, Jason Akeju, Oluwaseun eng R01 DK125786/DK/NIDDK NIH HHS/ R35 HL155318/HL/NHLBI NIH HHS/ T32 HL007208/HL/NHLBI NIH HHS/ R03 AG060179/AG/NIA NIH HHS/ R01 AG053582/AG/NIA NIH HHS/ R01 AG061034/AG/NIA NIH HHS/ K08 GM134220/GM/NIGMS NIH HHS/ K08 HL140200/HL/NHLBI NIH HHS/ R21 EB030756/EB/NIBIB NIH HHS/ Switzerland Front Aging Neurosci. 2021 Aug 11;13:699763. doi: 10.3389/fnagi.2021.699763. eCollection 2021.I | 08/31/2021 | ||
| DNA Damage, n-3 Long-Chain PUFA Levels and Proteomic Profile in Brazilian Children and Adolescents | Barros TT, et al. | 2021 | Nutrients | 13 | 8 | https://www.doi.org/10.3390/nu13082483 | 34,444,642 | Adolescent Brazil Child Class I Phosphatidylinositol 3-Kinases/blood Class Ia Phosphatidylinositol 3-Kinase/blood Cross-Sectional Studies Cyclin C/blood Cyclin-Dependent Kinase 8/blood *DNA Damage Docosahexaenoic Acids/*blood Eicosapentaenoic Acid/*blood Fatty Acids, Omega-3/*blood Female Humans Hydrolases/blood Inflammation/metabolism Male Protein Kinase C beta/blood Proteomics DNA damage adolescents fatty acids proteomic of the Nestle group. J.K. works for Vydiant, a for-profit company. S.M. is on the faculty of the Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteite Amsterdam. | Fatty acids play a significant role in maintaining cellular and DNA protection and we previously found an inverse relationship between blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and DNA damage. The aim of this study was to explore differences in proteomic profiles, for 117 pro-inflammatory proteins, in two previously defined groups of individuals with different DNA damage and EPA and DHA levels. Healthy children and adolescents (n = 140) aged 9 to 13 years old in an urban area of Brazil were divided by k-means cluster test into two clusters of DNA damage (tail intensity) using the comet assay (cluster 1 = 5.9% +/- 1.2 and cluster 2 = 13.8% +/- 3.1) in our previous study. The cluster with higher DNA damage and lower levels of DHA (6.2 +/- 1.6 mg/dL; 5.4 +/- 1.3 mg/dL, p = 0.003) and EPA (0.6 +/- 0.2 mg/dL; 0.5 +/- 0.1 mg/dL, p < 0.001) presented increased expression of the proteins CDK8-CCNC, PIK3CA-PIK3R1, KYNU, and PRKCB, which are involved in pro-inflammatory pathways. Our findings support the hypothesis that low levels of n-3 long-chain PUFA may have a less protective role against DNA damage through expression of pro-inflammatory proteins, such as CDK8-CCNC, PIK3CA-PIK3R1, KYNU, and PRKCB. | Barros, Tamiris Trevisan de Venancio, Vinicius de Paula Hernandes, Livia Cristina Antunes, Lusania Maria Greggi Hillesheim, Elaine Salomao, Roberta Garcia Mathias, Mariana Giaretta Coelho-Landell, Carolina Almeida Toffano, Roseli Borges Donega Almada, Maria Olimpia Ribeiro do Vale Camelo-Junior, Jose Simon Moco, Sofia Cominetti, Ornella Ued, Fabio da Veiga Kaput, Jim Monteiro, Jacqueline Pontes eng 2012/20421-8/Fundacao de Amparo a Pesquisa do Estado de Sao Paulo/ 131224/2015-8/Conselho Nacional de Desenvolvimento Cientifico e Tecnologico/ RDHS 000054/Nestle Institute of Health Sciences/ Switzerland Nutrients. 2021 Jul 21;13(8):2483. doi: 10.3390/nu13082483.I | 08/28/2021 | ||
| Validation of Chemokine Biomarkers in Duchenne Muscular Dystrophy | Ogundele M, et al. | 2021 | Life (Basel) | 11 | 8 | https://www.doi.org/10.3390/life11080827 | 34,440,571 | Becker muscular dystrophy Duchenne muscular dystrophy chemokines disease severity inflammatory biomarkers validation studies | Duchenne muscular dystrophy (DMD) is a progressive muscle disease involving complex skeletal muscle pathogenesis. The pathogenesis is triggered by sarcolemma instability due to the lack of dystrophin protein expression, leading to Ca(2+) influx, muscle fiber apoptosis, inflammation, muscle necrosis, and fibrosis. Our lab recently used two high-throughput multiplexing techniques (e.g., SomaScan((R)) aptamer assay and tandem mass tag-(TMT) approach) and identified a series of serum protein biomarkers tied to different pathobiochemical pathways. In this study, we focused on validating the circulating levels of three proinflammatory chemokines (CCL2, CXCL10, and CCL18) that are believed to be involved in an early stage of muscle pathogenesis. We used highly specific and reproducible MSD ELISA assays and examined the association of these chemokines with DMD pathogenesis, age, disease severity, and response to glucocorticoid treatment. As expected, we confirmed that these three chemokines were significantly elevated in serum and muscle samples of DMD patients relative to age-matched healthy controls (p-value < 0.05, CCL18 was not significantly altered in muscle samples). These three chemokines were not significantly elevated in Becker muscular dystrophy (BMD) patients, a milder form of dystrophinopathy, when compared in a one-way ANOVA to a control group but remained significantly elevated in the age-matched DMD group (p < 0.05). CCL2 and CCL18 but not CXCL10 declined with age in DMD patients, whereas all three chemokines remained unchanged with age in BMD and controls. Only CCL2 showed significant association with time to climb four steps in the DMD group (r = 0.48, p = 0.038) and neared significant association with patients' reported outcome in the BMD group (r = 0.39, p = 0.058). Furthermore, CCL2 was found to be elevated in a serum of the mdx mouse model of DMD, relative to wild-type mouse model. This study suggests that CCL2 might be a suitable candidate biomarker for follow-up studies to demonstrate its physiological significance and clinical utility in DMD. | Ogundele, Michael Zhang, Jesslyn S Goswami, Mansi V Barbieri, Marissa L Dang, Utkarsh J Novak, James S Hoffman, Eric P Nagaraju, Kanneboyina Cinrg-Dnhs Investigators Hathout, Yetrib eng R01 AR061875/AR/NIAMS NIH HHS/ P50HD090254/NH/NIH HHS/ W81XWH-16-1-0557/U.S. Department of Defense/ Switzerland Life (Basel). 2021 Aug 13;11(8):827. doi: 10.3390/life11080827.I | 08/28/2021 | ||
| Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease | Pierson SK, et al. | 2021 | Blood Adv | 5 | 17 | 3445-3456 | https://www.doi.org/10.1182/bloodadvances.2020004016 | 34,438,448 | *Castleman Disease/drug therapy *Herpesvirus 8, Human Humans Interleukin-6 Proteomics Signal Transduction United States | Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti-IL-6 therapy, siltuximab, is the only US Food and Drug Administration-approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8-associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration. | Pierson, Sheila K Shenoy, Sushila Oromendia, Ana B Gorzewski, Alexander M Langan Pai, Ruth-Anne Nabel, Christopher Shield Ruth, Jason R Parente, Sophia A T Arenas, Daniel J Guilfoyle, Mary Reddy, Manjula Weinblatt, Michael Shadick, Nancy Bower, Mark Pria, Alessia Dalla Masaki, Yasufumi Katz, Laura Mezey, Jason Beineke, Philip Lee, David Tendler, Craig Kambayashi, Taku Fossa, Alexander van Rhee, Frits Fajgenbaum, David C eng R01 HL141408/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Blood Adv. 2021 Sep 14;5(17):3445-3456. doi: 10.1182/bloodadvances.2020004016.I | 08/27/2021 | |
| Smoking induces sex-specific changes in the small airway proteome | Kokelj S, et al. | 2021 | Respir Res | 22 | 1 | 234 | https://www.doi.org/10.1186/s12931-021-01825-6 | 34,429,114 | Cigarette Smoking/genetics/*metabolism/pathology Cohort Studies Female Humans Lung/*metabolism/pathology Male Middle Aged Proteomics/*methods *Sex Characteristics *Smokers Spirometry/methods Tobacco Smoking/*genetics/metabolism/pathology Copd Exhaled particles Inflammation Proteomics Respiratory tract lining fluid Small airways Smoking personal fees from PExA AB during the conduct of the study and was employed by PExA AB while writing the manuscript, but not during the planning and completion of the study. HKO and BG are full-time employees of AstraZeneca. | INTRODUCTION: Cigarette smoke triggers many cellular and signaling responses in the lung and the resulting inflammation plays a central role in smoke-related lung diseases, such as COPD. We explored the effects of smoking on the small airway proteome in samples obtained by collection of exhaled particles with the aim to identify specific proteins dysregulated by smoking. METHODS: Exhaled particles were obtained from 38 current smokers, 47 former smokers and 22 healthy controls with the PExA method. 120 ng of sample was collected from individual subjects and analyzed with the SOMAscan proteomics platform. General linear model-based statistics were performed. RESULTS: Two hundred and three proteins were detected in at least half of 107 total samples. Active smoking exerted a significant impact on the protein composition of respiratory tract lining fluid (RTLF), with 81 proteins altered in current smokers compared to never smokers (p < 0.05, q < 0.124). Among the proteins most clearly discriminating between current and never smokers were sRAGE, FSTL3, SPOCK2 and protein S, all of them being less abundant in current smokers. Analysis stratified for sex unveiled sex differences with more pronounced proteomic alterations due to active smoking in females than males. Proteins whose abundance was altered by active smoking in women were to a larger extent related to the complement system. The small airway protein profile of former smokers appeared to be more similar to that observed in never smokers. CONCLUSIONS: The study shows that smoking has a strong impact on protein expression in the small airways, and that smoking affects men and women differently, suggesting PExA sampling combined with high sensitivity protein analysis offers a promising platform for early detection of COPD and identification of novel COPD drug targets. | Kokelj, Spela Ostling, Jorgen Georgi, Benjamin Fromell, Karin Ekdahl, Kristina Nilsson Olsson, Henric K Olin, Anna-Carin eng 2016-00639/Forskningsradet om Halsa, Arbetsliv och Valfard/ 21080209/Hjart-Lungfonden/ 2016-2075-5.1/Vetenskapsradet/ 2016-04519/Linneuniversitetet/ England Respir Res. 2021 Aug 24;22(1):234. doi: 10.1186/s12931-021-01825-6.I | 08/26/2021 | |
| Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the GIPR Region | Bowker N, et al. | 2021 | Diabetes | 70 | 11 | 2706-2719 | https://www.doi.org/10.2337/db21-0103 | 34,426,508 | Adult Aged Cardiovascular Diseases/*blood Diabetes Mellitus, Type 2/*blood/genetics/metabolism Female Finland Gastric Inhibitory Polypeptide/*blood/genetics/metabolism *Genetic Predisposition to Disease Genetic Variation Genome-Wide Association Study Genotype Humans Male Middle Aged Receptors, Gastrointestinal Hormone/genetics/*metabolism Risk Factors United Kingdom | There is considerable interest in GIPR agonism to enhance the insulinotropic and extrapancreatic effects of GIP, thereby improving glycemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the GIPR locus. Using Bayesian multitrait colocalization, we identified a GIPR missense variant, rs1800437 (G allele; E354), as the putatively causal variant shared among fasting GIP levels, glycemic traits, and adiposity-related traits (posterior probability for colocalization [PP(coloc)] > 0.97; PP explained by the candidate variant [PP(explained)] = 1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in APOE (rs7412; distance to E354 approximately 770 Kb; R (2) with E354 = 0.004; PP(coloc) > 0.99; PP(explained) = 1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (odds ratio [OR] per copy of E354 after adjustment 1.03; 95% CI 1.02, 1.04; P = 0.003). Instead, E354's association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272 (R (2) with E354 = 0.27), an intronic variant in SNRPD2 (OR for E354 after adjustment for rs1964272: 1.01; 95% CI 0.99, 1.03; P = 0.06). We demonstrate that associations with GIP and anthropometric and glycemic traits are driven by genetic signals distinct from those driving CAD and lipid traits in the GIPR region and that higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect that has yet to be assessed in clinical trials. | Bowker, Nicholas Hansford, Robert Burgess, Stephen Foley, Christopher N Auyeung, Victoria P W Erzurumluoglu, A Mesut Stewart, Isobel D Wheeler, Eleanor Pietzner, Maik Gribble, Fiona Reimann, Frank Bhatnagar, Pallav Coghlan, Matthew P Wareham, Nicholas J Langenberg, Claudia eng MC_UU_00014/3/MRC_/Medical Research Council/United Kingdom DH_/Department of Health/United Kingdom C864/A14136/CRUK_/Cancer Research UK/United Kingdom MC_PC_13046/MRC_/Medical Research Council/United Kingdom G0401527/MRC_/Medical Research Council/United Kingdom 106262/Z/14/Z/WT_/Wellcome Trust/United Kingdom G1000143/MRC_/Medical Research Council/United Kingdom 14136/CRUK_/Cancer Research UK/United Kingdom WT_/Wellcome Trust/United Kingdom MC_UU_00006/1/MRC_/Medical Research Council/United Kingdom MC_UU_12012/3/MRC_/Medical Research Council/United Kingdom 106263/Z/14/Z/WT_/Wellcome Trust/United Kingdom MR/N003284/1/MRC_/Medical Research Council/United Kingdom MC_UU_12015/1/MRC_/Medical Research Council/United Kingdom MC_PC_13048/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Diabetes. 2021 Nov;70(11):2706-2719. doi: 10.2337/db21-0103. Epub 2021 Aug 23.I | 08/25/2021 | |
| Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality | Snider JM, et al. | 2021 | J Clin Invest | 131 | 19 | https://www.doi.org/10.1172/JCI149236 | 34,428,181 | Adolescent Adult Aged Aged, 80 and over COVID-19/*blood/*mortality Child Disease-Free Survival Female Group II Phospholipases A2/*blood Humans Male Middle Aged SARS-CoV-2/*metabolism Severity of Illness Index Survival Rate Covid-19 Cellular immune response Inflammation Molecular pathology officer of MicroRid Technologies Inc. | There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality. | Snider, Justin M You, Jeehyun Karen Wang, Xia Snider, Ashley J Hallmark, Brian Zec, Manja M Seeds, Michael C Sergeant, Susan Johnstone, Laurel Wang, Qiuming Sprissler, Ryan Carr, Tara F Lutrick, Karen Parthasarathy, Sairam Bime, Christian Zhang, Hao Helen Luberto, Chiara Kew, Richard R Hannun, Yusuf A Guerra, Stefano McCall, Charles E Yao, Guang Del Poeta, Maurizio Chilton, Floyd H eng I01 BX002624/BX/BLRD VA/ P30 ES006694/ES/NIEHS NIH HHS/ R01 AI125770/AI/NIAID NIH HHS/ P01 CA097132/CA/NCI NIH HHS/ UL1 TR001420/TR/NCATS NIH HHS/ R01 AI136934/AI/NIAID NIH HHS/ Clinical Trial Multicenter Study Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Clin Invest. 2021 Oct 1;131(19):e149236. doi: 10.1172/JCI149236.I | 08/25/2021 | ||
| Cognitive stimulation in the workplace, plasma proteins, and risk of dementia: three analyses of population cohort studies | Kivimaki M, et al. | 2021 | BMJ | 374 | n1804 | https://www.doi.org/10.1136/bmj.n1804 | 34,407,988 | Aged Aged, 80 and over Blood Proteins/analysis Dementia/blood/*epidemiology Europe/epidemiology Female Humans Incidence Male Neuropsychological Tests Occupational Diseases/blood/*epidemiology/psychology Occupations/*statistics & numerical data Proportional Hazards Models Prospective Studies Risk Factors Sedentary Behavior United Kingdom/epidemiology United States/epidemiology Workplace/*psychology | OBJECTIVES: To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association. DESIGN: Multicohort study with three sets of analyses. SETTING: United Kingdom, Europe, and the United States. PARTICIPANTS: Three associations were examined: cognitive stimulation and dementia risk in 107 896 participants from seven population based prospective cohort studies from the IPD-Work consortium (individual participant data meta-analysis in working populations); cognitive stimulation and proteins in a random sample of 2261 participants from one cohort study; and proteins and dementia risk in 13 656 participants from two cohort studies. MAIN OUTCOME MEASURES: Cognitive stimulation was measured at baseline using standard questionnaire instruments on active versus passive jobs and at baseline and over time using a job exposure matrix indicator. 4953 proteins in plasma samples were scanned. Follow-up of incident dementia varied between 13.7 to 30.1 years depending on the cohort. People with dementia were identified through linked electronic health records and repeated clinical examinations. RESULTS: During 1.8 million person years at risk, 1143 people with dementia were recorded. The risk of dementia was found to be lower for participants with high compared with low cognitive stimulation at work (crude incidence of dementia per 10 000 person years 4.8 in the high stimulation group and 7.3 in the low stimulation group, age and sex adjusted hazard ratio 0.77, 95% confidence interval 0.65 to 0.92, heterogeneity in cohort specific estimates I(2)=0%, P=0.99). This association was robust to additional adjustment for education, risk factors for dementia in adulthood (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, and prevalent diabetes at baseline), and cardiometabolic diseases (diabetes, coronary heart disease, stroke) before dementia diagnosis (fully adjusted hazard ratio 0.82, 95% confidence interval 0.68 to 0.98). The risk of dementia was also observed during the first 10 years of follow-up (hazard ratio 0.60, 95% confidence interval 0.37 to 0.95) and from year 10 onwards (0.79, 0.66 to 0.95) and replicated using a repeated job exposure matrix indicator of cognitive stimulation (hazard ratio per 1 standard deviation increase 0.77, 95% confidence interval 0.69 to 0.86). In analysis controlling for multiple testing, higher cognitive stimulation at work was associated with lower levels of proteins that inhibit central nervous system axonogenesis and synaptogenesis: slit homologue 2 (SLIT2, fully adjusted beta -0.34, P<0.001), carbohydrate sulfotransferase 12 (CHSTC, fully adjusted beta -0.33, P<0.001), and peptidyl-glycine alpha-amidating monooxygenase (AMD, fully adjusted beta -0.32, P<0.001). These proteins were associated with increased dementia risk, with the fully adjusted hazard ratio per 1 SD being 1.16 (95% confidence interval 1.05 to 1.28) for SLIT2, 1.13 (1.00 to 1.27) for CHSTC, and 1.04 (0.97 to 1.13) for AMD. CONCLUSIONS: The risk of dementia in old age was found to be lower in people with cognitively stimulating jobs than in those with non-stimulating jobs. The findings that cognitive stimulation is associated with lower levels of plasma proteins that potentially inhibit axonogenesis and synaptogenesis and increase the risk of dementia might provide clues to underlying biological mechanisms. | Kivimaki, Mika Walker, Keenan A Pentti, Jaana Nyberg, Solja T Mars, Nina Vahtera, Jussi Suominen, Sakari B Lallukka, Tea Rahkonen, Ossi Pietilainen, Olli Koskinen, Aki Vaananen, Ari Kalsi, Jatinderpal K Goldberg, Marcel Zins, Marie Alfredsson, Lars Westerholm, Peter J M Knutsson, Anders Theorell, Tores Ervasti, Jenni Oksanen, Tuula Sipila, Pyry N Tabak, Adam G Ferrie, Jane E Williams, Stephen A Livingston, Gill Gottesman, Rebecca F Singh-Manoux, Archana Zetterberg, Henrik Lindbohm, Joni V eng MR/R024227/1/MRC_/Medical Research Council/United Kingdom MR/S011676/1/MRC_/Medical Research Council/United Kingdom P30 AG066507/AG/NIA NIH HHS/ Meta-Analysis Research Support, Non-U.S. Gov't England BMJ. 2021 Aug 18;374:n1804. doi: 10.1136/bmj.n1804.I | 08/20/2021 | ||
| A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance | Anisul M, et al. | 2021 | Elife | 10 | https://www.doi.org/10.7554/eLife.69719 | 34,402,426 | 2',5'-Oligoadenylate Synthetase/genetics COVID-19/genetics/immunology/physiopathology/*virology Cell Adhesion Molecules *Genome-Wide Association Study Humans Lectins, C-Type Proteome Receptors, Cell Surface SARS-CoV-2/*physiology Scavenger Receptors, Class A/genetics Severity of Illness Index fas Receptor/genetics Covid-19 apoptosis epidemiology genetic colocalization genetics genomics global health human mendelian randomization proteins partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners. JS none, ES Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners. ES is also a full-time employee of Bristol-Myers Squibb. MH Dr Holmes has consulted for Boehringer Ingelheim, and in adherence to the University of Oxford's Clinical Trial Service Unit & Epidemiological Studies Unit (CSTU) staff policy, did not accept personal honoraria or other payments from pharmaceutical companies. JM JM is a full-time employee of Bristol-Myers Squibb and retains stock or stock options in Bristol-Myers Squibb. The author has no other competing interests to declare. TG TG received grants from Biogen and GlaxoSmithKline. The author has no other competing interests to declare. ID Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners. ID also received travel costs within the last 36 months from Takeda for speaking at their Reverse Translation Symposium. The author has no other competing interests to declare. | BACKGROUND: The virus SARS-CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19. METHODS: To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome-wide genetic colocalisation tests, and polygenic (pan) and cis-Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets. RESULTS: Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble Fas (colocalisation probability >0.9, p=1 x 10(-4)), implicating Fas-mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis-Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic, and a look-up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19. CONCLUSIONS: Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19. FUNDING: MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Individuals who become infected with the virus that causes COVID-19 can experience a wide variety of symptoms. These can range from no symptoms or minor symptoms to severe illness and death. Key demographic factors, such as age, gender and race, are known to affect how susceptible an individual is to infection. However, molecular factors, such as unique gene mutations and gene expression levels can also have a major impact on patient responses by affecting the levels of proteins in the body. Proteins that are too abundant or too scarce may mean the difference between dying from or surviving COVID-19. Identifying the molecular factors in a host that affect how viruses can infect individuals, evade immune defences or trigger severe illness, could provide new ways to treat patients with COVID-19. Such factors are likely to remain constant, even when the virus mutates into new strains. Hence, insights would likely apply across all virus strains, including current strains, such as alpha and delta, and any new strains that may emerge in the future. Using such a 'natural experiment' approach, Karim et al. compared the genetic profiles of over 30,000 COVID-19 patients and a million healthy individuals. Nine proteins were found to have an impact on COVID-19 infection and disease severity. Four proteins were ranked as top priorities for potential treatment targets. One protein, called CD209 (also known as DC-SIGN), is involved in how the virus enters the host cells, and had one of the strongest associations with COVID-19. Two proteins, called IL-6R and FAS, were involved in the immune response and could be responsible for the immune over-activation often seen in severe COVID-19. Finally, one protein, called OAS1, formed part of the body's innate antiviral defence system and appeared to reduce susceptibility to COVID-19. Knowing more about the proteins that influence the severity of COVID-19 opens up new ways to predict, protect and treat patients who may have severe or fatal reactions to infection. Indeed, one of the identified proteins (IL-6R) had already been targeted in recent clinical trials with some encouraging results. Considering CD209 as a potential receptor for the virus could provide another avenue for therapeutics, similar to previously successful approaches to block the virus' known interaction with a receptor protein. Ultimately, this research could supply an entirely new set of treatment options to help combat the COVID-19 pandemic. eng | Anisul, Mohd Shilts, Jarrod Schwartzentruber, Jeremy Hayhurst, James Buniello, Annalisa Shaikho Elhaj Mohammed, Elmutaz Zheng, Jie Holmes, Michael Ochoa, David Carmona, Miguel Maranville, Joseph Gaunt, Tom R Emilsson, Valur Gudnason, Vilmundur McDonagh, Ellen M Wright, Gavin J Ghoussaini, Maya Dunham, Ian eng Wellcome Trust/United Kingdom MC_UU_00011/4/MRC_/Medical Research Council/United Kingdom 206194/WT_/Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov't England Elife. 2021 Aug 17;10:e69719. doi: 10.7554/eLife.69719.I | 08/18/2021 | |||
| Distinct Molecular Signatures of Clinical Clusters in People With Type 2 Diabetes: An IMI-RHAPSODY Study | Slieker RC, et al. | 2021 | Diabetes | 70 | 11 | 2683-2693 | https://www.doi.org/10.2337/db20-1281 | 34,376,475 | Cluster Analysis Cohort Studies Cross-Sectional Studies Diabetes Mellitus, Type 2/*metabolism Humans Insulin Resistance | Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity, investigators of a previous study clustered people with diabetes according to five diabetes subtypes. The aim of the current study is to investigate the etiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic (N = 12,828), metabolomic (N = 2,945), lipidomic (N = 2,593), and proteomic (N = 1,170) data were obtained in plasma. For each data type, each cluster was compared with the other four clusters as the reference. The insulin-resistant cluster showed the most distinct molecular signature, with higher branched-chain amino acid, diacylglycerol, and triacylglycerol levels and aberrant protein levels in plasma were enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher levels of cytokines. The mild diabetes cluster with high HDL showed the most beneficial molecular profile with effects opposite of those seen in the insulin-resistant cluster. This study shows that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease. | Slieker, Roderick C Donnelly, Louise A Fitipaldi, Hugo Bouland, Gerard A Giordano, Giuseppe N Akerlund, Mikael Gerl, Mathias J Ahlqvist, Emma Ali, Ashfaq Dragan, Iulian Elders, Petra Festa, Andreas Hansen, Michael K van der Heijden, Amber A Mansour Aly, Dina Kim, Min Kuznetsov, Dmitry Mehl, Florence Klose, Christian Simons, Kai Pavo, Imre Pullen, Timothy J Suvitaival, Tommi Wretlind, Asger Rossing, Peter Lyssenko, Valeriya Legido Quigley, Cristina Groop, Leif Thorens, Bernard Franks, Paul W Ibberson, Mark Rutter, Guy A Beulens, Joline W J 't Hart, Leen M Pearson, Ewan R eng WT_/Wellcome Trust/United Kingdom 102820/Z/13/Z/WT_/Wellcome Trust/United Kingdom WT098424AIA/WT_/Wellcome Trust/United Kingdom 212625/Z/18/Z/WT_/Wellcome Trust/United Kingdom MR/R022259/1/MRC_/Medical Research Council/United Kingdom MR/J0003042/1/MRC_/Medical Research Council/United Kingdom MR/L020149/1/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Diabetes. 2021 Nov;70(11):2683-2693. doi: 10.2337/db20-1281. Epub 2021 Aug 10.I | 08/12/2021 | |
| The COVIDome Explorer researcher portal | Sullivan KD, et al. | 2021 | Cell Rep | 36 | 7 | 109527 | https://www.doi.org/10.1016/j.celrep.2021.109527 | 34,348,131 | Access to Information Adult COVID-19/*genetics/immunology/*metabolism Case-Control Studies Data Mining *Databases, Genetic Datasets as Topic Female Gene Expression Profiling Humans Male *Metabolome Metabolomics Middle Aged *Proteome Proteomics *Transcriptome Young Adult Covid-19 Crp Sars data portal immune system infection inflammation metabolism multi-omics serpins for Elly Lilly and has provided consulting services to Gilead Sciences Inc. J.M.E. also serves on the Cell Reports Advisory Board. The remaining authors declare no competing interests. | COVID-19 pathology involves dysregulation of diverse molecular, cellular, and physiological processes. To expedite integrated and collaborative COVID-19 research, we completed multi-omics analysis of hospitalized COVID-19 patients, including matched analysis of the whole-blood transcriptome, plasma proteomics with two complementary platforms, cytokine profiling, plasma and red blood cell metabolomics, deep immune cell phenotyping by mass cytometry, and clinical data annotation. We refer to this multidimensional dataset as the COVIDome. We then created the COVIDome Explorer, an online researcher portal where the data can be analyzed and visualized in real time. We illustrate herein the use of the COVIDome dataset through a multi-omics analysis of biosignatures associated with C-reactive protein (CRP), an established marker of poor prognosis in COVID-19, revealing associations between CRP levels and damage-associated molecular patterns, depletion of protective serpins, and mitochondrial metabolism dysregulation. We expect that the COVIDome Explorer will rapidly accelerate data sharing, hypothesis testing, and discoveries worldwide. | Sullivan, Kelly Daniel Galbraith, Matthew Dominic Kinning, Kohl Thomas Bartsch, Kyle William Levinsky, Nik Caldwell Araya, Paula Smith, Keith Patrick Granrath, Ross Erich Shaw, Jessica Rose Baxter, Ryan Michael Jordan, Kimberly Rae Russell, Seth Aaron Dzieciatkowska, Monika Ewa Reisz, Julie Ann Gamboni, Fabia Cendali, Francesca Isabelle Ghosh, Tusharkanti Monte, Andrew Albert Bennett, Tellen Demeke Miller, Michael George Hsieh, Elena Wen-Yuan D'Alessandro, Angelo Hansen, Kirk Charles Espinosa, Joaquin Maximiliano eng R01 HL146442/HL/NHLBI NIH HHS/ RM1 GM131968/GM/NIGMS NIH HHS/ P30 DK048520/DK/NIDDK NIH HHS/ R01 AI150305/AI/NIAID NIH HHS/ UL1 TR002535/TR/NCATS NIH HHS/ P30 CA046934/CA/NCI NIH HHS/ K23 AR070897/AR/NIAMS NIH HHS/ R35 GM124939/GM/NIGMS NIH HHS/ R01 HL148151/HL/NHLBI NIH HHS/ R21 HL150032/HL/NHLBI NIH HHS/ R01 HL149714/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cell Rep. 2021 Aug 17;36(7):109527. doi: 10.1016/j.celrep.2021.109527. Epub 2021 Jul 28.I | 08/05/2021 | |
| Comparison of proteomic methods in evaluating biomarker-AKI associations in cardiac surgery patients | Liu RX, et al. | 2021 | Transl Res | 238 | 49-62 | https://www.doi.org/10.1016/j.trsl.2021.07.005 | 34,343,625 | Acute Kidney Injury/*blood Aged Aged, 80 and over Aptamers, Peptide Biomarkers/*blood Blood Chemical Analysis/methods Blood Proteins/*analysis Cardiac Surgical Procedures/*adverse effects Female Humans Immunoassay/methods Male Middle Aged Preoperative Period Proteomics/*methods | Although immunoassays are the most widely used protein measurement method, aptamer-based methods such as the SomaScan platform can quantify up to 7000 proteins per biosample, creating new opportunities for unbiased discovery. However, there is limited research comparing the consistency of biomarker-disease associations between immunoassay and aptamer-based platforms. In a substudy of the TRIBE-AKI cohort, preoperative and postoperative plasma samples from 294 patients with previous immunoassay measurements were analyzed using the SomaScan platform. Inter-platform Spearman correlations (r(s)) and biomarker-AKI associations were compared across 30 preoperative and 34 postoperative immunoassay-aptamer pairs. Possible factors contributing to inter-platform differences were examined including target protein characteristics, immunoassay, and SomaScan coefficients of variation, other assay characteristics, and sample storage time. The median r(s) was 0.54 (interquartile range [IQR] 0.34-0.83) in postoperative samples and 0.41 (IQR 0.21-0.69) in preoperative samples. We observed a trend of greater r(s) in biomarkers with greater concentrations; the Spearman correlation between the concentration of protein and the inter-platform correlation was 0.64 in preoperative pairs and 0.53 in postoperative pairs. Of proteins measured by immunoassays, we observed significant biomarker-AKI associations for 13 proteins preop and 24 postop; of all corresponding aptamers, 8 proteins preop and 12 postop. All proteins significantly associated with AKI as measured by SomaScan were also significantly associated with AKI as measured by immunoassay. All biomarker-AKI odds ratios were significantly different (P < 0.05) between platforms in 14% of aptamer-immunoassay pairs, none of which had high (r(s) > 0.50) inter-platform correlations. Although similar biomarker-disease associations were observed overall, biomarkers with high physiological concentrations tended to have the highest-confidence inter-platform operability in correlations and biomarker-disease associations. Aptamer assays provide excellent precision and an unprecedented coverage and promise for disease associations but interpretation of results should keep in mind a broad range of correlations with immunoassays. | Liu, Richard X Thiessen-Philbrook, Heather R Vasan, Ramachandran S Coresh, Josef Ganz, Peter Bonventre, Joseph V Kimmel, Paul L Parikh, Chirag R eng R01 HL085757/HL/NHLBI NIH HHS/ HHSN268201500001C/HL/NHLBI NIH HHS/ UL1 TR001863/TR/NCATS NIH HHS/ P30 DK079310/DK/NIDDK NIH HHS/ U01 DK106962/DK/NIDDK NIH HHS/ RF1 AG063507/AG/NIA NIH HHS/ R01 DK072381/DK/NIDDK NIH HHS/ UH3 DK114866/DK/NIDDK NIH HHS/ HHSN268201500001I/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ U01 DK082185/DK/NIDDK NIH HHS/ N01HC25195/HL/NHLBI NIH HHS/ 75N92019D00031/HL/NHLBI NIH HHS/ Comparative Study Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Transl Res. 2021 Dec;238:49-62. doi: 10.1016/j.trsl.2021.07.005. Epub 2021 Jul 31.I | 08/04/2021 | ||
| New candidate blood biomarkers potentially associated with white matter hyperintensities progression | Jimenez-Balado J, et al. | 2021 | Sci Rep | 11 | 1 | 14324 | https://www.doi.org/10.1038/s41598-021-93498-w | 34,253,757 | Aged Biomarkers/*metabolism Blood-Brain Barrier/metabolism Humans Hypertension/*metabolism Magnetic Resonance Imaging Matrix Metalloproteinase 9/metabolism Middle Aged Neutral Ceramidase/genetics/metabolism Proto-Oncogene Proteins c-met/metabolism White Matter/*metabolism | We aimed to discover blood biomarkers associated with longitudinal changes in white matter hyperintensities (WMH). This study was divided into a discovery phase and a replication phase. Subjects in both studies were patients with hypertension, aged 50-70, who underwent two magnetic resonance imaging (MRI) sessions and blood extractions over a 4-year follow-up period. In the discovery phase, we screened 1305 proteins in 12 subjects with WMH progression and in 12 matched control subjects. We found that 41 proteins were differentially expressed: 13 were upregulated and 28 were downregulated. We subsequently selected three biomarkers for replication in baseline and follow-up samples in 80 subjects with WMH progression and in 80 control subjects. The selected protein candidates for the replication were MMP9 (matrix metalloproteinase-9), which was higher in cases, MET (hepatocyte growth factor receptor) and ASAH2 (neutral ceramidase), which were both lower in cases of WMH progression. Baseline biomarker concentrations did not predict WMH progression. In contrast, patients with WMH progression presented a steeper decline in MET over time. Furthermore, cases showed higher MMP9 and lower ASAH2 levels than controls at the follow-up. These results indicate that MMP9, MET, and ASAH2 are potentially associated with the progression of WMH, and could therefore be interesting candidates to validate in future studies. | Jimenez-Balado, Joan Pizarro, Jesus Riba-Llena, Iolanda Penalba, Anna Faura, Julia Pala, Elena Montaner, Joan Hernandez-Guillamon, Mar Delgado, Pilar eng Research Support, Non-U.S. Gov't England Sci Rep. 2021 Jul 12;11(1):14324. doi: 10.1038/s41598-021-93498-w.I | 07/14/2021 | |
| Soluble Neuropilin-1 Response to Hypoglycemia in Type 2 Diabetes: Increased Risk or Protection in SARS-CoV-2 Infection? | Moin ASM, et al. | 2021 | Front Endocrinol (Lausanne) | 12 | 665134 | https://www.doi.org/10.3389/fendo.2021.665134 | 34,248,841 | ADAM Proteins/*metabolism Aged Angiotensin-Converting Enzyme 2/*metabolism Angiotensins/metabolism Covid-19 Diabetes Mellitus, Type 2/*metabolism Female Glucose Clamp Technique Humans Hypoglycemia/*metabolism Male Membrane Proteins/*metabolism Middle Aged Neuropilin-1/*metabolism Protective Factors Renin/metabolism Risk Factors SARS-CoV-2 Semaphorin-3A/*metabolism Vascular Endothelial Growth Factor A/*metabolism ACE inhibitors Adam9 Neuropilin-1 type 2 diabetes commercial or financial relationships that could be construed as a potential conflict of interest. | INTRODUCTION: Neuropilin-1(NRP1) is a cofactor that enhances SARS-CoV-2 coronavirus cell infectivity when co-expressed with angiotensin-converting enzyme 2(ACE2). The Renin-Angiotensin System (RAS) is activated in type 2 diabetes (T2D); therefore, the aim of this study was to determine if hypoglycaemia-induced stress in T2D would potentiate serum NRP1(sNRP1) levels, reflecting an increased risk for SARS-CoV-2 infection. METHODS: A case-control study of aged-matched T2D (n = 23) and control (n = 23) subjects who underwent a hyperinsulinemic clamp over 1-hour to hypoglycemia(<40mg/dl) with subsequent timecourse of 4-hours and 24-hours. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement determined RAS-related proteins: renin (REN), angiotensinogen (AGT), ACE2, soluble NRP1(sNRP1), NRP1 ligands (Vascular endothelial growth factor, VEGF and Class 3 Semaphorins, SEM3A) and NRP1 proteolytic enzyme (A Disintegrin and Metalloproteinase 9, ADAM9). RESULTS: Baseline RAS overactivity was present with REN elevated and AGT decreased in T2D (p<0.05); ACE2 was unchanged. Baseline sNRP1, VEGF and ADAM9 did not differ between T2D and controls and remained unchanged in response to hypoglycaemia. However, 4-hours post-hypoglycemia, sNRP1, VEGF and ADAM9 were elevated in T2D(p<0.05). SEMA3A was not different at baseline; at hypoglycemia, SEMA3A decreased in controls only. Post-hypoglycemia, SEMA3A levels were higher in T2D versus controls. sNRP1 did not correlate with ACE2, REN or AGT. T2D subjects stratified according to ACE inhibitor (ACEi) therapies showed no difference in sNRP1 levels at either glucose normalization or hypoglycaemia. CONCLUSION: Hypoglycemia potentiated both plasma sNRP1 level elevation and its ligands VEGF and SEMA3A, likely through an ADAM9-mediated mechanism that was not associated with RAS overactivity or ACEi therapy; however, whether this is protective or promotes increased risk for SARS-CoV-2 infection in T2D is unclear. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov, identifier NCT03102801. | Moin, Abu Saleh Md Al-Qaissi, Ahmed Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Switzerland Front Endocrinol (Lausanne). 2021 Jun 23;12:665134. doi: 10.3389/fendo.2021.665134. eCollection 2021.I | 07/13/2021 | ||
| Type 2 Diabetes Coagulopathy Proteins May Conflict With Biomarkers Reflective of COVID-19 Severity | Moin ASM, et al. | 2021 | Front Endocrinol (Lausanne) | 12 | 658304 | https://www.doi.org/10.3389/fendo.2021.658304 | 34,248,840 | Aged Biomarkers/metabolism Blood Coagulation Blood Coagulation Factors/*metabolism COVID-19/*metabolism Case-Control Studies Complement Activation Diabetes Mellitus, Type 2/*metabolism Factor IX/metabolism Female Glucose Clamp Technique Heparin Cofactor II/metabolism Humans Hypoglycemia/*metabolism Kininogens/metabolism Male Middle Aged Peptides/metabolism Platelet Activation Platelet Factor 4/metabolism Prospective Studies Protein C/metabolism Proteomics SARS-CoV-2 Severity of Illness Index Thrombospondin 1/metabolism beta-Thromboglobulin/metabolism Covid-19 biomarkers hypoglycemia type 2 diabetes commercial or financial relationships that could be construed as a potential conflict of interest. | OBJECTIVE: Detailed proteomic analysis in a cohort of patients with differing severity of COVID-19 disease identified biomarkers within the complement and coagulation cascades as biomarkers for disease severity has been reported; however, it is unclear if these proteins differ sufficiently from other conditions to be considered as biomarkers. METHODS: A prospective, parallel study in T2D (n = 23) and controls (n = 23). A hyperinsulinemic clamp was performed and normoglycemia induced in T2D [4.5 +/- 0.07 mmol/L (81 +/- 1.2 mg/dl)] for 1-h, following which blood glucose was decreased to | Moin, Abu Saleh Md Al-Qaissi, Ahmed Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Switzerland Front Endocrinol (Lausanne). 2021 Jun 25;12:658304. doi: 10.3389/fendo.2021.658304. eCollection 2021.I | 07/13/2021 | ||
| Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders | Yang C, et al. | 2021 | Nat Neurosci | 24 | 9 | 1302-1312 | https://www.doi.org/10.1038/s41593-021-00886-6 | 34,239,129 | Aged *Alzheimer Disease/genetics/metabolism Brain/*metabolism Cerebrospinal Fluid/*metabolism Female Gene Expression Regulation High-Throughput Screening Assays/methods Humans Male Middle Aged Plasma/*metabolism Proteome Proteomics/methods *Quantitative Trait Loci | Understanding the tissue-specific genetic controls of protein levels is essential to uncover mechanisms of post-transcriptional gene regulation. In this study, we generated a genomic atlas of protein levels in three tissues relevant to neurological disorders (brain, cerebrospinal fluid and plasma) by profiling thousands of proteins from participants with and without Alzheimer's disease. We identified 274, 127 and 32 protein quantitative trait loci (pQTLs) for cerebrospinal fluid, plasma and brain, respectively. cis-pQTLs were more likely to be tissue shared, but trans-pQTLs tended to be tissue specific. Between 48.0% and 76.6% of pQTLs did not co-localize with expression, splicing, DNA methylation or histone acetylation QTLs. Using Mendelian randomization, we nominated proteins implicated in neurological diseases, including Alzheimer's disease, Parkinson's disease and stroke. This first multi-tissue study will be instrumental to map signals from genome-wide association studies onto functional genes, to discover pathways and to identify drug targets for neurological diseases. | Yang, Chengran Farias, Fabiana H G Ibanez, Laura Suhy, Adam Sadler, Brooke Fernandez, Maria Victoria Wang, Fengxian Bradley, Joseph L Eiffert, Brett Bahena, Jorge A Budde, John P Li, Zeran Dube, Umber Sung, Yun Ju Mihindukulasuriya, Kathie A Morris, John C Fagan, Anne M Perrin, Richard J Benitez, Bruno A Rhinn, Herve Harari, Oscar Cruchaga, Carlos eng P30 AG066444/AG/NIA NIH HHS/ R01 AG064877/AG/NIA NIH HHS/ R01 AG057777/AG/NIA NIH HHS/ RF1 AG053303/AG/NIA NIH HHS/ RF1 AG044546/AG/NIA NIH HHS/ R01 NS118146/NS/NINDS NIH HHS/ U01 AG058922/AG/NIA NIH HHS/ R01 AG044546/AG/NIA NIH HHS/ P01 AG003991/AG/NIA NIH HHS/ P50 AG005681/AG/NIA NIH HHS/ P01 AG026276/AG/NIA NIH HHS/ RF1 AG058501/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Nat Neurosci. 2021 Sep;24(9):1302-1312. doi: 10.1038/s41593-021-00886-6. Epub 2021 Jul 8.I | 07/10/2021 | |
| Effects of adiposity on the human plasma proteome: observational and Mendelian randomisation estimates | Goudswaard LJ, et al. | 2021 | Int J Obes (Lond) | 45 | 10 | 2221-2229 | https://www.doi.org/10.1038/s41366-021-00896-1 | 34,226,637 | Adiposity/*physiology Adult Body Mass Index Cohort Studies Female Humans Male Mendelian Randomization Analysis Middle Aged Prospective Studies Proteome/*analysis/metabolism Surveys and Questionnaires | BACKGROUND: Variation in adiposity is associated with cardiometabolic disease outcomes, but mechanisms leading from this exposure to disease are unclear. This study aimed to estimate effects of body mass index (BMI) on an extensive set of circulating proteins. METHODS: We used SomaLogic proteomic data from up to 2737 healthy participants from the INTERVAL study. Associations between self-reported BMI and 3622 unique plasma proteins were explored using linear regression. These were complemented by Mendelian randomisation (MR) analyses using a genetic risk score (GRS) comprised of 654 BMI-associated polymorphisms from a recent genome-wide association study (GWAS) of adult BMI. A disease enrichment analysis was performed using DAVID Bioinformatics 6.8 for proteins which were altered by BMI. RESULTS: Observationally, BMI was associated with 1576 proteins (P < 1.4 x 10(-5)), with particularly strong evidence for a positive association with leptin and fatty acid-binding protein-4 (FABP4), and a negative association with sex hormone-binding globulin (SHBG). Observational estimates were likely confounded, but the GRS for BMI did not associate with measured confounders. MR analyses provided evidence for a causal relationship between BMI and eight proteins including leptin (0.63 standard deviation (SD) per SD BMI, 95% CI 0.48-0.79, P = 1.6 x 10(-15)), FABP4 (0.64 SD per SD BMI, 95% CI 0.46-0.83, P = 6.7 x 10(-12)) and SHBG (-0.45 SD per SD BMI, 95% CI -0.65 to -0.25, P = 1.4 x 10(-5)). There was agreement in the magnitude of observational and MR estimates (R(2) = 0.33) and evidence that proteins most strongly altered by BMI were enriched for genes involved in cardiovascular disease. CONCLUSIONS: This study provides evidence for a broad impact of adiposity on the human proteome. Proteins strongly altered by BMI include those involved in regulating appetite, sex hormones and inflammation; such proteins are also enriched for cardiovascular disease-related genes. Altogether, results help focus attention onto new proteomic signatures of obesity-related disease. | Goudswaard, Lucy J Bell, Joshua A Hughes, David A Corbin, Laura J Walter, Klaudia Davey Smith, George Soranzo, Nicole Danesh, John Di Angelantonio, Emanuele Ouwehand, Willem H Watkins, Nicholas A Roberts, David J Butterworth, Adam S Hers, Ingeborg Timpson, Nicholas J eng 204813/WT_/Wellcome Trust/United Kingdom MR/L003120/1/MRC_/Medical Research Council/United Kingdom PG/16/3/31833/BHF_/British Heart Foundation/United Kingdom 102215/WT_/Wellcome Trust/United Kingdom A19169/CRUK_/Cancer Research UK/United Kingdom WT_/Wellcome Trust/United Kingdom MC_UU_12013/3/MRC_/Medical Research Council/United Kingdom MC_UU_00011/1/MRC_/Medical Research Council/United Kingdom 202802/WT_/Wellcome Trust/United Kingdom Observational Study Research Support, Non-U.S. Gov't England Int J Obes (Lond). 2021 Oct;45(10):2221-2229. doi: 10.1038/s41366-021-00896-1. Epub 2021 Jul 5.I | 07/07/2021 | |
| Crowdsourcing assessment of maternal blood multi-omics for predicting gestational age and preterm birth | Tarca AL, et al. | 2021 | Cell Rep Med | 2 | 6 | 100323 | https://www.doi.org/10.1016/j.xcrm.2021.100323 | 34,195,686 | Adult Asymptomatic Diseases Biomarkers/blood Blood Proteins/classification/*genetics/metabolism Cell-Free Nucleic Acids/blood/classification/*genetics Crowdsourcing/methods Female *Gestational Age Humans Infant, Newborn Longitudinal Studies Pre-Eclampsia/blood/diagnosis/*genetics Pregnancy Premature Birth/blood/diagnosis/*genetics Proteomics/methods ROC Curve *Transcriptome aptamers collaborative competition human transcriptome arrays machine learning plasma proteomics predictive modeling preterm labor and delivery spontaneous preterm birth whole blood transcriptomics patent, which involves the prediction of preterm birth using proteomics data. All of the other authors declare no competing interests. | Identification of pregnancies at risk of preterm birth (PTB), the leading cause of newborn deaths, remains challenging given the syndromic nature of the disease. We report a longitudinal multi-omics study coupled with a DREAM challenge to develop predictive models of PTB. The findings indicate that whole-blood gene expression predicts ultrasound-based gestational ages in normal and complicated pregnancies (r = 0.83) and, using data collected before 37 weeks of gestation, also predicts the delivery date in both normal pregnancies (r = 0.86) and those with spontaneous preterm birth (r = 0.75). Based on samples collected before 33 weeks in asymptomatic women, our analysis suggests that expression changes preceding preterm prelabor rupture of the membranes are consistent across time points and cohorts and involve leukocyte-mediated immunity. Models built from plasma proteomic data predict spontaneous preterm delivery with intact membranes with higher accuracy and earlier in pregnancy than transcriptomic models (AUROC = 0.76 versus AUROC = 0.6 at 27-33 weeks of gestation). | Tarca, Adi L Pataki, Balint Armin Romero, Roberto Sirota, Marina Guan, Yuanfang Kutum, Rintu Gomez-Lopez, Nardhy Done, Bogdan Bhatti, Gaurav Yu, Thomas Andreoletti, Gaia Chaiworapongsa, Tinnakorn Hassan, Sonia S Hsu, Chaur-Dong Aghaeepour, Nima Stolovitzky, Gustavo Csabai, Istvan Costello, James C eng KL2 TR003143/TR/NCATS NIH HHS/ HHSN275201300006C/HD/NICHD NIH HHS/ R35 GM133346/GM/NIGMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Cell Rep Med. 2021 Jun 15;2(6):100323. doi: 10.1016/j.xcrm.2021.100323. eCollection 2021 Jun 15.I | 07/02/2021 | |
| Evaluating microbiome-directed fibre snacks in gnotobiotic mice and humans | Delannoy-Bruno O, et al. | 2021 | Nature | 595 | 7,865 | 91-95 | https://www.doi.org/10.1038/s41586-021-03671-4 | 34,163,075 | Adolescent Adult Animals Bacteroides/drug effects/isolation & purification Blood Proteins/analysis Dietary Fiber/*pharmacology Feces/*microbiology Female Gastrointestinal Microbiome/*drug effects *Germ-Free Life Humans Male Mice Mice, Inbred C57BL Middle Aged Obesity/microbiology Overweight/microbiology Proteome/analysis/drug effects *Snacks Young Adult | Changing food preferences brought about by westernization that have deleterious health effects(1,2)-combined with myriad forces that are contributing to increased food insecurity-are catalysing efforts to identify more nutritious and affordable foods(3). Consumption of dietary fibre can help to prevent cardiovascular disease, type 2 diabetes and obesity(4-6). A substantial number of reports have explored the effects of dietary fibre on the gut microbial community(7-9). However, the microbiome is complex, dynamic and exhibits considerable intra- and interpersonal variation in its composition and functions. The large number of potential interactions between the components of the microbiome makes it challenging to define the mechanisms by which food ingredients affect community properties. Here we address the question of how foods containing different fibre preparations can be designed to alter functions associated with specific components of the microbiome. Because a marked increase in snack consumption is associated with westernization, we formulated snack prototypes using plant fibres from different sustainable sources that targeted distinct features of the gut microbiomes of individuals with obesity when transplanted into gnotobiotic mice. We used these snacks to supplement controlled diets that were consumed by adult individuals with obesity or who were overweight. Fibre-specific changes in their microbiomes were linked to changes in their plasma proteomes indicative of an altered physiological state. | Delannoy-Bruno, Omar Desai, Chandani Raman, Arjun S Chen, Robert Y Hibberd, Matthew C Cheng, Jiye Han, Nathan Castillo, Juan J Couture, Garret Lebrilla, Carlito B Barve, Ruteja A Lombard, Vincent Henrissat, Bernard Leyn, Semen A Rodionov, Dmitry A Osterman, Andrei L Hayashi, David K Meynier, Alexandra Vinoy, Sophie Kirbach, Kyleigh Wilmot, Tara Heath, Andrew C Klein, Samuel Barratt, Michael J Gordon, Jeffrey I eng DK70977/NH/NIH HHS/ P01 DK078669/DK/NIDDK NIH HHS/ R01 DK070977/DK/NIDDK NIH HHS/ P30 DK056341/DK/NIDDK NIH HHS/ DK078669/NH/NIH HHS/ F30 DK124967/DK/NIDDK NIH HHS/ R01 DK124193/DK/NIDDK NIH HHS/ UL1 TR002345/TR/NCATS NIH HHS/ Clinical Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nature. 2021 Jul;595(7865):91-95. doi: 10.1038/s41586-021-03671-4. Epub 2021 Jun 23.I | 06/25/2021 | |
| Predicting the probability of death using proteomics | Eiriksdottir T, et al. | 2021 | Commun Biol | 4 | 1 | 758 | https://www.doi.org/10.1038/s42003-021-02289-6 | 34,145,379 | Adolescent Adult Aged Aged, 80 and over Biomarkers/*blood Blood Proteins/*analysis Female Frailty/*mortality Humans Iceland Kaplan-Meier Estimate Male Middle Aged Prognosis Proteomics/*methods Risk Risk Assessment Risk Factors Young Adult | Predicting all-cause mortality risk is challenging and requires extensive medical data. Recently, large-scale proteomics datasets have proven useful for predicting health-related outcomes. Here, we use measurements of levels of 4,684 plasma proteins in 22,913 Icelanders to develop all-cause mortality predictors both for short- and long-term risk. The participants were 18-101 years old with a mean follow up of 13.7 (sd. 4.7) years. During the study period, 7,061 participants died. Our proposed predictor outperformed, in survival prediction, a predictor based on conventional mortality risk factors. We could identify the 5% at highest risk in a group of 60-80 years old, where 88% died within ten years and 5% at the lowest risk where only 1% died. Furthermore, the predicted risk of death correlates with measures of frailty in an independent dataset. Our results show that the plasma proteome can be used to assess general health and estimate the risk of death. | Eiriksdottir, Thjodbjorg Ardal, Steinthor Jonsson, Benedikt A Lund, Sigrun H Ivarsdottir, Erna V Norland, Kristjan Ferkingstad, Egil Stefansson, Hreinn Jonsdottir, Ingileif Holm, Hilma Rafnar, Thorunn Saemundsdottir, Jona Norddahl, Gudmundur L Thorgeirsson, Gudmundur Gudbjartsson, Daniel F Sulem, Patrick Thorsteinsdottir, Unnur Stefansson, Kari Ulfarsson, Magnus O eng England Commun Biol. 2021 Jun 18;4(1):758. doi: 10.1038/s42003-021-02289-6.I | 06/20/2021 | |
| Plasma Proteomics of Renal Function: A Trans-ethnic Meta-analysis and Mendelian Randomization Study | Matias-Garcia P, et al. | 2021 | J Am Soc Nephrol | 32 | 7 | 1747-63 | https://www.doi.org/10.1681/ASN.2020071070 | 34,135,082 | BACKGROUND: Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. METHODS: A cross-sectional study of 993 plasma proteins among 2,882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified trans-ethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR . RESULTS: Fifty-seven plasma proteins were associated with eGFR, including one novel protein. Twenty-three of these were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. CONCLUSIONS: In a discovery-replication setting, we identified 57 proteins trans-ethnically associated with eGFR. The revealed causal relationships are an important stepping-stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation. | Matias-Garcia, Pamela Wilson, Rory Guo, Qi Zaghlool, Shaza Eales, James Xu, Xiaoguang Charchar, Fadi Dormer, John Maalmi, Haifa Schlosser, Pascal Elhadad, Mohamed Nano, Jana Sharma, Sapna Peters, Annette Fornoni, Alessia Mook-Kanamori, Dennis Winkelmann, Juliane Danesh, John Di Angelantonio, Emanuele Ouwehand, Willem Watkins, Nicholas Roberts, David Petrera, Agnese Graumann, Johannes Koenig, Wolfgang Hveem, Kristian Jonasson, Christian Kottgen, Anna Butterworth, Adam Prunotto, Marco Hauck, Stefanie Herder, Christian Suhre, Karsten Gieger, Christian Tomaszewski, Maciej Teumer, Alexander Waldenberger, Melanie eng PG/17/35/33001/BHF_/British Heart Foundation/United Kingdom RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom CH/12/2/29428/BHF_/British Heart Foundation/United Kingdom RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom PG/19/16/34270/BHF_/British Heart Foundation/United Kingdom J Am Soc Nephrol. 2021 Jun 16;32(7):1747-63. doi: 10.1681/ASN.2020071070.I | 06/18/2021 | ||
| Comprehensive aptamer-based screen of 1317 proteins uncovers improved stool protein markers of colorectal cancer | Li H, et al. | 2021 | J Gastroenterol | 56 | 7 | 659-672 | https://www.doi.org/10.1007/s00535-021-01795-y | 34,117,903 | *Aptamers, Nucleotide Area Under Curve Biomarkers/*analysis Colorectal Neoplasms/*diagnosis Cross-Sectional Studies Enzyme-Linked Immunosorbent Assay/methods *Feces Humans ROC Curve Statistics, Nonparametric Biomarker Colorectal cancer Stool | BACKGROUND: To screen and validate novel stool protein biomarkers of colorectal cancer (CRC). METHODS: A novel aptamer-based screen of 1317 proteins was used to uncover elevated proteins in the stool of patients with CRC, as compared to healthy controls (HCs) in a discovery cohort. Selected biomarker candidates from the discovery cohort were ELISA validated in three independent cross-sectional cohorts comprises 76 CRC patients, 15 adenoma patients, and 63 healthy controls, from two different ethnicities. The expression of the potential stool biomarkers within CRC tissue was evaluated using single-cell RNA-seq datasets. RESULTS: A total of 92 proteins were significantly elevated in CRC samples as compared to HCs in the discovery cohort. Among Caucasians, the 5 most discriminatory proteins among the 16 selected proteins, ordered by their ability to distinguish CRC from adenoma and healthy controls, were MMP9, haptoglobin, myeloperoxidase, fibrinogen, and adiponectin. Except myeloperoxidase, the others were significantly associated with depth of tumor invasion. The 8 stool proteins with the highest AUC values were also discriminatory in a second cohort of Indian CRC patients. Several of the stool biomarkers elevated in CRC were also expressed within CRC tissue, based on the single-cell RNA-seq analysis. CONCLUSIONS: Stool MMP9, fibrinogen, myeloperoxidase, and haptoglobin emerged as promising CRC stool biomarkers, outperforming stool Hemoglobin. Longitudinal studies are warranted to assess the clinical utility of these novel biomarkers in early diagnosis of CRC. | Li, Hao Vanarsa, Kamala Zhang, Ting Soomro, Sanam Cicalese, Pietro Antonio Duran, Valeria Dasari, Shobha Lee, Kyung Hyun Pedroza, Claudia Kisiel, John B Qin, Huanlong Bresalier, Robert S Chia, Nicholas Mohan, Chandra eng Japan J Gastroenterol. 2021 Jul;56(7):659-672. doi: 10.1007/s00535-021-01795-y. Epub 2021 Jun 12.I | 06/13/2021 | |
| Serum Proteomics and Plasma Fibulin-3 in Differentiation of Mesothelioma From Asbestos-Exposed Controls and Patients With Other Pleural Diseases | Tsim S, et al. | 2021 | J Thorac Oncol | 16 | 10 | 1705-1717 | https://www.doi.org/10.1016/j.jtho.2021.05.018 | 34,116,230 | *Asbestos Biomarkers, Tumor Calcium-Binding Proteins Extracellular Matrix Proteins GPI-Linked Proteins Humans *Lung Neoplasms/diagnosis *Mesothelioma/diagnosis/etiology *Pleural Neoplasms/diagnosis/etiology Proteomics Retrospective Studies Biomarker Fibulin-3 Mesothelin Mesothelioma SOMAscan | INTRODUCTION: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory. METHODS: A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure. RESULTS: A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557-0.664], p = 0.0015) and 0.516 [0.443-0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume. CONCLUSIONS: SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification. | Tsim, Selina Alexander, Laura Kelly, Caroline Shaw, Ann Hinsley, Samantha Clark, Stephen Evison, Matthew Holme, Jayne Cameron, Euan J Sharma, Davand Wright, Angela Grundy, Seamus Grieve, Douglas Ionescu, Alina Breen, David P Paramasivam, Elankumaran Psallidas, Ioannis Mukherjee, Dipak Chetty, Mahendran Cox, Giles Hart-Thomas, Alan Naseer, Rehan Edwards, John Daneshvar, Cyrus Panchal, Rakesh Munavvar, Mohammed Ostroff, Rachel Alexander, Leigh Hall, Holly Neilson, Matthew Miller, Crispin McCormick, Carol Thomson, Fiona Chalmers, Anthony J Maskell, Nick A Blyth, Kevin G eng A17196/CRUK_/Cancer Research UK/United Kingdom A31287/CRUK_/Cancer Research UK/United Kingdom A29801/CRUK_/Cancer Research UK/United Kingdom Multicenter Study Observational Study Research Support, Non-U.S. Gov't J Thorac Oncol. 2021 Oct;16(10):1705-1717. doi: 10.1016/j.jtho.2021.05.018. Epub 2021 Jun 9.I | 06/12/2021 | |
| Effect of TNFalpha stimulation on expression of kidney risk inflammatory proteins in human umbilical vein endothelial cells cultured in hyperglycemia | Md Dom ZI, et al. | 2021 | Sci Rep | 11 | 1 | 11133 | https://www.doi.org/10.1038/s41598-021-90496-w | 34,045,516 | Down-Regulation/drug effects Fibroblasts/drug effects/metabolism Human Umbilical Vein Endothelial Cells/*drug effects/metabolism Humans Hyperglycemia/*metabolism Inflammation/*metabolism Receptors, Tumor Necrosis Factor/*metabolism Tumor Necrosis Factor-alpha/*pharmacology Up-Regulation/drug effects | We recently identified a kidney risk inflammatory signature (KRIS), comprising 6 TNF receptors (including TNFR1 and TNFR2) and 11 inflammatory proteins. Elevated levels of these proteins in circulation were strongly associated with risk of the development of end-stage kidney disease (ESKD) during 10-year follow-up. It has been hypothesized that elevated levels of these proteins in circulation might reflect (be markers of) systemic exposure to TNFalpha. In this in vitro study, we examined intracellular and extracellular levels of these proteins in human umbilical vein endothelial cells (HUVECs) exposed to TNFalpha in the presence of hyperglycemia. KRIS proteins as well as 1300 other proteins were measured using the SOMAscan proteomics platform. Four KRIS proteins (including TNFR1) were down-regulated and only 1 protein (IL18R1) was up-regulated in the extracellular fraction of TNFalpha-stimulated HUVECs. In the intracellular fraction, one KRIS protein was down-regulated (CCL14) and 1 protein was up-regulated (IL18R1). The levels of other KRIS proteins were not affected by exposure to TNFalpha. HUVECs exposed to a hyperglycemic and inflammatory environment also showed significant up-regulation of a distinct set of 53 proteins (mainly in extracellular fraction). In our previous study, circulating levels of these proteins were not associated with progression to ESKD in diabetes. | Md Dom, Zaipul I Pipino, Caterina Krolewski, Bozena O'Neil, Kristina Satake, Eiichiro Krolewski, Andrzej S eng P30 DK036836/DK/NIDDK NIH HHS/ R01 DK041526/DK/NIDDK NIH HHS/ DK041526-27/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. 2021 May 27;11(1):11133. doi: 10.1038/s41598-021-90496-w.I | 05/29/2021 | |
| Human plasma proteomic profiles indicative of cardiorespiratory fitness | Robbins JM, et al. | 2021 | Nat Metab | 3 | 6 | 786-797 | https://www.doi.org/10.1038/s42255-021-00400-z | 34,045,743 | Biomarkers *Blood Proteins *Cardiorespiratory Fitness Exercise Humans Life Style Metabolic Networks and Pathways Oxygen Consumption *Proteome *Proteomics/methods | Maximal oxygen uptake (VO(2)max) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VO(2)max, and of increases of VO(2)max in response to exercise training (DeltaVO(2)max), are largely unknown. Here, we measure ~5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VO(2)max and DeltaVO(2)max, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual's DeltaVO(2)max. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of ~75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans. | Robbins, Jeremy M Peterson, Bennet Schranner, Daniela Tahir, Usman A Rienmuller, Theresa Deng, Shuliang Keyes, Michelle J Katz, Daniel H Beltran, Pierre M Jean Barber, Jacob L Baumgartner, Christian Carr, Steven A Ghosh, Sujoy Shen, Changyu Jennings, Lori L Ross, Robert Sarzynski, Mark A Bouchard, Claude Gerszten, Robert E eng R01 NR019628/NR/NINR NIH HHS/ P30 DK040561/DK/NIDDK NIH HHS/ R01 HL047327/HL/NHLBI NIH HHS/ R01 HL047323/HL/NHLBI NIH HHS/ U24 DK112340/DK/NIDDK NIH HHS/ U54 GM104940/GM/NIGMS NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ R01 HL146462/HL/NHLBI NIH HHS/ P30 GM118430/GM/NIGMS NIH HHS/ R01 HL045670/HL/NHLBI NIH HHS/ K23 HL150327/HL/NHLBI NIH HHS/ R01 HL047317/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Germany Nat Metab. 2021 Jun;3(6):786-797. doi: 10.1038/s42255-021-00400-z. Epub 2021 May 27.I | 05/29/2021 | |
| Proteomic signatures of inflammatory skin diseases: a focus on atopic dermatitis | Mikhaylov D, et al. | 2021 | Expert Rev Proteomics | 18 | 5 | 345-361 | https://www.doi.org/10.1080/14789450.2021.1935247 | 34,033,497 | Biomarkers *Dermatitis, Atopic/genetics Humans Inflammation Proteomics Skin Atopic dermatitis Olink SOMAscan mass spectrometry microbiome personalized medicine proteins two-dimensional gel electrophoresis | Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by cutaneous and systemic inflammation and barrier abnormalities. Over the past few decades, proteomic studies have been increasingly applied to AD research to compliment transcriptomic evaluations. Proteomic analyses helped identify new biomarkers of AD, allowing investigation of both the cutaneous AD profile and the systemic inflammation associated with the disease.Areas covered: This review discusses key studies that utilized various proteomic technologies to analyze AD skin and/or blood, which facilitated discovery of biomarkers related to pathogenesis, disease severity, systemic inflammation, and therapeutic response. Moreover, this review summarizes proteomic studies that helped define various AD endotypes/phenotypes. A literature search was conducted by querying Scopus, Google Scholar, PubMed/Medline, and Clinicaltrials.gov up to January 2021.Expert opinion: Use of proteomics in AD has allowed for identification of novel AD-related protein biomarkers. This approach continues to evolve and is becoming increasingly common for the study of AD, in conjunction with other -omics platforms, as proteomics shifts to quicker and more sensitive methods for detection of potential protein biomarkers. Although many biomarkers have been identified thus far, future larger studies are necessary to further correlate these markers with clinical parameters. | Mikhaylov, Daniela Del Duca, Ester Guttman-Yassky, Emma eng Review England Expert Rev Proteomics. 2021 May;18(5):345-361. doi: 10.1080/14789450.2021.1935247. Epub 2021 Jun 4.I | 05/26/2021 | |
| SOMAscan Proteomics Identifies Serum Biomarkers Associated With Liver Fibrosis in Patients With NASH | Luo Y, et al. | 2021 | Hepatol Commun | 5 | 5 | 760-773 | https://www.doi.org/10.1002/hep4.1670 | 34,027,267 | Nonalcoholic steatohepatitis (NASH) is a major cause of liver-related morbidity and mortality worldwide. Liver fibrosis stage, a key component of NASH, has been linked to the risk of mortality and liver-related clinical outcomes. Currently there are no validated noninvasive diagnostics that can differentiate between fibrosis stages in patients with NASH; many existing tests do not reflect underlying disease pathophysiology. Noninvasive biomarkers are needed to identify patients at high-risk of NASH with advanced fibrosis. This was a retrospective study of patients with histologically proven NASH with fibrosis stages 0-4. The SOMAscan proteomics platform was used to quantify 1,305 serum proteins in a discovery cohort (n = 113). In patients with advanced (stages 3-4) versus early fibrosis (stages 0-2), 97 proteins with diverse biological functions were differentially expressed. Next, fibrosis-stage classification models were explored using a machine learning-based approach to prioritize the biomarkers for further evaluation. A four-protein model differentiated patients with stage 0-1 versus stage 2-4 fibrosis (area under the receiver operating characteristic curve [AUROC] = 0.74), while a 12-protein classifier differentiated advanced versus early fibrosis (AUROC = 0.83). Subsequently, the model's performance was validated in two independent cohorts (n = 71 and n = 32) with similar results (AUROC = 0.74-0.78). Our advanced fibrosis model performed similarly to or better than Fibrosis-4 index, aspartate aminotransferase-to-platelet ratio index, and nonalcoholic fatty liver disease (NAFLD) fibrosis score-based models for all three cohorts. Conclusion: A SOMAscan proteomics-based exploratory classifier for advanced fibrosis, consisting of biomarkers that reflect the complexity of NASH pathophysiology, demonstrated similar performance in independent validation cohorts and performed similarly or better than Fibrosis-4 index, aspartate aminotransferase-to-platelet ratio index, and NAFLD fibrosis score. Further studies are warranted to evaluate the clinical utility of these biomarker panels in patients with NAFLD. | Luo, Yi Wadhawan, Samir Greenfield, Alex Decato, Benjamin E Oseini, Abdul M Collen, Rebecca Shevell, Diane E Thompson, John Jarai, Gabor Charles, Edgar D Sanyal, Arun J eng Hepatol Commun. 2021 Jan 20;5(5):760-773. doi: 10.1002/hep4.1670. eCollection 2021 May.I | 05/25/2021 | ||
| Metabolic syndrome and the plasma proteome: from association to causation | Elhadad MA, et al. | 2021 | Cardiovasc Diabetol | 20 | 1 | 111 | https://www.doi.org/10.1186/s12933-021-01299-2 | 34,016,094 | Adult Aged Aged, 80 and over Apolipoprotein B-100/blood/genetics Apolipoprotein E2/blood/genetics Biomarkers/blood Blood Proteins/*analysis/genetics Cardiometabolic Risk Factors Cross-Sectional Studies Female Germany/epidemiology Humans Incidence Male Mendelian Randomization Analysis Metabolic Syndrome/*blood/diagnosis/epidemiology/genetics Middle Aged Norway/epidemiology Predictive Value of Tests Prevalence Prospective Studies *Proteome *Proteomics Proto-Oncogene Mas Proto-Oncogene Proteins c-ret/blood/genetics Risk Assessment Blood proteins Cardiovascular disease Diabetes mellitus Metabolic syndrome Proteomics Risk factors type 2 | BACKGROUND: The metabolic syndrome (MetS), defined by the simultaneous clustering of cardio-metabolic risk factors, is a significant worldwide public health burden with an estimated 25% prevalence worldwide. The pathogenesis of MetS is not entirely clear and the use of molecular level data could help uncover common pathogenic pathways behind the observed clustering. METHODS: Using a highly multiplexed aptamer-based affinity proteomics platform, we examined associations between plasma proteins and prevalent and incident MetS in the KORA cohort (n = 998) and replicated our results for prevalent MetS in the HUNT3 study (n = 923). We applied logistic regression models adjusted for age, sex, smoking status, and physical activity. We used the bootstrap ranking algorithm of least absolute shrinkage and selection operator (LASSO) to select a predictive model from the incident MetS associated proteins and used area under the curve (AUC) to assess its performance. Finally, we investigated the causal effect of the replicated proteins on MetS using two-sample Mendelian randomization. RESULTS: Prevalent MetS was associated with 116 proteins, of which 53 replicated in HUNT. These included previously reported proteins like leptin, and new proteins like NTR domain-containing protein 2 and endoplasmic reticulum protein 29. Incident MetS was associated with 14 proteins in KORA, of which 13 overlap the prevalent MetS associated proteins with soluble advanced glycosylation end product-specific receptor (sRAGE) being unique to incident MetS. The LASSO selected an eight-protein predictive model with an (AUC = 0.75; 95% CI = 0.71-0.79) in KORA. Mendelian randomization suggested causal effects of three proteins on MetS, namely apolipoprotein E2 (APOE2) (Wald-Ratio = - 0.12, Wald-p = 3.63e-13), apolipoprotein B (APOB) (Wald-Ratio = - 0.09, Wald-p = 2.54e-04) and proto-oncogene tyrosine-protein kinase receptor (RET) (Wald-Ratio = 0.10, Wald-p = 5.40e-04). CONCLUSIONS: Our findings offer new insights into the plasma proteome underlying MetS and identify new protein associations. We reveal possible casual effects of APOE2, APOB and RET on MetS. Our results highlight protein candidates that could potentially serve as targets for prevention and therapy. | Elhadad, Mohamed A Wilson, Rory Zaghlool, Shaza B Huth, Cornelia Gieger, Christian Grallert, Harald Graumann, Johannes Rathmann, Wolfgang Koenig, Wolfgang Sinner, Moritz F Hveem, Kristian Suhre, Karsten Thorand, Barbara Jonasson, Christian Waldenberger, Melanie Peters, Annette eng Multicenter Study Research Support, Non-U.S. Gov't England Cardiovasc Diabetol. 2021 May 20;20(1):111. doi: 10.1186/s12933-021-01299-2.I | 05/22/2021 | |
| Multiomic Profiling in Black and White Populations Reveals Novel Candidate Pathways in Left Ventricular Hypertrophy and Incident Heart Failure Specific to Black Adults | Katz DH, et al. | 2021 | Circ Genom Precis Med | 14 | 3 | e003191 | https://www.doi.org/10.1161/CIRCGEN.120.003191 | 34,019,435 | Adult *African Americans Aged Biomarkers/blood Chemokine CX3CL1/*blood Cystatin C/blood *Echocardiography Female *Heart Failure/blood/diagnostic imaging/physiopathology Humans *Hypertrophy, Left Ventricular/blood/diagnostic imaging/physiopathology Incidence Male Middle Aged Natriuretic Peptide, Brain/blood Peptide Fragments/blood Sex Factors *Whites continental population groups heart failure hospitalization hypertrophy, left ventricular proteomics | BACKGROUND: Increased left ventricular (LV) mass is associated with adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect Black individuals. To understand the underlying mechanisms, we undertook a proteomic screen in a Black cohort and compared the findings to results from a White cohort. METHODS: We measured 1305 plasma proteins using the SomaScan platform in 1772 Black participants (mean age, 56 years; 62% women) in JHS (Jackson Heart Study) with LV mass assessed by 2-dimensional echocardiography. Incident HF was assessed in 1600 participants. We then compared protein associations in JHS to those observed in White participants from FHS (Framingham Heart Study; mean age, 54 years; 56% women). RESULTS: In JHS, there were 110 proteins associated with LV mass and 13 proteins associated with incident HF hospitalization with false discovery rate <5% after multivariable adjustment. Several proteins showed expected associations with both LV mass and HF, including NT-proBNP (N-terminal pro-B-type natriuretic peptide; beta=0.04; P=2x10(-8); hazard ratio, 1.48; P=0.0001). The strongest association with LV mass was novel: LKHA4 (leukotriene-A4 hydrolase; beta=0.05; P=5x10(-15)). This association was confirmed on an alternate proteomics platform and further supported by related metabolomic data. Fractalkine/CX3CL1 (C-X3-C Motif Chemokine Ligand 1) showed a novel association with incident HF (hazard ratio, 1.32; P=0.0002). While established biomarkers such as cystatin C and NT-proBNP showed consistent associations in Black and White individuals, LKHA4 and fractalkine were significantly different between the two groups. CONCLUSIONS: We identified several novel biological pathways specific to Black adults hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and fractalkine. | Katz, Daniel H Tahir, Usman A Ngo, Debby Benson, Mark D Gao, Yan Shi, Xu Nayor, Matthew Keyes, Michelle J Larson, Martin G Hall, Michael E Correa, Adolfo Sinha, Sumita Shen, Dongxiao Herzig, Matthew Yang, Qiong Robbins, Jeremy M Chen, Zsu-Zsu Cruz, Daniel E Peterson, Bennet Vasan, Ramachandran S Wang, Thomas J Wilson, James G Gerszten, Robert E eng KL2 TR002542/TR/NCATS NIH HHS/ HHSN268201800014I/HB/NHLBI NIH HHS/ R01 DK081572/DK/NIDDK NIH HHS/ HHSN268201800014C/HL/NHLBI NIH HHS/ HHSN268201800013I/MD/NIMHD NIH HHS/ HHSN268201800011I/HB/NHLBI NIH HHS/ K08 HL145095/HL/NHLBI NIH HHS/ HHSN268201800012I/HB/NHLBI NIH HHS/ HHSN268201800012C/HL/NHLBI NIH HHS/ P30 DK040561/DK/NIDDK NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ HHSN268201800011C/HL/NHLBI NIH HHS/ K23 HL138260/HL/NHLBI NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ T32 HL007374/HL/NHLBI NIH HHS/ HHSN268201800015I/HB/NHLBI NIH HHS/ F32 HL150992/HL/NHLBI NIH HHS/ HHSN268201800010I/HB/NHLBI NIH HHS/ Clinical Trial Multicenter Study Circ Genom Precis Med. 2021 Jun;14(3):e003191. doi: 10.1161/CIRCGEN.120.003191. Epub 2021 May 21.I | 05/22/2021 | |
| Plasma Proteomic Profile Predicts Survival in Heart Failure With Reduced Ejection Fraction | Gui H, et al. | 2021 | Circ Genom Precis Med | 14 | 3 | e003140 | https://www.doi.org/10.1161/CIRCGEN.120.003140 | 33,999,650 | Aged Biomarkers/blood Disease-Free Survival Female *Heart Failure/blood/mortality Humans Male Natriuretic Peptide, Brain/*blood *Proteomics *Stroke Volume Survival Rate heart failure mortality plasma prognosis risk | BACKGROUND: It remains unclear whether the plasma proteome adds value to established predictors in heart failure (HF) with reduced ejection fraction (HFrEF). We sought to derive and validate a plasma proteomic risk score (PRS) for survival in patients with HFrEF (HFrEF-PRS). METHODS: Patients meeting Framingham criteria for HF with EF<50% were enrolled (N=1017) and plasma underwent SOMAscan profiling (4453 targets). Patients were randomly divided 2:1 into derivation and validation cohorts. The HFrEF-PRS was derived using Cox regression of all-cause mortality adjusted for clinical score and NT-proBNP (N-terminal pro-B-type natriuretic peptide), then was tested in the validation cohort. Risk stratification improvement was evaluated by C statistic, integrated discrimination index, continuous net reclassification index, and median improvement in risk score for 1-year and 3-year mortality. RESULTS: Participants' mean age was 68 years, 48% identified as Black, 35% were female, and 296 deaths occurred. In derivation (n=681), 128 proteins associated with mortality, 8 comprising the optimized HFrEF-PRS. In validation (n=336) the HFrEF-PRS associated with mortality (hazard ratio, 2.27 [95% CI, 1.84-2.82], P=6.3x10(-14)), Kaplan-Meier curves differed significantly between HFrEF-PRS quartiles (P=2.2x10(-6)), and it remained significant after adjustment for clinical score and NT-proBNP (hazard ratio, 1.37 [95% CI, 1.05-1.79], P=0.021). The HFrEF-PRS improved metrics of risk stratification (C statistic change, 0.009, P=0.612; integrated discrimination index, 0.041, P=0.010; net reclassification index=0.391, P=0.078; median improvement in risk score=0.039, P=0.016) and associated with cardiovascular death and HF phenotypes (eg, 6-minute walk distance, EF change). Most HFrEF-PRS proteins had little known connection to HFrEF. CONCLUSIONS: A plasma multiprotein score improved risk stratification in patients with HFrEF and identified novel candidates. | Gui, Hongsheng She, Ruicong Luzum, Jasmine Li, Jia Bryson, Timothy D Pinto, Yigal Sabbah, Hani N Williams, L Keoki Lanfear, David E eng R01 DK113003/DK/NIDDK NIH HHS/ R01 HL132154/HL/NHLBI NIH HHS/ P01 HL074237/HL/NHLBI NIH HHS/ K08 HL146990/HL/NHLBI NIH HHS/ R01 DK064695/DK/NIDDK NIH HHS/ R01 HL118267/HL/NHLBI NIH HHS/ R01 HL103871/HL/NHLBI NIH HHS/ R01 AI079139/AI/NIAID NIH HHS/ R01 HL141845/HL/NHLBI NIH HHS/ L30 HL110279/HL/NHLBI NIH HHS/ Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circ Genom Precis Med. 2021 Jun;14(3):e003140. doi: 10.1161/CIRCGEN.120.003140. Epub 2021 May 17.I | 05/18/2021 | |
| Novel Murine Biomarkers of Radiation Exposure Using An Aptamer-Based Proteomic Technology | Sproull M, et al. | 2021 | Front Pharmacol | 12 | 633131 | https://www.doi.org/10.3389/fphar.2021.633131 | 33,981,223 | biodosimetry biomarker medical countermeasure radiation somascan commercial or financial relationships that could be construed as a potential conflict of interest. | Purpose: There is a need to identify new biomarkers of radiation exposure both for use in the development of biodosimetry blood diagnostics for radiation exposure and for clinical use as markers of radiation injury. In the current study, a novel high-throughput proteomics screening approach was used to identify proteomic markers of radiation exposure in the plasma of total body irradiated mice. A subset panel of significantly altered proteins was selected to build predictive models of radiation exposure and received radiation dose useful for population screening in a future radiological or nuclear event. Methods: Female C57BL6 Mice of 8-14 weeks of age received a single total body irradiation (TBI) dose of 2, 3.5, 8 Gy or sham radiation and plasma was collected by cardiac puncture at days 1, 3, and 7 post-exposure. Plasma was then screened using the aptamer-based SOMAscan proteomic assay technology, for changes in expression of 1,310 protein analytes. A subset panel of protein biomarkers which demonstrated significant changes (p < 0.05) in expression following radiation exposure were used to build predictive models of radiation exposure and radiation dose. Results: Detectable values were obtained for all 1,310 proteins included in the SOMAscan assay. For the Control vs. Radiation model, the top predictive proteins were immunoglobulin heavy constant mu (IGHM), mitogen-activated protein kinase 14 (MAPK14), ectodysplasin A2 receptor (EDA2R) and solute carrier family 25 member 18 (SLC25A18). For the Control vs. Dose model, the top predictive proteins were cyclin dependent kinase 2/cyclin A2 (CDK2. CCNA2), E-selectin (SELE), BCL2 associated agonist of cell death (BAD) and SLC25A18. Following model validation with a training set of samples, both models tested with a new sample cohort had overall predictive accuracies of 85% and 73% for the Control vs. Radiation and Control vs. Dose models respectively. Conclusion: The SOMAscan proteomics platform is a useful screening tool to evaluate changes in biomarker expression. In our study we were able to identify a novel panel of radiation responsive proteins useful for predicting whether an animal had received a radiation exposure and to what dose they had received. Such diagnostic tools are needed for future medical management of radiation exposures. | Sproull, Mary Shankavaram, Uma Camphausen, Kevin eng Switzerland Front Pharmacol. 2021 Apr 26;12:633131. doi: 10.3389/fphar.2021.633131. eCollection 2021.I | 05/14/2021 | ||
| The CRTAC1 Protein in Plasma Is Associated With Osteoarthritis and Predicts Progression to Joint Replacement: A Large-Scale Proteomics Scan in Iceland | Styrkarsdottir U, et al. | 2021 | Arthritis Rheumatol | 73 | 11 | 2025-2034 | https://www.doi.org/10.1002/art.41793 | 33,982,893 | Adult Aged *Arthroplasty, Replacement Biomarkers/blood Calcium-Binding Proteins/*blood Case-Control Studies Disease Progression Female Humans Iceland Male Middle Aged Osteoarthritis/*blood/diagnosis/surgery Prospective Studies Proteomics | OBJECTIVE: Biomarkers for diagnosis and progression of osteoarthritis (OA) are lacking. This study was undertaken to identify circulating biomarkers for OA that could predict disease occurrence and/or progression to joint replacement. METHODS: Using the SomaScan platform, we measured 4,792 proteins in plasma from 37,278 individuals, of whom 12,178 individuals had OA and 2,524 had undergone joint replacement. We performed a case-control study for identification of potential protein biomarkers for hip, knee, and/or hand OA, and a prospective study for identification of biomarkers for joint replacement. RESULTS: Among the large panel of plasma proteins assessed, cartilage acidic protein 1 (CRTAC1) was the most strongly associated with both OA diagnosis (odds ratio 1.46 [95% confidence interval 1.41-1.52] for knee OA, odds ratio 1.36 [95% confidence interval 1.29-1.43] for hip OA, and odds ratio 1.33 [95% confidence interval 1.26-1.40] for hand OA) and progression to joint replacement (hazard ratio 1.40 [95% confidence interval 1.30-1.51] for knee replacement and hazard ratio 1.31 [95% confidence interval 1.19-1.45] for hip replacement). Patients with OA who were in the highest quintile of risk of joint replacement, based on known risk factors (i.e., age, sex, and body mass index) and plasma CRTAC1 level, were 16 times more likely to undergo knee replacement within 5 years of plasma sample collection than those in the lowest quintile, and 6.5 times more likely to undergo hip replacement. CRTAC1 was not associated with other types of inflammatory arthritis. A specific protein profile was identified in those patients who had undergone joint replacement prior to plasma sample collection. CONCLUSION: Through a hypothesis-free approach, we identified CRTAC1 in plasma as a novel promising candidate biomarker for OA that is both associated with occurrence of OA and predictive of progression to joint replacement. This biomarker might also be useful in the selection of suitable patients for clinical trial enrollment. | Styrkarsdottir, Unnur Lund, Sigrun H Saevarsdottir, Saedis Magnusson, Magnus I Gunnarsdottir, Kristbjorg Norddahl, Gudmundur L Frigge, Michael L Ivarsdottir, Erna V Bjornsdottir, Gyda Holm, Hilma Thorgeirsson, Gudmundur Rafnar, Thorunn Jonsdottir, Ingileif Ingvarsson, Thorvaldur Jonsson, Helgi Sulem, Patrick Thorsteinsdottir, Unnur Gudbjartsson, Daniel Stefansson, Kari eng Research Support, Non-U.S. Gov't Arthritis Rheumatol. 2021 Nov;73(11):2025-2034. doi: 10.1002/art.41793. Epub 2021 Sep 28.I | 05/14/2021 | |
| Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions | Filbin MR, et al. | 2021 | Cell Rep Med | 2 | 5 | 100287 | https://www.doi.org/10.1016/j.xcrm.2021.100287 | 33,969,320 | Ards COVID-19 severity T cell activation acute respiratory distress syndrome death versus survival intracellular death signatures longitudinal lung epithelial cells lung monocyte/macrophages pancreatic exocrine proteases plasma proteomics employees of Olink Proteomics. G.S.H. is an employee of Genentech (as of November 2020). L.L.J. is an employee and stockholder of Novartis. N.H. holds equity in BioNTech and is a consultant for Related Sciences. | Mechanisms underlying severe coronavirus disease 2019 (COVID-19) disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNA-seq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune-cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell-type-specific intracellular death signatures, cellular angiotensin-converting enzyme 2 (ACE2) expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease. | Filbin, Michael R Mehta, Arnav Schneider, Alexis M Kays, Kyle R Guess, Jamey R Gentili, Matteo Fenyves, Bank G Charland, Nicole C Gonye, Anna L K Gushterova, Irena Khanna, Hargun K LaSalle, Thomas J Lavin-Parsons, Kendall M Lilley, Brendan M Lodenstein, Carl L Manakongtreecheep, Kasidet Margolin, Justin D McKaig, Brenna N Rojas-Lopez, Maricarmen Russo, Brian C Sharma, Nihaarika Tantivit, Jessica Thomas, Molly F Gerszten, Robert E Heimberg, Graham S Hoover, Paul J Lieb, David J Lin, Brian Ngo, Debby Pelka, Karin Reyes, Miguel Smillie, Christopher S Waghray, Avinash Wood, Thomas E Zajac, Amanda S Jennings, Lori L Grundberg, Ida Bhattacharyya, Roby P Parry, Blair Alden Villani, Alexandra-Chloe Sade-Feldman, Moshe Hacohen, Nir Goldberg, Marcia B eng T32 CA071345/CA/NCI NIH HHS/ U19 AI082630/AI/NIAID NIH HHS/ UL1 TR001102/TR/NCATS NIH HHS/ UL1 TR002541/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cell Rep Med. 2021 May 18;2(5):100287. doi: 10.1016/j.xcrm.2021.100287. Epub 2021 May 3.I | 05/11/2021 | |
| Integrated trajectories of the maternal metabolome, proteome, and immunome predict labor onset | Stelzer IA, et al. | 2021 | Sci Transl Med | 13 | 592 | https://www.doi.org/10.1126/scitranslmed.abd9898 | 33,952,678 | Biomarkers Female Humans *Labor Onset/immunology/metabolism Longitudinal Studies *Metabolome Pregnancy *Proteome | Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. More than 7000 plasma analytes and peripheral immune cell responses were analyzed using untargeted mass spectrometry, aptamer-based proteomic technology, and single-cell mass cytometry in serial blood samples collected during the last 100 days of pregnancy. The high-dimensional dataset was integrated into a multiomic model that predicted the time to spontaneous labor [R = 0.85, 95% confidence interval (CI) [0.79 to 0.89], P = 1.2 x 10(-40), N = 53, training set; R = 0.81, 95% CI [0.61 to 0.91], P = 3.9 x 10(-7), N = 10, independent test set]. Coordinated alterations in maternal metabolome, proteome, and immunome marked a molecular shift from pregnancy maintenance to prelabor biology 2 to 4 weeks before delivery. A surge in steroid hormone metabolites and interleukin-1 receptor type 4 that preceded labor coincided with a switch from immune activation to regulation of inflammatory responses. Our study lays the groundwork for developing blood-based methods for predicting the day of labor, anchored in mechanisms shared in preterm and term pregnancies. | Stelzer, Ina A Ghaemi, Mohammad S Han, Xiaoyuan Ando, Kazuo Hedou, Julien J Feyaerts, Dorien Peterson, Laura S Rumer, Kristen K Tsai, Eileen S Ganio, Edward A Gaudilliere, Dyani K Tsai, Amy S Choisy, Benjamin Gaigne, Lea P Verdonk, Franck Jacobsen, Danielle Gavasso, Sonia Traber, Gavin M Ellenberger, Mathew Stanley, Natalie Becker, Martin Culos, Anthony Fallahzadeh, Ramin Wong, Ronald J Darmstadt, Gary L Druzin, Maurice L Winn, Virginia D Gibbs, Ronald S Ling, Xuefeng B Sylvester, Karl Carvalho, Brendan Snyder, Michael P Shaw, Gary M Stevenson, David K Contrepois, Kevin Angst, Martin S Aghaeepour, Nima Gaudilliere, Brice eng R35 GM137936/GM/NIGMS NIH HHS/ R61 NS114926/NS/NINDS NIH HHS/ T32 GM099608/GM/NIGMS NIH HHS/ R35 GM138353/GM/NIGMS NIH HHS/ R01 AG058417/AG/NIA NIH HHS/ 2018100/DDCF/Doris Duke Charitable Foundation/ R01 HL139844/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Sci Transl Med. 2021 May 5;13(592):eabd9898. doi: 10.1126/scitranslmed.abd9898.I | 05/07/2021 | ||
| Duodenal Microbiota in Stunted Undernourished Children with Enteropathy. Reply | Chen RY, et al. | 2021 | N Engl J Med | 384 | 18 | 1778 | https://www.doi.org/10.1056/NEJMc2030388 | 33,951,373 | Child Duodenum Humans *Intestinal Diseases *Microbiota | Chen, Robert Y Ahmed, Tahmeed Gordon, Jeffrey I eng Comment Letter N Engl J Med. 2021 May 6;384(18):1778. doi: 10.1056/NEJMc2030388.I | 05/06/2021 | ||
| Effect of longevity genetic variants on the molecular aging rate | Gurinovich A, et al. | 2021 | Geroscience | 43 | 3 | 1237-1251 | https://www.doi.org/10.1007/s11357-021-00376-4 | 33,948,810 | Aged, 80 and over Aging/genetics *Genome-Wide Association Study Genotype Humans *Longevity/genetics Proteomics Extreme human longevity Genetic variants Molecular aging rate SOMAscan array stock-holder of Regeneron Pharmaceuticals. | We conducted a genome-wide association study of 1320 centenarians from the New England Centenarian Study (median age = 104 years) and 2899 unrelated controls using >9 M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The genetic variants with the most significant associations were correlated to 4131 proteins that were profiled in the serum of a subset of 224 study participants using a SOMAscan array. The genetic associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazi Jewish descent. The proteomic associations were replicated in a proteomic scan of approximately 1000 Ashkenazi Jewish participants from a third cohort. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E-16) and under-expression of APOB in carriers of the APOE2 allele (p < 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2A/CDKN2B in chromosome 9) that suggests a genetic regulation of GDF15. The analyses showed that longevity variants correlate with proteome signatures that could be manipulated to discover healthy-aging targets. | Gurinovich, Anastasia Song, Zeyuan Zhang, William Federico, Anthony Monti, Stefano Andersen, Stacy L Jennings, Lori L Glass, David J Barzilai, Nir Millman, Sofiya Perls, Thomas T Sebastiani, Paola eng R24 GM134210/GM/NIGMS NIH HHS/ U19 AG056278/AG/NIA NIH HHS/ U19-AG023122/AG/NIA NIH HHS/ T32 AG023475/AG/NIA NIH HHS/ R01 AG061155/AG/NIA NIH HHS/ S10 OD021728/OD/NIH HHS/ P30 AG038072/AG/NIA NIH HHS/ R01 AG061844/AG/NIA NIH HHS/ UH2AG064704/AG/NIA NIH HHS/ F31 DE029701/DE/NIDCR NIH HHS/ UH2 AG064704/AG/NIA NIH HHS/ U19 AG023122/AG/NIA NIH HHS/ R01 AG046949/AG/NIA NIH HHS/ P30AG038072/AG/NIA NIH HHS/ R01 AG044829/AG/NIA NIH HHS/ R01 AG057909/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Switzerland Geroscience. 2021 Jun;43(3):1237-1251. doi: 10.1007/s11357-021-00376-4. Epub 2021 May 4.I | 05/06/2021 | |
| Identification and Validation of Nutrient State-Dependent Serum Protein Mediators of Human CD4(+) T Cell Responsiveness | Han K, et al. | 2021 | Nutrients | 13 | 5 | https://www.doi.org/10.3390/nu13051492 | 33,924,911 | Adult Aged Blood Proteins/*metabolism CD4-Positive T-Lymphocytes/*metabolism Cells, Cultured Fasting/*metabolism Female Humans Inflammation/*blood Male Middle Aged Nutrients/*blood Obesity/*blood Pilot Projects Reproducibility of Results Young Adult CD4+ T cell activation Igfbp1 Il1rl1 Mfge8 Pyy SOMAscan fasting integrative bioinformatics refeeding | Intermittent fasting and fasting mimetic diets ameliorate inflammation. Similarly, serum extracted from fasted healthy and asthmatic subjects' blunt inflammation in vitro, implicating serum components in this immunomodulation. To identify the proteins orchestrating these effects, SOMAScan technology was employed to evaluate serum protein levels in healthy subjects following an overnight, 24-h fast and 3 h after refeeding. Partial least square discriminant analysis identified several serum proteins as potential candidates to confer feeding status immunomodulation. The characterization of recombinant IGFBP1 (elevated following 24 h of fasting) and PYY (elevated following refeeding) in primary human CD4(+) T cells found that they blunted and induced immune activation, respectively. Furthermore, integrated univariate serum protein analysis compared to RNA-seq analysis from peripheral blood mononuclear cells identified the induction of IL1RL1 and MFGE8 levels in refeeding compared to the 24-h fasting in the same study. Subsequent quantitation of these candidate proteins in lean versus obese individuals identified an inverse regulation of serum levels in the fasted subjects compared to the obese subjects. In parallel, IL1RL1 and MFGE8 supplementation promoted increased CD4(+) T responsiveness to T cell receptor activation. Together, these data show that caloric load-linked conditions evoke serological protein changes, which in turn confer biological effects on circulating CD4(+) T cell immune responsiveness. | Han, Kim Singh, Komudi Rodman, Matthew J Hassanzadeh, Shahin Baumer, Yvonne Huffstutler, Rebecca D Chen, Jinguo Candia, Julian Cheung, Foo Stagliano, Katherine E R Pirooznia, Mehdi Powell-Wiley, Tiffany M Sack, Michael N eng Validation Study Switzerland Nutrients. 2021 Apr 28;13(5):1492. doi: 10.3390/nu13051492.I | 05/01/2021 | ||
| Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children | Ramaswamy A, et al. | 2021 | Immunity | 54 | 5 | 1083-1095 e7 | https://www.doi.org/10.1016/j.immuni.2021.04.003 | 33,891,889 | Adolescent Alarmins/immunology Autoantibodies/immunology CD8-Positive T-Lymphocytes/immunology COVID-19/*immunology/*pathology Child Child, Preschool Cytotoxicity, Immunologic/genetics Endothelium/immunology/pathology Humans Killer Cells, Natural/immunology Myeloid Cells/immunology Plasma Cells/immunology Receptors, Antigen, T-Cell/genetics/immunology SARS-CoV-2/*immunology Severity of Illness Index Systemic Inflammatory Response Syndrome/*immunology/*pathology Mis-c SARS-CoV-2 Trbv11-2 alarmins cytotoxicity inflammation pediatric plasmablasts Squibb, Novartis, Sanofi, and Genentech. He has been a consultant for Bayer Pharmaceuticals, Bristol Myers Squibb, Compass Therapeutics, EMD Serono, Genentech, Juno Therapeutics, Novartis Pharmaceuticals, Proclara Biosciences, Sage Therapeutics, and Sanofi Genzyme. Further information regarding funding is available on: https://openpaymentsdata.cms.gov/physician/166753/general-payments. N.K. reports personal fees from Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Indalo, Theravance, LifeMax, Three Lake Partners, RohBar in the last 36 months, and Equity in Pliant. N.K. is also a recipient of a grant from Veracyte and non-financial support from Miragen. All outside the submitted work In addition, N.K. has patents on New Therapies in Pulmonary Fibrosis and ARDS (unlicensed) and Peripheral Blood Gene Expression as biomarkers in IPF (licensed to biotech). S.H.K. receives consulting fees from Northrop Grumman. K.B.H. receives consulting fees from Prellis Biologics. B.S. is a former SomaLogic, Inc. (Boulder, CO, USA) employee and a company shareholder. All other authors declared that they have no competing interests. | Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction. MIS-C patients showed elevated expression of cytotoxicity genes in NK and CD8(+) T cells and expansion of specific IgG-expressing plasmablasts. Clinically severe MIS-C patients displayed skewed memory T cell TCR repertoires and autoimmunity characterized by endothelium-reactive IgG. The alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures we defined have potential for application in the clinic to better diagnose and potentially predict disease severity early in the course of MIS-C. | Ramaswamy, Anjali Brodsky, Nina N Sumida, Tomokazu S Comi, Michela Asashima, Hiromitsu Hoehn, Kenneth B Li, Ningshan Liu, Yunqing Shah, Aagam Ravindra, Neal G Bishai, Jason Khan, Alamzeb Lau, William Sellers, Brian Bansal, Neha Guerrerio, Pamela Unterman, Avraham Habet, Victoria Rice, Andrew J Catanzaro, Jason Chandnani, Harsha Lopez, Merrick Kaminski, Naftali Dela Cruz, Charles S Tsang, John S Wang, Zuoheng Yan, Xiting Kleinstein, Steven H van Dijk, David Pierce, Richard W Hafler, David A Lucas, Carrie L eng UL1 TR001863/TR/NCATS NIH HHS/ R21 AI144315/AI/NIAID NIH HHS/ R01 AI104739/AI/NIAID NIH HHS/ K08 HL136898/HL/NHLBI NIH HHS/ T32 AI007019/AI/NIAID NIH HHS/ R21 LM012884/LM/NLM NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Immunity. 2021 May 11;54(5):1083-1095.e7. doi: 10.1016/j.immuni.2021.04.003. Epub 2021 Apr 13.I | 04/24/2021 | |
| Early Interleukin-22 and Neutrophil Proteins Are Correlated to Future Lung Damage in Children With Cystic Fibrosis | Renwick J, et al. | 2021 | Front Pediatr | 9 | 640184 | https://www.doi.org/10.3389/fped.2021.640184 | 33,869,115 | biomarkers bronchoalveolar lavage cystic fibrosis neutrophils proteomics commercial or financial relationships that could be construed as a potential conflict of interest. | Cystic Fibrosis (CF) lung damage begins early in life. Lung function decline is associated with pulmonary infections, neutrophil infiltration and inflammation. In CF, neutrophils have an altered phenotype. In this pilot study, we aimed to determine if signals of dysfunctional neutrophil responses were evident early in life and whether these signals may be associated with lung damage in later childhood. We examined the pulmonary protein profiles of 14 clinical stable infants and pre-school children with CF employing the aptamer-based affinity platform, SOMAscan(R). High resolution computed tomography (HRCT) was performed on all children after age 6 years and Brody score calculated. A Spearman's rank order correlation analysis and Benjamini-Hochberg adjustment was used to correlate protein concentrations in early life to Brody scores in later childhood. Early life concentrations of azurocidin and myeloperoxidase, were positively correlated with Brody score after age 6 (p = 0.0041 and p = 0.0182, respectively). Four other neutrophil associated proteins; Complement C3 (p = 0.0026), X-ray repair CCP 6 (p = 0.0059), C3a anaphylatoxin des Arginine (p = 0.0129) and cytokine receptor common subunit gamma (p = 0.0214) were all negatively correlated with Brody scores. Interestingly, patients with more severe lung damage after age 6 had significantly lower levels of IL-22 in early years of life (p = 0.0243). IL-22 has scarcely been reported to have implications in CF. Identification of early biomarkers that may predict more severe disease progression is particularly important for the future development of early therapeutic interventions in CF disease. We recommend further corroboration of these findings in prospective validation studies. | Renwick, Julie Reece, Emma Walsh, Jamie Walsh, Ross Persaud, Thara O'Leary, Cathal Donnelly, Seamas C Greally, Peter eng Switzerland Front Pediatr. 2021 Mar 31;9:640184. doi: 10.3389/fped.2021.640184. eCollection 2021.I | 04/20/2021 | ||
| Platelet Protein-Related Abnormalities in Response to Acute Hypoglycemia in Type 2 Diabetes | Moin ASM, et al. | 2021 | Front Endocrinol (Lausanne) | 12 | 651009 | https://www.doi.org/10.3389/fendo.2021.651009 | 33,859,620 | Aged Blood Platelet Disorders/*blood/*etiology Blood Platelets/*chemistry Blood Proteins/*analysis COVID-19/*blood/complications Case-Control Studies Diabetes Mellitus, Type 2/*blood/*complications Female Glucose Clamp Technique Humans Hypoglycemia/*blood/*complications Lipids/blood Male Middle Aged Platelet Activation Thromboembolism/blood/etiology Covid-19 SARS-CoV-2 obesity platelet type 2 diabetes commercial or financial relationships that could be construed as a potential conflict of interest. | INTRODUCTION: Patients with severe COVID-19 infections have coagulation abnormalities indicative of a hypercoagulable state, with thromboembolic complications and increased mortality. Platelets are recognized as mediators of inflammation, releasing proinflammatory and prothrombotic factors, and are hyperactivated in COVID-19 infected patients. Activated platelets have also been reported in type 2 diabetes (T2D) patients, putting these patients at higher risk for thromboembolic complications of COVID-19 infection. METHODS: A case-control study of T2D (n=33) and control subjects (n=30) who underwent a hyperinsulinemic clamp to induce normoglycemia in T2D subjects: T2D: baseline glucose 7.5 +/- 0.3mmol/l (135.1 +/- 5.4mg/dl), reduced to 4.5 +/- 0.07mmol/l (81 +/- 1.2mg/dl) with 1-hour clamp; Controls: maintained at 5.1 +/- 0.1mmol/l (91.9 +/- 1.8mg/dl). Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was used to determine a panel of platelet proteins. RESULTS: Prothrombotic platelet proteins were elevated in T2D versus controls: platelet factor 4 (PF4, p<0.05); platelet glycoprotein VI (PGVI p<0.05); P-selectin (p<0.01) and plasminogen activator inhibitor I (PAI-1, p<0.01). In addition, the antithrombotic platelet-related proteins, plasmin (p<0.05) and heparin cofactor II (HCFII, p<0.05), were increased in T2D. Normalization of glucose in the T2D cohort had no effect on platelet protein levels. CONCLUSION: T2D patients have platelet hyperactivation, placing them at higher risk for thromboembolic events. When infected with COVID-19, this risk may be compounded, and their propensity for a more severe COVID-19 disease course increased. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03102801, identifier NCT03102801. | Moin, Abu Saleh Md Al-Qaissi, Ahmed Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Switzerland Front Endocrinol (Lausanne). 2021 Mar 30;12:651009. doi: 10.3389/fendo.2021.651009. eCollection 2021.I | 04/17/2021 | ||
| Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19 | Gaziano L, et al. | 2021 | Nat Med | 27 | 4 | 668-676 | https://www.doi.org/10.1038/s41591-021-01310-z | 33,837,377 | Angiotensin-Converting Enzyme 2/genetics/physiology COVID-19/drug therapy/*genetics *Drug Repositioning Genome-Wide Association Study Humans Interleukin-10 Receptor beta Subunit/genetics/physiology Mendelian Randomization Analysis/*methods Quantitative Trait Loci Receptor, Interferon alpha-beta/genetics/physiology *SARS-CoV-2 | Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 x 10(-6); IFNAR2, P = 9.8 x 10(-11) and IL-10RB, P = 2.3 x 10(-14)) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19. | Gaziano, Liam Giambartolomei, Claudia Pereira, Alexandre C Gaulton, Anna Posner, Daniel C Swanson, Sonja A Ho, Yuk-Lam Iyengar, Sudha K Kosik, Nicole M Vujkovic, Marijana Gagnon, David R Bento, A Patricia Barrio-Hernandez, Inigo Ronnblom, Lars Hagberg, Niklas Lundtoft, Christian Langenberg, Claudia Pietzner, Maik Valentine, Dennis Gustincich, Stefano Tartaglia, Gian Gaetano Allara, Elias Surendran, Praveen Burgess, Stephen Zhao, Jing Hua Peters, James E Prins, Bram P Angelantonio, Emanuele Di Devineni, Poornima Shi, Yunling Lynch, Kristine E DuVall, Scott L Garcon, Helene Thomann, Lauren O Zhou, Jin J Gorman, Bryan R Huffman, Jennifer E O'Donnell, Christopher J Tsao, Philip S Beckham, Jean C Pyarajan, Saiju Muralidhar, Sumitra Huang, Grant D Ramoni, Rachel Beltrao, Pedro Danesh, John Hung, Adriana M Chang, Kyong-Mi Sun, Yan V Joseph, Jacob Leach, Andrew R Edwards, Todd L Cho, Kelly Gaziano, J Michael Butterworth, Adam S Casas, Juan P eng MR/L003120/1/MRC_/Medical Research Council/United Kingdom RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom MC_UU_12015/1/MRC_/Medical Research Council/United Kingdom 754490/EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Sklodowska-Curie Actions (H2020 Excellent Science - Marie Sklodowska-Curie Actions)/ I01 CX001897/CX/CSRD VA/ MR/S004068/2/MRC_/Medical Research Council/United Kingdom MC_UU_00002/7/MRC_/Medical Research Council/United Kingdom I01 BX003362/BX/BLRD VA/ 204623/Z/16/Z/WT_/Wellcome Trust/United Kingdom MVP001/Department of Veteran Affairs/ RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom MVP035/Office of Research and Development, VA/ Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Nat Med. 2021 Apr;27(4):668-676. doi: 10.1038/s41591-021-01310-z. Epub 2021 Apr 9.I | 04/11/2021 | |
| A Microbiota-Directed Food Intervention for Undernourished Children | Chen RY, et al. | 2021 | N Engl J Med | 384 | 16 | 1517-1528 | https://www.doi.org/10.1056/NEJMoa2023294 | 33,826,814 | Anthropometry Bangladesh Blood Proteins/analysis Body Weight *Dietary Supplements Feces/microbiology Female *Food, Formulated *Gastrointestinal Microbiome Growth Humans Infant *Infant Nutritional Physiological Phenomena Male Malnutrition/*diet therapy/microbiology Proteome Weight Gain | BACKGROUND: More than 30 million children worldwide have moderate acute malnutrition. Current treatments have limited effectiveness, and much remains unknown about the pathogenesis of this condition. Children with moderate acute malnutrition have perturbed development of their gut microbiota. METHODS: In this study, we provided a microbiota-directed complementary food prototype (MDCF-2) or a ready-to-use supplementary food (RUSF) to 123 slum-dwelling Bangladeshi children with moderate acute malnutrition between the ages of 12 months and 18 months. The supplementation was given twice daily for 3 months, followed by 1 month of monitoring. We obtained weight-for-length, weight-for-age, and length-for-age z scores and mid-upper-arm circumference values at baseline and every 2 weeks during the intervention period and at 4 months. We compared the rate of change of these related phenotypes between baseline and 3 months and between baseline and 4 months. We also measured levels of 4977 proteins in plasma and 209 bacterial taxa in fecal samples. RESULTS: A total of 118 children (59 in each study group) completed the intervention. The rates of change in the weight-for-length and weight-for-age z scores are consistent with a benefit of MDCF-2 on growth over the course of the study, including the 1-month follow-up. Receipt of MDCF-2 was linked to the magnitude of change in levels of 70 plasma proteins and of 21 associated bacterial taxa that were positively correlated with the weight-for-length z score (P<0.001 for comparisons of both protein and bacterial taxa). These proteins included mediators of bone growth and neurodevelopment. CONCLUSIONS: These findings provide support for MDCF-2 as a dietary supplement for young children with moderate acute malnutrition and provide insight into mechanisms by which this targeted manipulation of microbiota components may be linked to growth. (Supported by the Bill and Melinda Gates Foundation and the National Institutes of Health; ClinicalTrials.gov number, NCT04015999.). | Chen, Robert Y Mostafa, Ishita Hibberd, Matthew C Das, Subhasish Mahfuz, Mustafa Naila, Nurun N Islam, M Munirul Huq, Sayeeda Alam, M Ashraful Zaman, Mahabub U Raman, Arjun S Webber, Daniel Zhou, Cyrus Sundaresan, Vinaik Ahsan, Kazi Meier, Martin F Barratt, Michael J Ahmed, Tahmeed Gordon, Jeffrey I eng R01 DK030292/DK/NIDDK NIH HHS/ P30 DK056341/DK/NIDDK NIH HHS/ F30 DK124967/DK/NIDDK NIH HHS/ T32 GM007200/GM/NIGMS NIH HHS/ DK30292/DK/NIDDK NIH HHS/ Comparative Study Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't N Engl J Med. 2021 Apr 22;384(16):1517-1528. doi: 10.1056/NEJMoa2023294. Epub 2021 Apr 7.I | 04/08/2021 | |
| Plasma Proteomic Profiling in Hypertrophic Cardiomyopathy Patients before and after Surgical Myectomy Reveals Post-Procedural Reduction in Systemic Inflammation | Larson A, et al. | 2021 | Int J Mol Sci | 22 | 5 | https://www.doi.org/10.3390/ijms22052474 | 33,804,404 | Adult Aged Biomarkers/*blood Cardiac Surgical Procedures/*methods Cardiomyopathy, Hypertrophic/metabolism/pathology/*surgery Female Humans Inflammation/blood/*prevention & control Male Middle Aged Proteome/*analysis aptamer cardiovascular disease hypertrophic cardiomyopathy myectomy surgery proteomics design of the study in the collection, analyses, or interpretation of data in the writing of the manuscript, or in the decision to publish the results. | Left Ventricular Outflow Tract (LVOT) obstruction occurs in approximately 70% of Hypertrophic Cardiomyopathy (HCM) patients and currently requires imaging or invasive testing for diagnosis, sometimes in conjunction with provocative physiological or pharmaceutical stimuli. To identify potential biomarkers of LVOT obstruction, we performed proteomics profiling of 1305 plasma proteins in 12 HCM patients with documented LVOT obstruction, referred for surgical myectomy. Plasma was collected at the surgical preoperative visit, approximately one month prior to surgery and then at the post-surgical visit, approximately 3 months later. Proteomic profiles were generated using the aptamer-based SOMAscan assay. Principal Component Analysis using the highest statistically significant proteins separated all preoperative samples from all postoperative samples. Further analysis revealed a set of 25 proteins that distinguished the preoperative and postoperative states with a paired t-test p-value of <0.01. Ingenuity Pathway analysis facilitated the generation of protein interaction networks and the elucidation of key upstream regulators of differentially expressed proteins, such as interferon-gamma, TGF-beta1, and TNF. Biological pathways affected by surgery included organ inflammation, migration, and motility of leukocytes, fibrosis, vasculogenesis, angiogenesis, acute coronary events, endothelial proliferation, eicosanoid metabolism, calcium flux, apoptosis, and morphology of the cardiovascular system. Our results indicate that surgical relief of dynamic outflow tract obstruction in HCM patients is associated with unique alterations in plasma proteomic profiles that likely reflect improvement in organ inflammation and physiological function. | Larson, Amy Libermann, Towia A Bowditch, Heather Das, Gaurav Diakos, Nikolaos Huggins, Gordon S Rastegar, Hassan Chen, Frederick Y Rowin, Ethan J Maron, Martin S Chin, Michael T eng UL1 TR002544/TR/NCATS NIH HHS/ F32HL147492/NH/NIH HHS/ UL1TR002544/NH/NIH HHS/ 18IPA34170294/American Heart Association/ Switzerland Int J Mol Sci. 2021 Mar 1;22(5):2474. doi: 10.3390/ijms22052474.I | 04/04/2021 | ||
| BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection | Mills RJ, et al. | 2021 | Cell | 184 | 8 | 2167-2182 e22 | https://www.doi.org/10.1016/j.cell.2021.03.026 | 33,811,809 | Angiotensin-Converting Enzyme 2/metabolism Animals COVID-19/*complications/drug therapy Cardiotonic Agents/*therapeutic use Cell Cycle Proteins/*antagonists & inhibitors/metabolism Cell Line Cytokines/metabolism Female Heart Diseases/*drug therapy/etiology Human Embryonic Stem Cells Humans Inflammation/complications/drug therapy Mice Mice, Inbred C57BL Quinazolinones/*therapeutic use Transcription Factors/*antagonists & inhibitors/metabolism Bromodomain and extraterminal family inhibitors Covid-19 drug discovery heart inflammation organoids co-inventors on patents relating to cardiac organoid maturation and cardiac therapeutics. J.E.H. is co-inventor on licensed patents for engineered heart muscle. R.J.M., E.R.P., D.M.T., B.G., and J.E.H. are co-founders, scientific advisors, and stockholders in Dynomics. D.M.T. and B.G. are employees of Dynomics. C.H., D.G., L.F., J.J., M.S., N.C.W.W., and E.K. are employees of Resverlogix. S.J.N. received honoraria and research support from Resverlogix. QIMR Berghofer Medical Research Institute filed a patent on the use of BETi. | Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory cytokine-storm", a cocktail of interferon gamma, interleukin 1beta, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage." | Mills, Richard J Humphrey, Sean J Fortuna, Patrick R J Lor, Mary Foster, Simon R Quaife-Ryan, Gregory A Johnston, Rebecca L Dumenil, Troy Bishop, Cameron Rudraraju, Rajeev Rawle, Daniel J Le, Thuy Zhao, Wei Lee, Leo Mackenzie-Kludas, Charley Mehdiabadi, Neda R Halliday, Christopher Gilham, Dean Fu, Li Nicholls, Stephen J Johansson, Jan Sweeney, Michael Wong, Norman C W Kulikowski, Ewelina Sokolowski, Kamil A Tse, Brian W C Devilee, Lynn Voges, Holly K Reynolds, Liam T Krumeich, Sophie Mathieson, Ellen Abu-Bonsrah, Dad Karavendzas, Kathy Griffen, Brendan Titmarsh, Drew Elliott, David A McMahon, James Suhrbier, Andreas Subbarao, Kanta Porrello, Enzo R Smyth, Mark J Engwerda, Christian R MacDonald, Kelli P A Bald, Tobias James, David E Hudson, James E eng Research Support, Non-U.S. Gov't Cell. 2021 Apr 15;184(8):2167-2182.e22. doi: 10.1016/j.cell.2021.03.026. Epub 2021 Mar 16.I | 04/04/2021 | |
| Advances in Aptamer-Based Biomarker Discovery | Huang J, et al. | 2021 | Front Cell Dev Biol | 9 | 659760 | https://www.doi.org/10.3389/fcell.2021.659760 | 33,796,540 | Cell-selex SOMAScan aptamer biomarker discovery human diseases commercial or financial relationships that could be construed as a potential conflict of interest. | The discovery and identification of biomarkers promote the rational and fast development of medical diagnosis and therapeutics. Clinically, the application of ideal biomarkers still is limited due to the suboptimal technology in biomarker discovery. Aptamers are single-stranded deoxyribonucleic acid or ribonucleic acid molecules and can selectively bind to varied targets with high affinity and specificity. Compared with antibody, aptamers have desirable advantages, such as flexible design, easy synthesis and convenient modification with different functional groups. Currently, different aptamer-based technologies have been developed to facilitate biomarker discovery, especially CELL-SELEX and SOMAScan technology. CELL-SELEX technology is mainly used to identify cell membrane surface biomarkers of various cells. SOMAScan technology is an unbiased biomarker detection method that can analyze numerous and even thousands of proteins in complex biological samples at the same time. It has now become a large-scale multi-protein biomarker discovery platform. In this review, we introduce the aptamer-based biomarker discovery technologies, and summarize and highlight the discovered emerging biomarkers recently in several diseases. | Huang, Jie Chen, Xinxin Fu, Xuekun Li, Zheng Huang, Yuhong Liang, Chao eng Review Switzerland Front Cell Dev Biol. 2021 Mar 16;9:659760. doi: 10.3389/fcell.2021.659760. eCollection 2021.I | 04/03/2021 | ||
| Replication study of plasma proteins relating to Alzheimer's pathology | Shi L, et al. | 2021 | Alzheimers Dement | 17 | 9 | 1452-1464 | https://www.doi.org/10.1002/alz.12322 | 33,792,144 | Aged *Alzheimer Disease/blood/pathology Amyloid beta-Peptides/*blood Apolipoprotein E4/blood/genetics Biomarkers/*blood *Blood Proteins Cognitive Dysfunction/blood/pathology Europe Female Humans Male Middle Aged *Proteomics tau Proteins/*blood ATN framework Alzheimer's disease biomarker dementia network analysis plasma proteomics replication | INTRODUCTION: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. METHODS: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. RESULTS: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E epsilon4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. DISCUSSION: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis." | Shi, Liu Winchester, Laura M Westwood, Sarah Baird, Alison L Anand, Sneha N Buckley, Noel J Hye, Abdul Ashton, Nicholas J Bos, Isabelle Vos, Stephanie J B Kate, Mara Ten Scheltens, Philip Teunissen, Charlotte E Vandenberghe, Rik Gabel, Silvy Meersmans, Karen Engelborghs, Sebastiaan De Roeck, Ellen E Sleegers, Kristel Frisoni, Giovanni B Blin, Olivier Richardson, Jill C Bordet, Regis Molinuevo, Jose L Rami, Lorena Wallin, Anders Kettunen, Petronella Tsolaki, Magda Verhey, Frans Lleo, Alberto Sala, Isabel Popp, Julius Peyratout, Gwendoline Martinez-Lage, Pablo Tainta, Mikel Johannsen, Peter Freund-Levi, Yvonne Frolich, Lutz Dobricic, Valerija Legido-Quigley, Cristina Barkhof, Frederik Andreasson, Ulf Blennow, Kaj Zetterberg, Henrik Streffer, Johannes Lill, Christina M Bertram, Lars Visser, Pieter Jelle Kolb, Hartmuth C Narayan, Vaibhav A Lovestone, Simon Nevado-Holgado, Alejo J eng DH_/Department of Health/United Kingdom Research Support, Non-U.S. Gov't Alzheimers Dement. 2021 Sep;17(9):1452-1464. doi: 10.1002/alz.12322. Epub 2021 Mar 31.I | 04/02/2021 | |
| Proteomics in aging research: A roadmap to clinical, translational research | Moaddel R, et al. | 2021 | Aging Cell | 20 | 4 | e13325 | https://www.doi.org/10.1111/acel.13325 | 33,730,416 | Aging/*blood/genetics Animals Biomarkers/blood Gene Expression Regulation Geroscience/methods Humans Hypoxia-Inducible Factor 1, alpha Subunit/blood MAP Kinase Signaling System/*genetics Mitogen-Activated Protein Kinases/blood Prognosis Proteome/*metabolism Proteomics/*methods Translational Research, Biomedical/*methods aging geroscience human proteomics | The identification of plasma proteins that systematically change with age and, independent of chronological age, predict accelerated decline of health is an expanding area of research. Circulating proteins are ideal translational omics" since they are final effectors of physiological pathways and because physicians are accustomed to use information of plasma proteins as biomarkers for diagnosis, prognosis, and tracking the effectiveness of treatments. Recent technological advancements, including mass spectrometry (MS)-based proteomics, multiplexed proteomic assay using modified aptamers (SOMAscan), and Proximity Extension Assay (PEA, O-Link), have allowed for the assessment of thousands of proteins in plasma or other biological matrices, which are potentially translatable into new clinical biomarkers and provide new clues about the mechanisms by which aging is associated with health deterioration and functional decline. We carried out a detailed literature search for proteomic studies performed in different matrices (plasma, serum, urine, saliva, tissues) and species using multiple platforms. Herein, we identified 232 proteins that were age-associated across studies. Enrichment analysis of the 232 age-associated proteins revealed metabolic pathways previously connected with biological aging both in animal models and in humans, most remarkably insulin-like growth factor (IGF) signaling, mitogen-activated protein kinases (MAPK), hypoxia-inducible factor 1 (HIF1), cytokine signaling, Forkhead Box O (FOXO) metabolic pathways, folate metabolism, advance glycation end products (AGE), and receptor AGE (RAGE) metabolic pathway. Information on these age-relevant proteins, likely expanded and validated in longitudinal studies and examined in mechanistic studies, will be essential for patient stratification and the development of new treatments aimed at improving health expectancy." | Moaddel, Ruin Ubaida-Mohien, Ceereena Tanaka, Toshiko Lyashkov, Alexey Basisty, Nathan Schilling, Birgit Semba, Richard D Franceschi, Claudio Gorospe, Myriam Ferrucci, Luigi eng K99 AG065484/AG/NIA NIH HHS/ R01 AG057723/AG/NIA NIH HHS/ U01 AG060906/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Review England Aging Cell. 2021 Apr;20(4):e13325. doi: 10.1111/acel.13325. Epub 2021 Mar 17.I | 03/18/2021 | |
| Seroconversion stages COVID19 into distinct pathophysiological states | Galbraith MD, et al. | 2021 | Elife | 10 | https://www.doi.org/10.7554/eLife.65508 | 33,724,185 | Biomarkers COVID-19/*epidemiology/immunology/metabolism/*virology Comorbidity Complement Activation/immunology Complement System Proteins/immunology Hematopoiesis Homeostasis Hospitalization Humans Hypoalbuminemia Interferons/metabolism Models, Biological *SARS-CoV-2 *Seroconversion Seroepidemiologic Studies Signal Transduction Covid19 Sars antibodies complement cytokines human immunology inflammation interferons interests declared, KS is a co-inventor on two patents related to JAK inhibition in COVID19: U.S. Provisional Patent Application Serial No. 62/992,855 entitled 'JAK1 Inhibition For Modulation Of Overdrive Anti-Viral Response To COVID-19' U.S. Provisional Patent Application Serial No. 62/993,749 entitled 'Compounds and Methods for Inhibition or Modulation of Viral Hypercytokinemia'. JE Reviewing editor, eLife, is a co-inventor on two patents related to JAK inhibition in COVID19: U.S. Provisional Patent Application Serial No. 62/992,855 entitled 'JAK1 Inhibition For Modulation Of Overdrive Anti-Viral Response To COVID-19' U.S. Provisional Patent Application Serial No. 62/993,749 entitled 'Compounds and Methods for Inhibition or Modulation of Viral Hypercytokinemia'. | COVID19 is a heterogeneous medical condition involving diverse underlying pathophysiological processes including hyperinflammation, endothelial damage, thrombotic microangiopathy, and end-organ damage. Limited knowledge about the molecular mechanisms driving these processes and lack of staging biomarkers hamper the ability to stratify patients for targeted therapeutics. We report here the results of a cross-sectional multi-omics analysis of hospitalized COVID19 patients revealing that seroconversion status associates with distinct underlying pathophysiological states. Low antibody titers associate with hyperactive T cells and NK cells, high levels of IFN alpha, gamma and lambda ligands, markers of systemic complement activation, and depletion of lymphocytes, neutrophils, and platelets. Upon seroconversion, all of these processes are attenuated, observing instead increases in B cell subsets, emergency hematopoiesis, increased D-dimer, and hypoalbuminemia. We propose that seroconversion status could potentially be used as a biosignature to stratify patients for therapeutic intervention and to inform analysis of clinical trial results in heterogenous patient populations. | Galbraith, Matthew D Kinning, Kohl T Sullivan, Kelly D Baxter, Ryan Araya, Paula Jordan, Kimberly R Russell, Seth Smith, Keith P Granrath, Ross E Shaw, Jessica R Dzieciatkowska, Monika Ghosh, Tusharkanti Monte, Andrew A D'Alessandro, Angelo Hansen, Kirk C Benett, Tellen D Hsieh, Elena Wy Espinosa, Joaquin M eng RM1GM131968/GM/NIGMS NIH HHS/ R01 AI150305/AI/NIAID NIH HHS/ R01AI150305/National Institute of Allergy and Infectious Diseases/ R01HL149714/HL/NHLBI NIH HHS/ R01HL148151/HL/NHLBI NIH HHS/ 3R01AI150305-01S1/National Institute of Allergy and Infectious Diseases/ UL1TR002535/TR/NCATS NIH HHS/ R21HL150032/HL/NHLBI NIH HHS/ 3UL1TR002535-03S2/TR/NCATS NIH HHS/ R35GM124939/GM/NIGMS NIH HHS/ P30CA046934/CA/NCI NIH HHS/ R01AI145988/National Institute of Allergy and Infectious Diseases/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Elife. 2021 Mar 16;10:e65508. doi: 10.7554/eLife.65508.I | 03/17/2021 | |||
| Vitamin D Association With Macrophage-Derived Cytokines in Polycystic Ovary Syndrome: An Enhanced Risk of COVID-19 Infection? | Moin ASM, et al. | 2021 | Front Endocrinol (Lausanne) | 12 | 638621 | https://www.doi.org/10.3389/fendo.2021.638621 | 33,716,989 | Adult Biomarkers/analysis Blood Proteins/analysis Body Mass Index COVID-19/complications/*epidemiology/immunology Cross-Sectional Studies Cytokines/*metabolism Female Humans Macrophage Activation Macrophages/chemistry/*metabolism Polycystic Ovary Syndrome/complications/*epidemiology/immunology Risk Assessment Tandem Mass Spectrometry Vitamin D/blood Vitamin D Deficiency/complications/*epidemiology COVID-19 risk factors cytokines macrophage polycystic ovary disease vitamin D commercial or financial relationships that could be construed as a potential conflict of interest. | BACKGROUND: Women with polycystic ovary syndrome (PCOS) often have vitamin D deficiency, a known risk factor for severe COVID-19 disease. Alveolar macrophage-derived cytokines contribute to the inflammation underlying pulmonary disease in COVID-19. We sought to determine if basal macrophage activation, as a risk factor for COVID-19 infection, was present in PCOS and, if so, was further enhanced by vitamin D deficiency. METHODS: A cross-sectional study in 99 PCOS and 68 control women who presented sequentially. Plasma levels of a macrophage-derived cytokine panel were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. Vitamin D was measured by tandem mass spectroscopy. RESULTS: Vitamin D was lower in PCOS women (p<0.0001) and correlated negatively with body mass index (BMI) in PCOS (r=0.28, p=0.0046). Basal macrophage activation markers CXCL5, CD163 and MMP9 were elevated, whilst protective CD200 was decreased (p<0.05); changes in these variables were related to, and fully accounted for, by BMI. PCOS and control women were then stratified according to vitamin D concentration. Vitamin D deficiency was associated with decreased CD80 and IFN-gamma in PCOS and IL-12 in both groups (p<0.05). These factors, important in initiating and maintaining the immune response, were again accounted for by BMI. CONCLUSION: Basal macrophage activation was higher in PCOS with macrophage changes related with increased infection risk associating with vitamin D; all changes were BMI dependent, suggesting that obese PCOS with vitamin D deficiency may be at greater risk of more severe COVID-19 infection, but that it is obesity-related rather than an independent PCOS factor. | Moin, Abu Saleh Md Sathyapalan, Thozhukat Butler, Alexandra E Atkin, Stephen L eng Switzerland Front Endocrinol (Lausanne). 2021 Feb 25;12:638621. doi: 10.3389/fendo.2021.638621. eCollection 2021.I | 03/16/2021 | ||
| Metabolic consequences of obesity on the hypercoagulable state of polycystic ovary syndrome | Moin ASM, et al. | 2021 | Sci Rep | 11 | 1 | 5320 | https://www.doi.org/10.1038/s41598-021-84586-y | 33,674,695 | Adult Biomarkers/*blood Body Mass Index Female Humans Inflammation/metabolism Insulin Resistance Obesity/*metabolism Polycystic Ovary Syndrome/*metabolism Risk Factors Young Adult | Polycystic ovary syndrome (PCOS) women have a hypercoagulable state; however, whether this is intrinsically due to PCOS or, alternatively, a consequence of its metabolic complications is unclear. We determined plasma coagulation pathway protein levels in PCOS (n = 146) and control (n = 97) women recruited to a PCOS biobank. Circulating levels of a panel of 18 clotting pathway proteins were determined by Slow Off-rate Modified Aptamer-scan plasma protein measurement. Cohorts were age matched, though PCOS had elevated body mass index (p < 0.001), insulin (p < 0.001) and C-reactive protein (CRP) (p < 0.0001). Eight pro-coagulation proteins were elevated in PCOS: plasminogen activator inhibitor-1 (p < 0.0001), fibrinogen (p < 0.01), fibrinogen gamma chain (p < 0.0001), fibronectin (p < 0.01), von Willebrand factor (p < 0.05), D-dimer (p < 0.0001), P-selectin (p < 0.05), and plasma kallikrein (p < 0.001). However, two anticoagulant proteins, vitamin K-dependent protein-S (p < 0.0001) and heparin cofactor-II (p < 0.001) were elevated and prothrombin was decreased (p < 0.05). CRP, as a marker of inflammation, and insulin resistance (HOMA-IR) correlated with 11 and 6 of the clotting proteins, respectively (p < 0.05). When matched for BMI < 25 (16 PCOS, 53 controls) HOMA-IR remained elevated (p < 0.05) and heparin cofactor-II was increased (p < 0.05). In a multivariate analysis accounting for inflammation, insulin resistance and BMI, there was no correlation of PCOS with any of the coagulation proteins. The hypercoagulable state in PCOS is not intrinsic to the disease as it can be fully accounted for by BMI, inflammation and insulin resistance. | Moin, Abu Saleh Md Sathyapalan, Thozhukat Diboun, Ilhame Elrayess, Mohamed A Butler, Alexandra E Atkin, Stephen L eng England Sci Rep. 2021 Mar 5;11(1):5320. doi: 10.1038/s41598-021-84586-y.I | 03/07/2021 | |
| Quantitative Proteomic Analysis of Diabetes Mellitus in Heart Failure With Preserved Ejection Fraction | Hanff TC, et al. | 2021 | JACC Basic Transl Sci | 6 | 2 | 89-99 | https://www.doi.org/10.1016/j.jacbts.2020.11.011 | 33,665,511 | ApoM, apolipoprotein M CI, confidence interval CILP2, cartilage intermediate layer protein 2 DM, diabetes mellitus HFpEF, heart failure with preserved ejection fraction HR, hazard ratio LASSO, least absolute shrinkage and selection operator apolipoprotein M diabetes heart failure mediation analysis proteomics Cohen is supported by K23-HL133843. Dr. Javaheri is supported by K08-HL138262. Dr. Zamani is supported by grant K23-HL-13055. Dr. Chirinos is supported by a research grant from Bristol-Myers Squibb and by grants R01-HL 121510- 01A1, R61-HL-146390, R01-AG058969, 1R01-HL104106, P01-HL094307, R03-HL146874-01, and R56-HL136730. Dr. Javaheri has been named co-inventor on the patent application for the use of fusion protein nanodiscs for the treatment of heart failure. Drs. Zhao, Walsh, Maranville, Wang, Adam, Ramirez-Valle, Schafer, Seiffert, Gordon, and Cvijic own stock in Bristol-Myers Squibb. Dr. Cappola has received research funding from Bristol-Myers Squibb. Dr. Zamani has consulted for Vyaire. Dr. Chirinos has been a consultant for Sanifit, Microsoft, Fukuda-Denshi, Bristol-Myers Squibb, OPKO Healthcare, Ironwood Pharmaceuticals, Pfizer, Akros Pharma, Merck, Bayer, JNJ, and Edwards Life Sciences and received research grants from National Institutes of Health, American College of Radiology Network, Fukuda Denshi, Bristol-Myers Squibb, and Microsoft, and has been named as inventor in a University of Pennsylvania patent for the use of inorganic nitrates/nitrites for the treatment of heart failure and preserved ejection fraction. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. | Diabetes mellitus (DM) is associated with a higher risk of heart failure hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Using SomaScan assays and proteomics analysis of plasma from participants in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial and the Penn Heart Failure Study, this study identified 10 proteins with significantly different expression in patients with HFpEF and DM. Of these, apolipoprotein M was found to mediate 72% (95% CI: 36% to 100%; p < 0.001) of the association between DM and the risk of cardiovascular death, aborted cardiac arrest, and heart failure hospitalization. | Hanff, Thomas C Cohen, Jordana B Zhao, Lei Javaheri, Ali Zamani, Payman Prenner, Stuart B Rietzschel, Ernst Jia, Yi Walsh, Alice Maranville, Joseph Wang, Zhaoqing Adam, Leonard Ramirez-Valle, Francisco Schafer, Peter Seiffert, Dietmar Gordon, David A Cvijic, Mary E Cappola, Thomas P Chirinos, Julio A eng K08 HL138262/HL/NHLBI NIH HHS/ P30 DK056341/DK/NIDDK NIH HHS/ JACC Basic Transl Sci. 2021 Feb 10;6(2):89-99. doi: 10.1016/j.jacbts.2020.11.011. eCollection 2021 Feb.I | 03/06/2021 | |
| A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity | Zhou S, et al. | 2021 | Nat Med | 27 | 4 | 659-667 | https://www.doi.org/10.1038/s41591-021-01281-1 |