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1,219 curated publications
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| Title | Author | Year | Journal | Volume | Issue | Pages | DOI | Accession number | Keywords | Abstract | All authors/Notes | Link | Epub date |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Prediction of new-onset atrial fibrillation in patients with hypertrophic cardiomyopathy using plasma proteomics profiling | Lumish, HS. et al. | 2024 | Europace | ||||||||||
| Urinary biomarkers associated with pathogenic pathways reflecting histological findings in lupus nephritis | Hiramoto, K. et al. | 2024 | Arthritis Rheumatol. | ||||||||||
| The Biomarkers in Extreme Longevity: Insights Gained from Metabolomics and Proteomics | Qiu, X. et al. | 2024 | Int J Med Sci | ||||||||||
| Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes in the COPDGene and ECLIPSE cohort studies | Moll, M. et al. | 2024 | eBioMedicine | ||||||||||
| Addressing statistical challenges in the analysis of proteomics data with extremely small sample size: a simulation study | Lee, KH. et al. | 2024 | BMC Genomics | ||||||||||
| Neutrophil and mononuclear leukocyte pathways and upstream regulators revealed by serum proteomics of adult and juvenile dermatomyositis | Sparling, AC. et al. | 2024 | Arthritis Res Ther. | ||||||||||
| Effect of genetically predicted sclerostin on cardiovascular biomarkers, risk factors, and disease outcomes | Alcalde-Herraiz, M. et al. | 2024 | Nat Commun. | ||||||||||
| Sodium-glucose cotransporter protein 2 inhibition, plasma proteins, and ischemic stroke: A mediation Mendelian randomization and colocalization study | Chen, Z. et al. | 2024 | J Stroke Cerebrovasc Dis. | ||||||||||
| Plasma Glutaminyl-Peptide Cyclotransferase Mediates Glucosamine-Metabolism-Driven Protection Against Hypertension: A Mendelian Randomization Study | Ge, F. et al. | 2024 | Int. J. Mol. Sci. | ||||||||||
| Machine learning-based clustering identifies obesity subgroups with differential multi-omics profiles and metabolic patterns | Anwar, MY. et al. | 2024 | Obesity | ||||||||||
| Exploring susceptibility and therapeutic targets for kidney stones through proteome-wide Mendelian randomization | Jiang, Q. et al. | 2024 | Hum Mol Genet. | ||||||||||
| Associations of plasma SMOC1 and soluble IL6RA levels with the progression from mild cognitive impairment to dementia | Morató, X. et al. | 2024 | Brain, Behavior, & Immunity | ||||||||||
| Plasma pQTL and brain eQTL integration identifies PNKP as a therapeutic target and reveals mechanistic insights into migraine pathophysiology | Lou, J. et al. | 2024 | J Headache Pain | ||||||||||
| Identification of novel drug targets for liver cirrhosis and its potential side-effects by human plasma proteome | Xiao, QA. et al. | 2024 | Sci Rep. | ||||||||||
| Genetic Evidence for the Causal Link Between Coagulation Factors and the Risk of Ovarian Cancer: A Two-Sample Mendelian Randomization Study | Dai, T. et al. | 2024 | International Journal of Women’s Health | ||||||||||
| Osteoprotegerin, Osteopontin, and Osteocalcin Are Associated With Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL | Maddaloni, E. et al. | 2024 | Diabetes Care | ||||||||||
| Association of Coagulation Factor XI Level With Cardiovascular Events and Cardiac Function in Community-Dwelling Adults: From ARIC and CHS | Ji, Y. et al. | 2024 | Circulation | ||||||||||
| Proteomic analysis identifies novel biological pathways that may link dietary quality to type 2 diabetes risk: evidence from African American and Asian cohorts | Lim, CGY et al. | 2024 | Am J Clin Nutr. | ||||||||||
| Protein biomarker signatures of preeclampsia - a longitudinal 5000-multiplex proteomics study | Degnes, ML. et al. | 2024 | Sci Rep. | ||||||||||
| Identifying prothrombin and bone sialoprotein as potential drug targets for idiopathic pulmonary fibrosis | Chen, Y. et al. | 2024 | BMC Pulm Med. | ||||||||||
| Transcriptomic and Proteomic Insights into Host Immune Responses in Pediatric Severe Malarial Anemia: Dysregulation in HSP60-70-TLR2/4 Signaling and Altered Glutamine Metabolism | Onyango, CO. et al. | 2024 | Pathogens | ||||||||||
| Comprehensive Proteomic Profiling of Human Myocardium Reveals Signaling Pathways Dysregulated in Hypertrophic Cardiomyopathy | Lumish, HS. et al. | 2024 | J Am Coll Cardiol. | ||||||||||
| Circadian misalignment disrupts biomarkers of cardiovascular disease risk and promotes a hypercoagulable state | McHill, AW. et al. | 2024 | Eur J Neurosci. | ||||||||||
| Inflammatory proteins associated with Alzheimer's disease reduced by a GLP1 receptor agonist: a post hoc analysis of the EXSCEL randomized placebo controlled trial | Koychev, I. et al. | 2024 | Alzheimers Res Ther. | ||||||||||
| Development, characterization, and replication of proteomic aging clocks: Analysis of 2 population-based cohorts | Wang, S. et al. | 2024 | PLoS Med. | ||||||||||
| Statistically and functionally fine-mapped blood eQTLs and pQTLs from 1,405 humans reveal distinct regulation patterns and disease relevance | Wang, QS. et al. | 2024 | Nat Genet. | ||||||||||
| Exploring the design of clinical research studies on the efficacy mechanisms in type 2 diabetes mellitus | Guan, H. et al. | 2024 | Front Endocrinol. | ||||||||||
| Recent developments in non-invasive methods for assessing metabolic dysfunction-associated fatty liver disease | Singh, A. et al. | 2024 | World J Gastroenterol | ||||||||||
| Application of large‑scale and multicohort plasma proteomics datato discover novel causal proteins in gastric cancer | Tang, W. et al. | 2024 | Discov Oncol. | ||||||||||
| Circulating RAC1 contributed to steroid-sensitive nephrotic syndrome: Mendelian randomization, single-cell RNA-sequencing, proteomic, and experimental evidence | Zhang, Y. et al. | 2024 | Ren Fail. | ||||||||||
| Circulating IL-17F, but not IL-17A, is elevated in severe COVID-19 and leads to an ERK1/2 and p38 MAPK-dependent increase in ICAM-1 cell surface expression and neutrophil adhesion on endothelial cells | Bédard-Matteau, J. et al. | 2024 | Front. Immunol. | ||||||||||
| Metabolomics and proteomics in occupational medicine: a comprehensive systematic review | Ochoa-Leite, C. et al. | 2024 | J Occup Med Toxicol. | ||||||||||
| Integrated multiomic analyses: An approach to improveunderstanding of diabetic kidney disease | Hill, C. et al. | 2024 | Diabet Med. | ||||||||||
| Systematic identification of therapeutic targets for coronary artery calcification: an integrated transcriptomic and proteomic Mendelian randomization | Chen, L. et al. | 2024 | Front. Cardiovasc. | ||||||||||
| Clustering-aided prediction of outcomes in patients with idiopathic pulmonary fibrosis | Wang, L. et al. | 2024 | Respir Res. | ||||||||||
| Variability of 7K and 11K SomaScan Plasma Proteomics Assays | Candia, J. et al. | 2024 | Proteome Res. | ||||||||||
| The Circulating Proteome─Technological Developments,Current Challenges, and Future Trends | Geyer, PE. et al. | 2024 | Trends. J Proteome Res. | ||||||||||
| Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer’s disease | Long, H. et al. | 2024 | Alzheimers Res Ther. | ||||||||||
| Integrating metabolomics and proteomics to identify novel drug targets for heart failure and atrial fibrillation | van Vugt, M. et al. | 2024 | Genome Med. | ||||||||||
| Plasma protein-based organ-specific aging and mortality models unveil diseases as accelerated aging of organismal systems | Goeminne, LJE. et al. | 2024 | Cell Metab. | ||||||||||
| Circulating proteins linked to apoptosis processes and fast development of end-stage kidney disease in diabetes | Ihara, K. et al. | 2024 | JCI Insight. | ||||||||||
| An integrated multi-omics analysis reveals osteokines involved in global regulation | Liang, W. et al. | 2024 | Cell Metab. | ||||||||||
| CSF proteomics identifies early changes in autosomal dominant Alzheimer's disease | Shen, Y. et al. | 2024 | Cell | ||||||||||
| Identification of proteins associated with type 2 diabetes risk in diverse racial and ethnic populations | Liu, S. et al. | 2024 | Diabetologia | ||||||||||
| A protein risk score for all-cause and respiratory-specific mortality in non-Hispanic white and African American individuals who smoke | Moll, M. et al. | 2024 | Sci Rep. | ||||||||||
| Proteomic networks and related genetic variants associated with smoking and chronic obstructive pulmonary disease | Konigsberg, IR. et al. | 2024 | BMC Genomics | ||||||||||
| Clinical-transcriptional prioritization of the circulating proteome in human heart failure | Perry, AS. et al. | 2024 | Cell Rep Med. | ||||||||||
| Multiomics: Functional Molecular Biomarkers of Micronutrients for Public Health Application | Allen, LH. et al. | 2024 | Annu Rev Nutr. | ||||||||||
| Diagnostics and omics technologies for the detection and prediction of metabolic dysfunction-associated steatotic liver disease-related malignancies | Lan, T. et al. | 2024 | Metabolism | ||||||||||
| Organ-specific Biodosimetry Modeling Using Proteomic Biomarkers of Radiation Exposure | Sproull, M. et al. | 2024 | Radiat Res. | ||||||||||
| Proteomic Correlates and Prognostic Significance of Kidney Injury in Heart Failure With Preserved Ejection Fraction | Salman, O. et al. | 2024 | J Am Heart Assoc. | ||||||||||
| Prognostic Significance and Biologic Associations of Senescence-Associated Secretory Phenotype Biomarkers in Heart Failure | Salman, O. et al. | 2024 | J Am Heart Assoc. | ||||||||||
| Novel approach to exploring protease activity and targets in HIV-associated obstructive lung disease using combined proteomic-peptidomic analysis | Samorodnitsky, S. et al. | 2024 | Respir Res. | ||||||||||
| Multi-trait analysis reveals risk loci for heart failure and the shared genetic etiology with blood lipids, blood pressure, and blood glucose | Zhu, Y. et al. | 2024 | Cell Rep. | ||||||||||
| Safety and antiviral effect of a triple combination of HIV-1 broadly neutralizing antibodies: a phase 1/2a trial | Julg, B. et al. | 2024 | Nat Med. | ||||||||||
| Identification of novel protein biomarkers and therapeutic targets for ankylosing spondylitis using human circulating plasma proteomics and genome analysis | Zhou, Z. et al. | 2024 | Anal Bioanal Chem. | ||||||||||
| Proteomic Mendelian randomization to identify protein biomarkers of telomere length | Zhao, J. et al. | 2024 | Sci Rep. | ||||||||||
| Hyaluronan and proteoglycan link protein 1 – A novel signaling molecule for rejuvenating aged skin | Fu, Z. et al. | 2024 | Matrix Biol. | ||||||||||
| Evaluation of circulating plasma proteins in prostate cancer using mendelian randomization | Cheng, L. et al. | 2024 | Discov Oncol. | ||||||||||
| Sequence variants influencing the regulation of serum IgG subclass levels | Olafsdottir, TA. et al. | 2024 | Nat Commun. | ||||||||||
| Identification of potential therapeutic targets for nonischemic cardiomyopathy in European ancestry: an integrated multiomics analysis | Shi, K. et al. | 2024 | Cardiovasc Diabetol. | ||||||||||
| Proteomics of left ventricular structure in the Multi-Ethnic Study of Atherosclerosis | Peterson, TE. et al. | 2024 | ESC Heart Fail. | ||||||||||
| Protein Biomarkers of Ultra-Processed Food Consumption and Risk of Coronary Heart Disease, Chronic Kidney Disease, and All-Cause Mortality | Du, S. et al. | 2024 | J Nutr. | ||||||||||
| Mapping biological influences on the human plasma proteome beyond the genome | Carrasco-Zanini, J. et al. | 2024 | Nat Metab. | ||||||||||
| Identification of novel proteins for coronary artery disease by integrating GWAS data and human plasma proteomes | Li, J. et al. | 2024 | Heliyon | ||||||||||
| Clinical and proteomic profiles of chronic kidney disease in heart failure with reduced and preserved ejection fraction | Voordes, GHD. et al. | 2024 | Int J Cardiol. | ||||||||||
| Proteomic Signatures of Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19: A Narrative Review | Dourdouna, MM. et al. | 2024 | Children | ||||||||||
| Plasma proteomics of acute tubular injury | Schmidt, IM. et al. | 2024 | Nat Commun. | ||||||||||
| Polygenic prediction of human longevity on the supposition of pervasive pleiotropy | Jabalameli, MR. et al. | 2024 | Sci Rep. | ||||||||||
| Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality | Wang, R. et al. | 2024 | Nat Commun. | ||||||||||
| Proteomic changes in Alzheimer disease associated with progressive Aβ plaque and tau tangle pathologies | Pichet Binette, A. et al. | 2024 | Nat Neurosci. | ||||||||||
| Proteomic Profile of the ICAM1 p.K56M HFpEF Risk Variant | Giro, P. et al. | 2024 | JACC | ||||||||||
| Endotypes of severe neutrophilic and eosinophilic asthma from multi-omics integration of U-BIOPRED sputum samples | Kermani, NZ. et al. | 2024 | Clin Transl Med. | ||||||||||
| Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson’s disease | Doostparast Torshizi, A. et al. | 2024 | Nat Commun. | ||||||||||
| A genetic and proteomic comparison of key AD biomarkers across tissues | Marsh, TW. et al. | 2024 | Alzheimers Dement. | ||||||||||
| Integrated Multi-Omics Analysis of Cerebrospinal Fluid in Postoperative Delirium | Tripp, BA. et al. | 2024 | Biomolecules | ||||||||||
| Osteopontin: A novel marker of pre-symptomatic sporadic Alzheimer’s disease | Quesnel, MJ. et al. | 2024 | Alzheimers Dement. | ||||||||||
| Proteomics approach to discovering non-invasive diagnostic biomarkers and understanding the pathogenesis of endometriosis: a systematic review and meta-analysis | Azeze, GG. et al. | 2024 | J Transl Med. | ||||||||||
| Serum CD133-Associated Proteins Identified by Machine Learning Are Connected to Neural Development, Cancer Pathways, and 12-Month Survival in Glioblastoma | Joyce, T. et al. | 2024 | Cancers | ||||||||||
| The application of aptamers in the field of aging and age-related diseases | Xu, L. et al. | 2024 | Clin. Transl. Disc. | ||||||||||
| Inhibition of JAK-STAT pathway corrects salivary gland inflammation and interferon driven immune activation in Sjögren's Disease | Gupta, S. et al. | 2024 | Ann Rheum Dis | ||||||||||
| Age-associated proteins explain the role of medial temporal lobe networks in Alzheimer's disease | Turnbull, A. et al. | 2024 | Geroscience | ||||||||||
| Early Circulating Biomarkers of Language Development in Single Ventricle Heart Disease | Wolfe, KR. et al. | 2024 | JAMA Pediatr. | ||||||||||
| Contrastive machine learning reveals Parkinson’s disease specific features associated with disease severity and progression | Zheng, L. et al. | 2024 | Commun Biol. | ||||||||||
| Deciphering the genetics and mechanisms of predisposition to multiple myeloma | Went, M. et al. | 2024 | Nat Commun. | ||||||||||
| Biomarkers in diagnosing and therapeutic monitoring of tuberculosis: areview | Leo, S. et al. | 2024 | Ann Med. | ||||||||||
| Multimodal analysis of dysregulated heme metabolism, hypoxic signaling, and stress erythropoiesis in Down syndrome | Donovan, M. et al. | 2024 | Cell Rep. | ||||||||||
| Proteome-Wide Mendelian Randomisation Identifies Causal Links of Plasma Proteins With Periodontitis | Zhan, C. et al. | 2024 | Int Dent J. | ||||||||||
| Proteomics identifies potential immunological drivers of postinfection brain atrophy and cognitive decline | Duggan, MR. et al. | 2024 | Nat Aging | ||||||||||
| Secretome analysis using Affinity Proteomics and Immunoassays: a focus on Tumor Biology | Beutgen, VM. et al. | 2024 | Mol Cell Proteomics. | ||||||||||
| Plasma proteome profiling in giant cell arteritis | Cunningham, KY. et al. | 2024 | Ann Rheum Dis. | ||||||||||
| Validation of candidate protein biomarkers previously identified by genetic instruments for prostate cancer risk: A prospective cohort analysis of directly measured protein levels in the ARIC study | Liu, T. et al. | 2024 | Prostate | ||||||||||
| Nonlinear dynamics of multi-omics profiles during human aging | Shen, X. et al. | 2024 | Nature Aging | ||||||||||
| Characterizing primary transcriptional responses to short term heat shock in Down syndrome | Cardiello, JF. et al. | 2024 | PLoS One | ||||||||||
| Proteome- and Transcriptome-Wide Genetic Analysis Identifies Biological Pathways and Candidate Drug Targets for Preeclampsia | Ardissino, M. et al. | 2024 | Circ Genom Precis Med. | ||||||||||
| Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer's disease | Frick, EA. et al. | 2024 | Nat Aging | ||||||||||
| A roadmap to the molecular human linking multiomics with population traits and diabetes subtypes | Halama, A. et al. | 2024 | Nat Commun. | ||||||||||
| Genotype-First Approach Identifies an Association between rs28374544/FOG2S657G and Liver Disease through Alterations in mTORC1 Signaling | Conlon, DM. et al. | 2024 | Genes | ||||||||||
| Causal effect of blood osteocalcin on the risk of Alzheimer's disease and the mediating role of energy metabolism | Guo, X. et al. | 2024 | Transl Psychiatry. | ||||||||||
| Causal associations of plasma proteins with lung squamous cell carcinoma risk: a proteome-wide Mendelian randomization and colocalization analysis | Wang, Q. et al. | 2024 | Clinical Cancer Bulletin | ||||||||||
| Proteome-Wide Genetic Investigation of Large Artery Stiffness | Dib, MJ. et al. | 2024 | JACC | ||||||||||
| Gut Microbiota, Metabolites, Circulating Cytokines and Growth Factors, Plasma Proteins, and Risk of Intracranial Aneurysms: A Two-Sample Mendelian Randomization Study | Maimaiti, A. et al. | 2024 | Acta Neurologica Scandinavica | ||||||||||
| Epigenetic scores derived in saliva are associated with gestational age at birth | Mckinnon, K. et al. | 2024 | Clin Epigenetics | ||||||||||
| Targeted degradation of extracellular mitochondrial aspartyl -tRNA synthetase modulates immune responses | Johnson, BS. et al. | 2024 | Nat Commun. | ||||||||||
| SomaLogic proteomics reveals new biomarkers and providesmechanistic, clinical insights into Acetyl coA Carboxylase (ACC) inhibition in Non-alcoholic Steatohepatitis (NASH) | Sivakumar, P. et al. | 2024 | Sci Rep. | ||||||||||
| Proteomic biomarkers related to obesity in heart failure with reduced ejection fraction and their associations with outcome | Petersen, TB. et al. | 2024 | Obesity (Silver Spring) | ||||||||||
| Crossing the Halfway Point: Aptamer-Based, Highly Multiplexed Assay for the Assessment of the Proteome | Kraemer, S. et al. | 2024 | J Proteome Res. | ||||||||||
| Anemia, Iron Deficiency, and Cause-Specific Mortality: The Atherosclerosis Risk in Communities (ARIC) Study | Cannon, EJ. et al. | 2024 | Gerontology | ||||||||||
| Interferon-γ induces combined pyroptotic angiopathy and APOL1 expression in human kidney disease | Juliar, BA. et al. | 2024 | Cell Rep. | ||||||||||
| Association between plasma proteome and pulmonary heart disease: A two-stage Mendelian randomization analysis | Li, S. et al. | 2024 | Clin Respir J. | ||||||||||
| Proteomic analysis of cardiorespiratory fitness for prediction of mortality and multisystem disease risks | Perry, AS. et al. | 2024 | Nat Med. | ||||||||||
| A microbiota-directed complementary food intervention in 12-18-month-old Bangladeshi children improves linear growth | Mostafa, I. et al. | 2024 | EBioMedicine | ||||||||||
| Discovery and Preclinical Evaluation of a Novel Inhibitor of FABP5, ART26.12, Effective in Oxaliplatin-Induced Peripheral Neuropathy | Warren, G. et al. | 2024 | J. Pain | ||||||||||
| A Cross-Sectional Exploratory Study of Cardiovascular Risk Biomarkers in Non-Obese Women with and without Polycystic Ovary Syndrome: Association with Vitamin D | Nandakumar, M. et al. | 2024 | Int. J. Mol. Sci. | ||||||||||
| High-throughput mass spectrometry maps the sepsis plasma proteome and differences in patient response | Mi, Y. et al. | 2024 | Sci Transl Med. | ||||||||||
| Structural overview of DNA and RNA G-quadruplexes in their interaction with proteins | Troisi, R. et al. | 2024 | Curr Opin Struct Biol. | ||||||||||
| Mid-life plasma proteins associated with late-life prefrailty and frailty: a proteomic analysis | Liu, F. et al. | 2024 | Geroscience | ||||||||||
| Plasma Proteomics of Exercise Blood Pressure and Incident Hypertension | Rao, P. et al. | 2024 | JAMA Cardiol. | ||||||||||
| Mechanisms of Hypercoagulability Driving Stroke Risk in Obesity: A Mendelian Randomization Study | Daghlas, I. et al. | 2024 | Neurology | ||||||||||
| Comparative Analysis of Protein Quantification by the SomaScan Assay versus Orthogonal Methods in Urine from People with Diabetic Kidney Disease | Lopez, L. et al. | 2024 | J. Proteome Res. | ||||||||||
| Identification of novel therapeutic targets for chronic kidney disease and kidney function by integrating multi-omics proteome with transcriptome | Si, S. et al. | 2024 | Genome Med. | ||||||||||
| Proteomic Signatures of Genetically Predicted and Pharmacologically Observed PCSK9 Inhibition | Kraaijenhof, JM. et al. | 2024 | J Am Heart Assoc. | ||||||||||
| Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Proteomic Substudy | Patel-Murray, N. et al. | 2024 | J Am Heart Assoc. | ||||||||||
| Promises and challenges of populational proteomics in health and disease | Sun, BB. et al. | 2024 | Mol Cell Proteomics | ||||||||||
| Exploring the early molecular pathogenesis of osteoarthritis using differential network analysis of human synovial fluid | Ryden, M. et al. | 2024 | Mol Cell Proteomics | ||||||||||
| Matrix metalloproteinase 9: an emerging biomarker for classification of adherent vestibular schwannoma | Nguyen, GY. et al. | 2024 | Neurooncol Adv. | ||||||||||
| Proteomic analysis of Alzheimer's disease cerebrospinal fluid reveals alterations associated with APOE ε4 and atomoxetine treatment | Dammer, EB. et al. | 2024 | Sci Transl Med. | ||||||||||
| An Early Gestation Plasma Inflammasome in Rural Bangladeshi Women | Kim, H. et al. | 2024 | Biomolecules | ||||||||||
| Plasma proteome mediate the impact of PM2.5 on stroke: A 2-step Mendelian randomization study | Yang, H. et al. | 2024 | Ecotoxicol Environ Saf. | ||||||||||
| Towards Healthy Longevity: Comprehensive Insights from Molecular Targets and Biomarkers to Biological Clocks | Yusri, K. et al. | 2024 | Int J Mol Sci. | ||||||||||
| Identifying novel proteins for migraine by integrating proteomes from blood and CSF with genome-wide association data | Niu, PP. et al. | 2024 | CNS Neurosci Ther. | ||||||||||
| Variegated overexpression of chromosome 21 genes reveals molecular and immune subtypes of Down syndrome | Donovan, M. et al. | 2024 | Nat Commun. | ||||||||||
| Generation Scotland: an update on Scotland's longitudinal family health study | Milbourn, H. et al. | 2024 | BMJ Open | ||||||||||
| Circulating small non-coding RNAs are associated with the insulin-resistant and obesity-related type 2 diabetes clusters | de Klerk, JA. et al. | 2024 | Diabetes Obes Metab. | ||||||||||
| Start codon variant in LAG3 is associated with decreased LAG-3 expression and increased risk of autoimmune thyroid disease | Saevarsdottir, S. et al. | 2024 | Nat Commun. | ||||||||||
| Exploring potential plasma drug targets for cholelithiasis through multiancestry Mendelian randomization | Liu, X. et al. | 2024 | Int J Surg. | ||||||||||
| Identifying plasma proteomic signatures from health to heart failure, across the ejection fraction spectrum | Andrzejczyk, K. et al. | 2024 | Sci Rep. | ||||||||||
| Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression | Duggan, M. et al. | 2024 | Brain Behav Immun. | ||||||||||
| Multiplex cerebrospinal fluid proteomics identifies biomarkers for diagnosis and prediction of Alzheimer's disease | Guo ,Y. et al. | 2024 | Nat Hum Behav. | ||||||||||
| CSF Proteomics in Patients With Progressive Supranuclear Palsy | Wise, A. et al. | 2024 | Neurology | ||||||||||
| Large-Scale Proteomics in Early Pregnancy and Hypertensive Disorders of Pregnancy | Greenland, P. et al. | 2024 | JAMA Cardiol. | ||||||||||
| Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders | Schmidt, AF. et al. | 2024 | Open Biol. | ||||||||||
| Multicenter proteome-wide Mendelian randomization study identifies causal plasma proteins in melanoma and non-melanoma skin cancers | Li, Y. et al. | 2024 | Commun Biol. | ||||||||||
| Genetic and multi-omic resources for Alzheimer disease and related dementia from the Knight Alzheimer Disease Research Center | Fernandez, MV. et al. | 2024 | Sci Data. | ||||||||||
| Epigenetic scores derived in saliva are associated with gestational age at birth | Mckinnon, K. et al. | 2024 | Clin Epigenetics | ||||||||||
| Proteomic Analysis of Prehypertensive and Hypertensive Patients: Exploring the Role of the Actin Cytoskeleton | Ashmar, SA. et al. | 2024 | Int. J. Mol. Sci. | ||||||||||
| A Cross-Sectional Study of Glomerular Hyperfiltration in Polycystic Ovary Syndrome | Butler, AE. et al. | 2024 | Int. J. Mol. Sci. | ||||||||||
| Identifying therapeutic targets for cancer among 2074 circulating proteins and risk of nine cancers | Smith-Byrne, K. et al. | 2024 | Nat Commun. | ||||||||||
| Pre-diagnostic plasma proteomics profile for hepatocellular carcinoma | Zhang, X. et al. | 2024 | J Natl Cancer Inst. | ||||||||||
| Comparison of Novel Proteomic Expression Profiles for Radiation Exposure in Male and Female C57BL6 Mice | Sproull, M. et al. | 2024 | Radiat Res. | ||||||||||
| Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer’s disease | Eteleeb, AM. et al. | 2024 | PLoS Biol. | ||||||||||
| Ratio of plasma IL-13/TNF- ∝ and CXCL10/CCL17 predicts mepolizumab and omalizumab response in asthma better than eosinophil count or immunoglobulin E level | Akenroye, A. et al. | 2024 | Sci Rep. | ||||||||||
| Advances in aqueous humor proteomics for biomarker discovery and disease mechanisms exploration: a spotlight on primary open angle glaucoma | Beutgen, V. et al. | 2024 | Front Mol Neurosci. | ||||||||||
| Noninvasive Diagnostic Methods in Liver Cirrhosis | Peng, Y. et al. | 2024 | Book Chapter | ||||||||||
| The Effect of Histo-Blood Group ABO System Transferase (BGAT) on Pregnancy Related Outcomes：A Mendelian Randomization Study | Sun, Y. et al. | 2024 | Comput Struct Biotechnol J. | ||||||||||
| Incident heart failure in chronic kidney disease: proteomics informs biology and risk stratification | Dubin, RF. et al. | 2024 | Eur Heart J. | ||||||||||
| Opportunities and barriers for omics-based biomarker discovery in steatotic liver diseases | Thiele, M. et la. | 2024 | J Hepatol. | ||||||||||
| Angiogenic and vasoactive proteins in the maternal-fetal interface in healthy pregnancies and preeclampsia | Westerberg, AC. et al. | 2024 | Am J Obstet Gynecol. | ||||||||||
| Paired plasma lipidomics and proteomics analysis in the conversion from mild cognitive impairment to Alzheimer's disease | Gómez-Pascual, A. et al. | 2024 | Comput Biol Med. | ||||||||||
| Unbiased kidney-centric molecular categorization of chronic kidney disease as a step towards precision medicine | Reznichenko, A. et al. | 2024 | Kidney Int. | ||||||||||
| Identification of plasma protein markers of allergic disease risk: a mendelian randomization approach to proteomic analysis | Cao, Z. et al. | 2024 | Genomics | ||||||||||
| Effect of Hypoglycemia and Rebound Hyperglycemia on Proteomic Cardiovascular Risk Biomarkers | Nandakumar, M. et al. | 2024 | Biomedicines | ||||||||||
| Causal effect of blood osteocalcin on the risk of Alzheimer’s disease and the mediating role of energy metabolism | Guo, X. et al. | 2024 | Transl Psychiatry | ||||||||||
| Aptamer-Based Proteomics in CKD | Kim, T. et al. | 2024 | Am J Kidney Dis. | ||||||||||
| Proteome-wide Mendelian randomization identifies potential therapeutic targets for nonalcoholic fatty liver diseases | Li, J. et al. | 2024 | Sci Rep. | ||||||||||
| High Throughput Plasma Proteomics and Risk of Heart Failure and Frailty in Late Life | Ramonfaur, D. et al. | 2024 | JAMA Cardiol. | ||||||||||
| Plasma Proteins Associated with Chronic Histopathologic Lesions on Kidney Biopsy | Kim, T. et al. | 2024 | J Am Soc Nephrol. | ||||||||||
| Small RNA sequencing reveals snoRNAs and piRNA-019825 as novel players in diabetic kidney disease | Hart, LM. et al. | 2024 | Endocrine | ||||||||||
| A plasma protein-based risk score to predict hip fractures | Austin, TR. et al. | 2024 | Nat Aging | ||||||||||
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| Predicted proteome association studies of breast, prostate, ovarian, and endometrial cancers implicate plasma protein regulation in cancer susceptibility | Gregga, I. et al. | 2023 | Cancer Epidemiol Biomarkers Prev. | 07/06/2023 | |||||||||
| Association of flame retardants, polybrominated diethyl ethers (PBDEs), with vitamin D in female subjects | Butler, AE. et al. | 2023 | Chemosphere | 07/11/2023 | |||||||||
| Non-invasive candidate protein signature predicts hepatic venous pressure gradient reduction in cirrhotic patients after sustained virologic response | Richards, SM. et al. | 2023 | Liver Int. | 07/13/2023 | |||||||||
| Proteomic profiling of longitudinal changes in kidney function among middle-aged and older men and women: the KORA S4/F4/FF4 study | Lin, JS. et al. | 2023 | BMC Med. | 07/05/2023 | |||||||||
| Proteome wide association studies of LRRK2 variants identify novel causal and druggable proteins for Parkinson's disease | Phillips, B. et al. | 2023 | NPJ Parkinsons Dis. | 07/08/2023 | |||||||||
| Activation of the Complement and Coagulation Systems in the Small Airways in Asthma | Kokelj, S. et al. | 2023 | Respiration. | 07/07/2023 | |||||||||
| Unbiased proteomics and multivariable regularized regression techniques identify SMOC1, NOG, APCS, and NTN1 in an Alzheimers disease brain proteomic signature | Roberts, JA. et al. | 2023 | NPJ Aging. | 07/06/2023 | |||||||||
| Clinical utility of a novel test for assessing cardiovascular disease risk in type 2 diabetes: a randomized controlled trial | Peabody, JW. et al. | 2023 | Diabetol Metab Syndr. | 07/13/2023 | |||||||||
| Dietary weight loss-induced improvements in metabolic function are enhanced by exercise in people with obesity and prediabetes | Beals, JW. et al. | 2023 | Nat Metab. | 06/26/2023 | |||||||||
| Causal associations between cardiorespiratory fitness and type 2 diabetes | Cai, L. et al. | 2023 | Nat Commun. | 07/03/2023 | |||||||||
| Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer's disease | Sung, YJ. et al. | 2023 | Sci Transl Med. | 07/05/2023 | |||||||||
| Associations of circulating proteins with lipoprotein profiles: proteomic analyses from the OmniHeart randomized trial and the Atherosclerosis Risk in Communities (ARIC) Study | Kim, H. et al. | 2023 | Clin Proteomics. | 07/03/2023 | |||||||||
| Large scale plasma proteome epitome profiling is an efficient tool for the discovery of cancer biomarkers | Lazar, J. et al. | 2023 | Mol Cell Proteomics | 05/19/2023 | |||||||||
| External validation of genetically predicted protein biomarkers for pancreatic cancer risk using aptamer-based plasma levels: A prospective analysis in the Atherosclerosis Risk in Communities Study | Liu, T. et al. | 2023 | Int J Cancer | 06/20/2023 | |||||||||
| Frailty Resilience Score: A Novel Measure of Frailty Resilience Associated with Protection from Frailty and Survival | Milman, S. et al. | 2023 | J Gerontol A Biol Sci Med Sci. | 05/29/2023 | |||||||||
| New Markers for Management of Mesothelioma | Nash, A. et al. | 2023 | Semin Respir Crit Care Med. | 05/30/2023 | |||||||||
| MS-based proteomics of body fluids: The end of the beginning | Bader, JM. et al. | 2023 | Mol Cell Proteomics | 05/18/2023 | |||||||||
| Biomarkers of ageing: Current state-of-art, challenges, and opportunities | Chen, R. et al. | 2023 | MedComm – Future Medicine | 06/18/2023 | |||||||||
| Mass Spectrometry-based Proteomics of Epithelial Ovarian Cancers: a Clinical Perspective | Quian, L. et al. | 2023 | Mol Cell Proteomics | 05/18/2023 | |||||||||
| The Human Gastric Juice: A Promising Source for Gastric Cancer Biomarkers | Felipez, N. et al. | 2023 | Int J Mol Sci. | ||||||||||
| A Question of Frame: The Role of the Bone Marrow Stromal Niche in Myeloid Malignancies | Tomasoni, C. et al. | 2023 | Hemasphere | 05/23/2023 | |||||||||
| Proteomics approaches to long COVID: status and outlooks | Liang, X. et al. | 2023 | Life Medicine | ||||||||||
| Machine learning algorithm improves detection of NASH (NAS-based) and at-risk NASH, a development and validation study | Lee J. et al. | 2023 | Hepatology | ||||||||||
| (Bio-)Sensors for Skin Grafts and Skin Flaps Monitoring | Ozsoylu, D. et al. | 2023 | Sensors and Actuators Report | ||||||||||
| Association between Organochlorine Pesticides and Vitamin D in Female Subjects | Brennan, E. et al. | 2023 | Biomedicines | 05/15/2023 | |||||||||
| A blood and bronchoalveolar lavage protein signature of rapid FEV1 decline in smoking-associated COPD | DiLillo, K. et al. | 2023 | Sci Rep. | 05/22/2023 | |||||||||
| Canonical correlation analysis for multi-omics: Application to cross-cohort analysis | Jiang, MZ. et al. | 2023 | PLoS Genet. | 05/22/2023 | |||||||||
| Sex-based differences in cardiovascular proteomic profiles and their associations with adverse outcomes in patients with chronic heart failure | de Bakker, M. et al. | 2023 | Biol Sex Differ. | 05/17/2023 | |||||||||
| Identification of serum biomarkers for necrotizing enterocolitis using aptamer-based proteomics | Mackay, S. | 2023 | Front Pediatr. | 05/31/2023 | |||||||||
| HFrEF subphenotypes based on 4210 repeatedly measured circulating proteins are driven by different biological mechanisms | Petersen, TB. et al. | 2023 | EBioMedicine | 06/14/2023 | |||||||||
| Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism | Iglesias, MJ. et al. | 2023 | Nat Commun | 06/07/2023 | |||||||||
| Renoprotective effects of genetically proxied fibroblast growth factor 21: Mendelian randomization, proteome-wide and metabolome-wide association study | Giontella, A. et al. | 2023 | Metabolism | 06/09/2023 | |||||||||
| Sequence variants affecting voice pitch in humans | Gisladottir, R. et al. | 2023 | Sci Adv. | ||||||||||
| Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality | Oddsson, A. et al. | 2023 | Nat Commun. | 06/10/2023 | |||||||||
| Cardiopulmonary Phenotypes and Protein Signatures in Children With Down Syndrome | DeBoer, E. et al. | 2023 | Clinical Pediatr. (Phila). | 06/12/2023 | |||||||||
| Magnetically Detected Protein Binding Using Spin-Labeled Slow Off-Rate Modified Aptamers | Lu, S. et al. | 2023 | ACS Sens. | 06/10/2023 | |||||||||
| Large scale proteomic studies create novel privacy considerations | Hill, AC. et al. | 2023 | Sci Rep. | The authors of this paper sought to demonstrate the need for similar privacy protections in proteomic research as genomic research already has. Since the discovery that single nucleotide polymorphisms (SNPs) can genetically distinguish individuals, multiple privacy protection policies regarding genetic information have been passed in the United States. Notably, these policies only explicitly address genetic information, leaving proteomics in a grey area and legally unprotected. The authors use limited proteome profiles without peptide sequencing to link specific individuals by using prior independent knowledge of QTLs The authors used the COPDGene and Jackson Heart studies to train a model to predict genotypes based on SomaScan proteomic measurements. The model was validated using the MESA, SPIROMICS, and splits from the COPDGene and Jackson Heart studies. The model identified independent subjects of European ancestry with 83-92% accuracy and African American subjects with ~90% accuracy. The authors determined that the minimum number of protein-pQTL pairs necessary to match a proteome to a genome is 100 pairs. The authors assessed whether newer and larger proteome assays were more or less accurate at identifying genetic profiles. To do so, they split the COPDGene subjects who had 5k data into a 50/50 train-test split and generated a new list of protein-QTL pairs. These protein-QTL pairs were also used to match proteomes and genomes of participants in the ARIC study who have 5k SomaScan data. Identification accuracy improved to_>_98% in COPDGene and ARIC participants. This study is the first to demonstrate on a large scale that proteomic data are not identity protected because an individual proteome can be matched to a specific genome with high accuracy even without protein sequence information. | 06/07/2023 | ||||||||
| Plasma proteomic profiles of pain subtypes in adolescentsand young adults with endometriosis | Sasamoto, S. et al. | 2023 | Hum Reprod | 05/17/2023 | |||||||||
| Evaluation of a New Aptamer-Based Array for Soluble Suppressor of Tumorgenicity (ST2) and N-terminal Pro-B-Type Natriuretic Peptide (NTproBNP) in Heart Failure Patients | Debbs, J. et al. | 2023 | J Cardiovasc Transl Res. | In this study, SomaScan and ELISA assays were used to measure NTproBNP and ST2 and the results and predictive performance of the two methods were compared. N-terminal pro-B-type natriuretic peptide (NTproBNP) and soluble suppressor of tumorgenicity 2 (ST2) are the two most widely used and recommended biomarkers used for the diagnosis and prognosis of heart failure. The SomaScan assay allows for the rapid detection of thousands of proteins simultaneously, including NTproBNP and ST2. Here, the authors wished to test the accuracy of the SomaScan method for detecting NTproBNP and ST2 by comparing the performance to commercial ELISA assays. EDTA plasma samples from participants from the Henry Ford Pharmacogenomic Registry who met Framingham criterion for HF and had an ejection fraction < 50% were analyzed. When ST2 results were compared, the two methods had similar hazard ratios and were statistically significant for predicting all-cause mortality both with and without adjustment to the MAGGIC score for heart failure. Similar results were seen for predicting cardiovascular mortality. The two methods for measuring ST2 had a Spearman correlation of 0.71 and a Pearson correlation of 0.74. To determine whether addition of each assay method for ST2 improved the accuracy of the MAGGIC model for predicting heart failure, ROC curves were generated. The addition of the ELISA ST2 resulted in an AUC of 0.69 and was statistically significant (p = 0.035), while the addition of the SomaScan ST2 resulted in an AUC of 0.68 but was not statistically significant (p = 0.121). When NTproBNP results were compared, the two methods also had similar hazard ratios for all-cause mortality and were statistically significant for predicting all-cause mortality both with and without adjustment to the MAGGIC score for heart failure. Similar results were also seen for predicting cardiovascular mortality. The two methods for NTproBNP had a Spearman correlation of 0.95 and a Pearson correlation of 0.88. The MAGGIC score model was not significantly improved with addition of either method for measuring NTproBNP. This study shows that SomaScan results correlate well with commercial ELISA-based assays for NTproBNP and ST2 and have comparable prognostic abilities for predicting heart failure survival, showing the potential for proteomics and multimarker diagnostic methods in health care. | 05/16/2023 | ||||||||
| Plasma proteomic risk markers of incident type 2 diabetes reflect physiologically distinct components of glucose-insulin homeostasis | Cronje, H. et al. | 2023 | Diabetes | In this study, the authors used the SomaScan 5k to conduct a large-scale proteomics association study of incident type 2 diabetes and longitudinal glucose trajectories. The Cardiovascular Health Study (CHS) is a population-based prospective study investigating cardiovascular disease risk factors in adults aged 65 years or older. The Health, Risk Factors, Exercise Training and Genetics (HERITAGE) is a 20-week, single-arm exercise intervention study investigating genetic and cardiometabolic contributors to endurance exercise response in participants recruited within family units. Plasma samples from CHS and HERITAGE studies were run on the SomaScan v4.0. Cox proportional hazard regression models were used to test associations of aptamers with incident type 2 diabetes. Linear mixed-effect models were used to assess associations of aptamers with 6-year longitudinal fasting glucose levels. Authors also assessed aptamer specificity. 51 proteins were associated with incident type 2 diabetes and all but two of the associated aptamers had published cis pQTLs; 12 have been validated by mass spectrometry, and 7 had strong (P > 0.70) correlations with Olink measurements. Protein associations with longitudinal glucose levels largely reflected those observed in the incident diabetes analyses. In the base model, 59 additional associations were statistically significant. Prospective protein associations were identified in a complementary analysis of multiple glucose homeostasis traits using intravenous glucose tolerance test (IVGTT). 52 significantly associated proteins from the main model were selected and their associations with the following four IVGTT traits in HERITAGE were tested: insulin sensitivity index, acute insulin response to glucose, disposition index, and glucose effectiveness. Insulin sensitivity index, acute insulin response to glucose, disposition index, and glucose effectiveness were respectively associated with 39, 9, 39, and 8 proteins. 90% of significantly associated proteins were associated with at least one IVGTT trait. The study overall observed three patterns of association: 1. Proteins reflecting higher insulin sensitivity were also markers of decreased diabetes risk and vice versa; 2. Proteins relating to pancreatic function had associations with diabetes and insulin secretion but not insulin sensitivity; 3. In the insulin-independent glucometabolic pathways, b-Glucuronidase (GUSB) was most strongly associated with incident diabetes. It is hypothesized that before the onset of overt diabetes, GUSB may be upregulated to compensate for hyperglycemia as the body becomes more insulin resistant. | 05/01/2023 | ||||||||
| The role of inflammation in anxiety and depression in the European U-BIOPRED asthma cohorts | Hou, R. et al. | 2023 | Brain Behav Immun. | In this study, the authors use data and samples from the largest European asthma cohort, the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) study, and utilize the largest proteomic assay on the market, SomaScan, to address the underlying mechanism between inflammation, asthma, anxiety, and depression. Studies have shown that people with asthma are more likely to experience anxiety, psychological distress, and depression which can lead to poor disease management and lower quality of life. Evidence suggests that inflammation is the link between asthma, anxiety, and depression; however, studies have been limited by small sample sizes, poor study design, and a limited number of available inflammatory markers. Here, behavioral data and serum samples from 198 non-smoking patients with severe asthma (SAn), 65 smoking patients with severe asthma (SAs), 61 non-smoking patients with mild-to-moderate asthma (MMA), and 20 healthy nonsmokers (HC) from the U-BIOPRED were analyzed. Average Hospital Anxiety and Depression Scale (HADS) scores for anxiety, depression, and HADS total scores from this cohort revealed a significantly higher levels in the SAn and SAs groups compared to the MMA and HC groups. Proteomic analysis of inflammatory markers revealed significantly higher levels of IL6, CCL18, MCP1, CCL17, and IL8 in the SAn and SAs groups. When looking at correlations between HADS scores and inflammatory markers, significant positive correlations were found between the depression score and IL6, MCP1, CCL18, and CCL17, the anxiety score and CCL17, and the total score and IL6, CCL18, and CCL17. Correlations between inflammatory markers for air flow obstruction and HADS scores were also analyzed, revealing a small negative correlation between eosinophil count and FeNO with depression and total HADS scores in the SAs group. The findings from this study confirmed higher rates of anxiety and depression in patients with severe asthma and using SomaScan found that certain inflammatory cytokines were significantly different in those patients, pointing to a possible underlying mechanism. | 05/03/2023 | ||||||||
| Identification of biomarkers for glycaemic deterioration in type 2 diabetes | Slieker, RC. et al. | 2023 | Nat Commun. | This study aimed to identify biomarkers for glycemic deteroriation in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes: metabolites, lipids and proteins. This represents the first study to use a multiomic approach for biomarker discovery and report systematically how metabolites of different classes impact progression of T2D. Individuals from three cohorts, DCS, GoDARTS and ANDIS were included. Protein data was generated using SomaScan 1.3k. In the 1195 investigated plasma proteins, the levels of 98 were nominally associated with time to insulin in the base model. The protein with the strongest association with time to insulin was GDF-15. Mendelian randomization was performed on six of the identified proteins to investigate casual associations. GDF15 is causally associated with diabetes progression and found a possible causal association for IL-18Ra and FAS. Metabolics data was generated using UHLPC-MS/MS. Two metabolites, Aminoadipic Acid (AADA) and Homocitrulline (Hcit) were significantly associated with diabetes progression. Lipid data was generated using mass spec. Nine lipids were associated with diabetes progression of which eight were associated with increased risk which all belonged to the Triacylglycerol (TAG) class. SomaStrengths: Biomarker identification, top proteins validated using ELISA | 05/03/2023 | ||||||||
| Predicting progression to Alzheimer's disease with human hippocampal progenitors exposed to serum | Maruszak, A. et al. | 2023 | Brain | In this study, the authors develop an in vitro model and a proteomic model using SomaScan data to predict progression of mild cognitive impairment (MCI) to Alzheimer’s disease using serum samples. Early intervention for Alzheimer’s disease is key and changes in hippocampal neurogenesis (HN) have been shown to be promising early markers for Alzheimer’s disease progression; however, results from previous studies have conflicting results on the directionality of those changes. Longitudinal studies are needed to address those discrepancies but are limited by the availability of viable techniques to study living human brains. In this study, an in vitro method to measure changes in HN is developed as a proxy by examining cell proliferation and differentiation of a human hippocampal progenitor cell line treated with longitudinal serum samples from MCI converters and non-converters. Cells treated with serum from MCI converters lead to decreased proliferation, increased cell death and increased neurogenesis. Using this in vitro system, a model was developed combining cell number, markers for cell proliferation, markers for cell differentiation, and education in years that was able to predict progression from MCI to Alzheimer’s with an AUC of 0.967 and an ability to predict disease progression up to 3.5 years before clinical diagnosis. Next, proteomics was employed to similarly explore development of a predictive model for conversion from MCI to Alzheimer’s. Samples were analyzed on SomaScan to measure 3620 unique proteins (4006 different protein epitopes) and, using machine learning, a panel of 15 proteins was identified that could distinguish between serum samples from MCI converters and non-converters with an AUC of 0.77. Pathway and network analysis was also performed on the differentially expressed proteins from the SomaScan data. Canonical pathways identified included Coagulation, Acute phase response signaling, Extrinsic prothrombin activation pathway, FXR/RXR activation, Notch signaling, Superpathway of methionine degradation, and Wnt/_-catenin Signaling. The top three networks identified were “Hematological System Development and Function, Organismal Functions, Organismal Injury and Abnormalities”, “Cell Death and Survival, Embryonic Development, Organismal Development”, and “Cell-to-Cell Signaling and Interaction, Cellular Function and Maintenance, Inflammatory Response”. This study demonstrates promising in vitro serum based models for predicting Alzheimer’s disease progression and provides insights into the underlying mechanisms of the disease in relation to changes in HN. | 05/02/2023 | ||||||||
| High density lipoprotein-associated proteins in non-obese women with and without polycystic ovary syndrome | Butler, A. et al. | 2023 | Front Endocrinol. | 04/26/2023 | |||||||||
| Circulating proteins to predict COVID-19 severity | Su CY. et al. | 2023 | Sci Rep. | 04/17/2023 | |||||||||
| Quantitative proteomic screening uncovers candidate diagnostic and monitoring serum biomarkers of ankylosing spondylitis | Hwang M. et al. | 2023 | Arthritis Res Ther. | 04/11/2023 | |||||||||
| A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures | Govaere O. et al. | 2023 | Nat Metab. | 04/10/2023 | |||||||||
| The 2022 Report on the Human Proteome from the HUPO Human Proteome Project | Omenn G. et al. | 2023 | J Proteome Res. | 04/07/2023 | |||||||||
| An atlas of genetic scores to predict multi-omic traits | Xu Y. et al. | 2023 | Nature | ||||||||||
| Unbiased Human Kidney Tissue Proteomics Identifies Matrix Metalloproteinase 7 as a Kidney Disease Biomarker | Hirohama D. et al. | 2023 | J Am Soc Nephrol. | 04/05/2023 | |||||||||
| Pregnancy-specific responses to COVID-19 revealed by high-throughput proteomics of human plasma | Gomez-Lopez, N. et al. | 2023 | Commun Med (Lond) | 04/04/2023 | |||||||||
| Plasma Proteomic Associations With Incident Ischemic Stroke in Older Adults: The Cardiovascular Health Study | Kalani R. et al. | 2023 | Neurology | 04/04/2023 | |||||||||
| Identification of Protein Biomarkers of the Dietary Approaches to Stop Hypertension Diet in Randomized Feeding Studies and Validation in an Observational Study | Kim H. et al. | 2023 | J Am Heart Assoc. | 04/04/2023 | |||||||||
| Proteomic cardiovascular risk assessment in chronic kidney disease | Deo R. et al. | 2023 | Eur Heart J. | 04/23/2023 | |||||||||
| Proteome and genome integration analysis of obesity | Zhao Q. et al. | 2023 | Chinese Medical Journal | 03/31/2023 | |||||||||
| Supportive Evidence For The Potential For Novel Biodiscovery In Osteoarthritis Through The Stepup Oa Consortium | Perry TA. et al. | 2023 | Osteoarthritis and Cartilage | ||||||||||
| Integrated Analysis of Tracheobronchial Fluid from Before and After Cardiopulmonary Bypass Reveals Activation of the Integrated Stress Response and Altered Pulmonary Microvascular Permeability | Habet V. et al. | 2023 | Yale J Biol Med. | 03/31/2023 | |||||||||
| Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): a comparative diagnostic accuracy study | Vali Y. et al. | 2023 | Lancet Gastroenterol Hepatol. | 03/20/2023 | |||||||||
| Associations between MICA and MICB genetic variants, protein levels, and colorectal cancer: Atherosclerosis Risk in Communities (ARIC) | Wang S. et al. | 2023 | Cancer Epidemiol Biomarkers Prev. | 03/23/2023 | |||||||||
| Lung proteome and metabolome endotype in HIV-associated obstructive lung disease | Samorodnitsky S.et al. | 2023 | ERJ Open Res. | 03/20/2023 | |||||||||
| Plasma gelsolin levels are associated with diabetes, sex, race, and poverty | Hooten NN et al. | 2023 | J Transl Med. | 03/10/2023 | |||||||||
| HDL-Associated Proteins in Subjects with Polycystic Ovary Syndrome: A Proteomic Study | Butler A. et al. | 2023 | Cells | 03/09/2023 | |||||||||
| Proteomic basis of mortality resilience mediated by FOXO3 longevity genotype | Donlon T. et al. | 2023 | Geroscience | 03/07/2023 | |||||||||
| Coagulation factor dysregulation in polycystic ovary syndrome is an epiphenomenon of obesity | Moin ASM. et al. | 2023 | Clin Endocrinol. (Oxf) | 03/01/2023 | |||||||||
| Exhaled biomarkers in adults with non-productive cough | Emilsson OI, et al. | 2023 | Respir Res. | 03/01/2023 | |||||||||
| SOMAscan Proteomics Identifies Novel Plasma Proteins in Amyotrophic Lateral Sclerosis Patients | Berrone, E. et al. | 2023 | Int J Mol Sci. | 01/18/2023 | |||||||||
| APOL1 Kidney Risk Variants and Proteomics | Chen, TK. et al. | 2022 | Clin J Am Soc Nephrol. | 05/17/2022 | |||||||||
| HLA-A, HSPA5, IGFBP5 and PSMA2 Are Restriction Factors for Zika Virus Growth in Astrocytic Cells | Sher, A. et al. | 2022 | Viruses | 12/29/2022 | |||||||||
| 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 | ||
| 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 | ||
| 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 | Li, Shimena | 2023 | J Trauma Acute Care Surg | 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. | 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 | Choung, RS. 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-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. 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 | |||||||
| 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 | |||||||
| 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 | |||||||
| 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 | Sharma, M, 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 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 = 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. 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 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 /=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 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 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 |