COVID-19:
4. Identify new drug candidates

The SomaScan® assay can point toward drug candidates by providing the missing link between genetics and disease

Highlighting protein “networks” involved in heart disease and diabetes

In this article, researchers from Novartis and the Icelandic Heart Association demonstrated that communication between networks of proteins can explain the connections between genes and complex disorders, such as heart disease and diabetes. They began with an established Icelandic study of aging (AGES-Reykjavik). Participants in AGES-Reykjavik were over 65 and included both healthy adults and those diagnosed with various conditions of old age. The research teams used a custom version of the SomaScan assay to measure the levels of over 4,000 different human proteins in 5,457 blood samples from individuals in the AGES-Reykjavik study. Using advanced computational tools the researchers found that the examined proteins clustered into 27 different groups or “networks”. Each network contained a few central players that were highly connected, and these “hub proteins” seemed to organize interactions and information flow within the network. When investigators incorporated genetic data on AGES participants, they found that the hub proteins were often regulated by genetic variations that had been previously linked to cardiovascular and metabolic diseases, but for which the biological underpinnings were unknown.

Science 2018

Linking GWAS variants to disease with proteomics

Over the past decade, genome-wide association studies (GWAS) have identified thousands of DNA variants that are linked to complex traits and diseases but have not explained exactly why they are important. In the largest study of its kind to-date, an international team led by researchers from the University of Cambridge and Merck used the SomaScan assay to measure the levels of 2,994 plasma proteins and compared those levels with 10.6 million DNA variants across 3,301 healthy individuals of European heritage. They identified 1,927 genetic variants that impact the levels of 1,478 plasma proteins, of which approximately 90% had not been previously reported. Many of the variants act in “trans” (i.e., they lie far from the gene whose activity is altered, typically on different chromosomes). Trans associations are particularly interesting because they can highlight biological connections that are difficult to predict otherwise.

Nature 2018

Finding new connections between gene variants and proteins in Cardiovascular Disease

Changes in protein levels reflect the functional consequences of gene variants and can help establish hereditary causes of disease. Previously, investigators at the Beth Israel Deaconess Medical Center used the SomaScan assay to identify 156 plasma proteins that associated with clinical risk factors for developing cardiovascular disease (CVD)—age, sex, cholesterol, blood pressure, diabetes, and smoking. In this study, the researchers integrated genomic data into their SomaScan-based proteomic profiling and found a number of new connections between gene variants and circulating proteins that are important in CVD. One of the DNA-protein associations led to the discovery that the gene for protein phosphatase 1 (PPM1G) regulates the levels of apolipoprotein E, a cholesterol transporter. This is the first time that PPM1G has been linked to lipid metabolism. The authors have made their gene variant-protein association data publicly available, which should hasten the discovery of additional insights into CVD biology, potential biomarkers and putative drug targets.

Circulation 2018

Identifying novel proteins associated with damage resulting from heart attacks

In this study, researchers at the Novartis Institute for BioMedical Research, Beth Israel Deaconess Medical Center, and Brigham and Women’s Hospital used the SomaScan platform to measure the levels of approximately 5,000 proteins in blood samples taken from patients undergoing a “planned” heart attack, a medical procedure that can help reduce severely overgrown heart muscle. They analyzed plasma taken before and at different time points after the procedure, looking for proteins whose levels changed significantly. Their results not only confirmed findings from a prior study that used an earlier, smaller version of the SomaScan platform, but also identified nearly 150 new proteins, many of which had not been previously associated with heart damage. Twenty-nine of the proteins that were significantly increased within an hour after a planned heart attack were also elevated in patients who suffered “unplanned” heart attacks. The SomaScan assay thus provides opportunities for unbiased discovery of disease markers to improve diagnosis, predict future events, monitor responses to therapies and identify targets for drug development.

Circulation 2017