Cholesterol-Related Gene Variants Impart Benefits, Point to New Drugs

From the DNA of nearly 300,000 veterans, scientists have singled out a handful of genetic mutations that not only govern levels of cholesterol, but may also inform the development and use of drugs for cardiovascular disease and diabetes, or abdominal aortic aneurysms.

The study scientists, led by a group at Stanford University School of Medicine, and the Palo Alto Veteran Affairs Health Care System, have already identified one marketed drug, cilostazol, that mimics the mutation in one of the genes, PDE3B, and which they suggest could be studied as a potential candidate for lowering the incidence of heart disease.

“All of these mutations are loss-of-function variants, meaning they either substantially diminish or stop the function of the gene altogether,” explains Derek Klarin, M.D. a clinical fellow in surgery at Harvard Medical School. “That makes a good case for developing a drug that copies what the mutation does; if a faulty PDE3B gene decreases risk for heart disease, it could be promising pharmaceutical inspiration. In this study, the PDE3B mutation was associated with lower triglycerides, higher HDLs, and a 20% lower risk of heart disease.” Dr. Karlin is co-lead author of the researchers’ published paper in Nature Genetics, which is titled, “Genetics of blood lipids among ~300,000 multi- ethnic participants of the Million Veteran Program.”

Blood concentrations of low-density lipoprotein cholesterol (LDL-C), triglycerides, total cholesterol, and high-density lipoprotein cholesterol (HDL-C) are heritable risk factors for atherosclerotic heart disease, the researchers write. Genome-wide association studies (GWAS) have identified at least 268 genetic loci that influence trigylceride and cholesterol levels, and many are being investigated as potential drug targets. However, as the team continues, “off-target effects have dampened enthusiasm for some of these molecules.”

They note the need to more fully understand the full spectrum of clinical consequences of genetic variants, using approaches such as phenome-wide association studies (PheWAS), which can shed light on potential unintended effects, as well as novel therapeutic indications for existing drug molecules.

Large-scale biobanks linked to electronic health records are helping scientists to link genetic variation to the risk of a wide range of diseases. For their studies on cholesterol and heart disease, Dr. Klarin and colleagues turned to the Million Veteran Program (MVP), which was established in 2011 as a research initiative to study the link between genes and disease among U.S. military veterans. The team first carried out a GWAS to link genetic variants, blood cholesterol levels, and cardiovascular health, in 297,626 veterans of different ethnicities. They then validated their findings using data from the Global Lipids Genetics Consortium.  The results picked out 188 of the 268 loci that have previously been associated with lipid levels, as well as an additional 118 novel loci.”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,” comments senior author Tim Assimes, M.D., Ph.D., associate professor of cardiovascular medicine. “From there, you can figure out what the best potential drug targets are.”

To home in on the effects on lipid levels of mutations that switch off their genes – predicted loss of function (pLOF) variants – the team subsequently combined their GWAS data with the results from a transcriptome-wide association study (TWAS), and phenome-wide association studies (PheWAS).

The combined, honed results highlighted one novel pLOF mutation in the gene PDE3B, which appeared to lower triglyceride levels, raise HDL-C, and protect against the development of coronary artery disease (CAD). The findings also highlighted a pLOF mutation in ANGPTL4, which reduced the risk for type 2 diabetes, and a pLOF mutation in PCSK9 that was linked with a reduced risk of abdominal aortic aneurysm as well as its previously identified link with decreasing the risk of heart disease.

The researchers say their results point to an existing generic drug, cilostazol, as a potential treatment for coronary artery disease, although they acknowledge that further studies will be needed to further investigate any cholesterol-lowering benefits of the drug in a clinical setting. “Amazingly, there’s a cheap, generic drug that I already use to treat my patients for vascular disease which also mimics the effects of the mutation in PDE3B on cholesterol levels, but no one has paid attention to these ‘side effects,'” comments co-lead author Scott Damrauer, M.D., assistant professor of surgery at the University of Pennsylvania and the Corporal Michael Crescenz VA Medical Center in Philadelphia. “The drug is typically only used to treat the symptoms of blockages in leg arteries to improve how far people with vascular disease can walk without pain. The next step is to investigate whether that same drug could wear multiple therapeutic hats … The genetics help suggest that this drug can decrease the risk of heart disease by lowering triglycerides, but it’s not proof,” he adds. “I would not prescribe it until a large randomized trial is completed with cilostazol or a related drug looking specifically at heart disease outcomes.”

There are also drugs on the market for reducing heart attack risk, which mimic the effects of the PCSK9 mutation, but it’s not known whether their use also leads to reduced numbers of aneurysms. And as yet, there have been no large-scale clinical-trials of any drugs that recapitulate the effects of the ANGPTL4 mutation.