Genetic Risk Could Guide Heart Disease Prevention

Damian McNamara

March 10, 2017

LA JOLLA, California — The use of genetic sequencing to identify which patients would benefit most from aggressive statin therapy for the primary prevention of a heart attack could soon be a clinical reality. And the discovery of genetic mutations associated with cardiovascular disease — but not linked to any known risk factors — opens the possibility of novel therapies to help people cut the risk for future events.

"Among those at high genetic risk, statins confer a greater benefit for primary prevention of coronary heart disease," said Sekar Kathiresan, MD, from Massachusetts General Hospital in Boston and the Broad Institute in Cambridge.

Dr Kathiresan and his colleagues demonstrated this in a recent study looking at 57 genetic variants associated with coronary heart disease in 10,456 patients (Circulation. Published online February 21, 2017). They found that the relative risk reduction conferred by statin therapy was greater in patients at high genetic risk than in those at lower risk (44% vs 24%)

"I think this is the first statin study in which one subgroup benefits more than another. Almost all other previous subgroup analyses have shown a very consistent response to statin therapy," he said here at the 10th Future of Genomic Medicine Conference.

"This has some clinical implications," he added. For example, the number needed to treat with statins to see a benefit is lower for people at high genetic risk than for those at low risk (13 vs 37).

"This introduces a concept that is emerging — stratifying prevention — and the use of the genome as a tool to identify a subset of individuals who may need earlier intervention, particularly more aggressive intervention," said Dr Kathiresan.

Despite some calls to give statin therapy to everyone, including the well-known adage that statins should be added to the drinking water, there are risks associated with it, he pointed out.

 
There remain a lot of questions about which healthy people should start a statin for primary prevention.
 

"Statins are highly effective in reducing risk of cardiovascular disease, and are actually underused overall, in my opinion," said Daniel Rader, MD, from the University of Pennsylvania Perelman School of Medicine in Philadelphia. "But there remain a lot of questions about which healthy people should start a statin for primary prevention. This is particularly true for younger people — say those under 40 — for whom the risk calculators are pretty useless."

Advances like this "could expand the number of people considered for statin therapy in a targeted manner," he told Medscape Medical News. "In the era of genomic medicine, this approach could be very important to guide the use of a preventive therapy like statins."

However, he added, "I don't favor the concept that people who appear to be at higher risk based on traditional risk factors would be spared a statin because of a low genetic risk score."

Genetics Raise Possibility of Unknown Risk Factors

In another study Dr Kathiresan was involved in, 55 gene regions were identified in which variants are associated with increased risk (Nat Genet. 2015;47:1121-1130). The genome-wide association meta-analysis of 1000 genomes related to coronary artery disease supports the idea that each of a large number of genetic risk factors contribute moderately to risk.

Not surprisingly, some of the genetic variants were associated with well-known risks, like low-density-lipoprotein cholesterol and inflammation. "What is somewhat surprising is that more than 60% of the gene variants don't relate to known risk factors, which suggests there is a lot of new biology to be explored and understood regarding the etiology of atherosclerosis," Dr Kathiresan said.

"The fact that more than half of the 55 loci across the genome associated with coronary artery disease are not associated with known risk factors is surprising and encouraging," Dr Rader said. "It suggests that there is a lot more to learn about the specific pathways that lead to coronary artery disease. Even more important, some of these pathways are likely to present targets for therapeutic intervention."

"This is beautiful work," said Eric Topol, MD, founder and director of the Scripps Translational Science Institute in La Jolla, California, and editor-in-chief of Medscape. He asked Dr Kathiresan when most people would know their genetic risk profile for coronary artery disease.

"According to your work and others, soon," Dr Kathiresan replied. It is the "whole diagnostics issue" that is limiting our ability to detect "this polygenic risk based on these 55 polymorphisms."

There are already many blood tests for predicting risk, so payers are skeptical about another assay and need to be convinced that it adds value. "It's not a technology issue, and not even that much of a cost issue. It's mostly about reimbursement," he explained. However, "with those data in hand, we may be able to develop a test more rapidly."

Dr Kathiresan reports that he is a consultant for Quest Diagnostics and has received a research grant from Bayer Healthcare. Dr Rader has disclosed no relevant financial relationships. Dr Topol has served or is serving as a director, officer, partner, employee, advisor, consultant, or trustee for Apple, AltheaDX, Biological Dynamics, Dexcom, Edico Genome, GenapSys, Gilead Sciences, Google, Illumina, Molecular Stethoscope, Myokardia, Quest Diagnostics, and Walgreen Company; and has received research grants from the National Institutes of Health and the Qualcomm Foundation.

10th Future of Genomic Medicine (FOGM) Conference. Presented March 2, 2017.

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