Researchers from the Stanford University School of Medicine and the Veterans Affairs Palo Alto Health Care System have discovered certain gene mutations that may lower the risk of certain health conditions, including one that could affect coronary heart disease.
For the study, published in Nature Genetics, data was collected from the Million Veteran Program (MVP) on 297,626 veterans with at least one blood lipid measurement, (black participants, 57,332; Hispanic participants, 24,743). Analyses focused specifically on three genes that targeted different health risks.
Cholesterol-related gene variants impart benefits: PCSK9 (abdominal aortic aneurysm), ANGPTL4 (T2D) and PDE3B (TG and CAD). Opportunity to new therapies https://t.co/Ho2RGlg3lh
— Thomas Dayspring (@Drlipid) October 2, 2018
“Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease),” the study authors wrote. PCSK9 had also previously been known to lower heart disease risk.
The team tested about 32 million variants for association with lipid levels and was able to confirm 188 genetic cholesterol markers they were already aware of and 118 new ones. They used phenomewide screen, or PheWAS, to analyze rare, specific mutations. They ultimately were most interested in PCSK9, ANGPTL4, and PDE3B mutations.
The power of genetic discovery through the Million Veteran Program . Thank you, US Veterans for making these discoveries possible and @EricTopol for highlighting our efforts. Wonderful collaboration involving multiple VAs and affiliated academic institutions. https://t.co/m0BSSmUSZr
— Tim L. Assimes, MD PhD (@tassimes) October 1, 2018
“The idea is to use genetic data linked to electronic health records from a very large number of individuals to find genetic variants that simultaneously improve lipid profiles and protect against cardiovascular disease,” said Tim Assimes, MD, PhD, associate professor of cardiovascular medicine and one of the study’s lead authors. “From there, you can figure out what the best potential drug targets are.”
“All of these mutations are loss-of-function variants, meaning they either substantially diminish or stop the function of the gene altogether,” said Derek Klarin, MD, clinical fellow in surgery at Harvard, another lead study author.
A large-scale analysis of DNA from nearly 300,000 U.S. military veterans could lead to the development of new therapies for cardiovascular disease, diabetes and aortic aneurysms (via @GENbio) https://t.co/QK6qdKM2KD
— Harvard Medical School (@harvardmed) October 3, 2018
Cilostazol is a drug already available that mutates the PDE3B gene. But Assimes said that the study results do not suggest cilostazol be prescribed for that purpose.
“The genetics help suggest that this drug can decrease the risk of heart disease by lowering triglycerides, but it’s not proof,” he said. “I would not prescribe it until a large randomized trial is completed with cilostazol or a related drug looking specifically at heart disease outcomes.