Genetic Risk Stratification: Tipping Point for Global Primary Prevention of Coronary Artery Disease

In 2003, Wald and Law1 predicted that coronary artery disease (CAD) would be markedly attenuated if not eliminated. CAD is a preventable disease based on randomized, placebo-controlled clinical trials that consistently showed 30% to 40% reduction in cardiac events with decreased plasma cholesterol.1 Epidemiologists claimed for decades that 40% to 50% of predisposition for CAD is genetic. Discovery of the first genetic risk variant in 2007 has led to an avalanche of >90 genetic risk variants predisposing to CAD, each of genome-wide significance and replicated in independent populations,2 but each with relatively low individual effect sizes. The total individual genetic risk burden for CAD is proportional to the number of genetic risk variants inherited. These variants account for ≈25% of genetic predisposition to CAD, which is less than the predicted 40%, signaling that more genetic risk variants are yet to be discovered. It is interesting to note that only one third of the genetic risk variants for CAD mediate their risk through known conventional risk factors. Exploration of the unknown pathways mediating the risk conferred by these genetic variants is already enabling new insights into the pathogenesis of coronary atherosclerosis (eg, inflammation, lack of protection of high-density lipoprotein cholesterol) and novel targets for the development of specific drugs. A major impetus for our pursuit of genetic risk variants was to better predict those at higher risk for CAD who would benefit most from preventive measures, particularly primary prevention. The genetic …