Genetic Risk Stratification Will Enhance Primary Prevention of Coronary Artery Disease

Abstract

Coronary artery disease, the number one cause of death in the world, is highly amenable to primary and secondary prevention. Primary prevention is limited because of lack of biomarkers to detect CAD in its asymptomatic phase. Conventional risk factors such as hypertension, are not evident until the 6th or 7th decade, which may be late for primary prevention particularly in males. The recent discovery of genetic risk variants for CAD has the potential through risk stratification to detect individuals most appropriate for primary prevention. First, genetic risk accounts for about 50% of predisposition to CAD; second, it is determined at conception and not influenced by age since DNA does not change in one’s lifetime. Thirdly, genetic risk can be determined at any time from birth onward which is close to ideal for early primary prevention. A review of the literature show genetic risk can be summarized in a single number, referred to as polygenic risk score (PRS), and used to risk stratify for CAD. The PRS has been evaluated in over 1 million individuals and those in the top 20% exhibit a one-to-four-fold greater risk for CAD than those in the bottom 20%. More importantly, clinical studies have shown that decreasing plasma LDL-C or modifying lifestyle decreases the genetic risk for CAD by 50%. The polygenic risk score, obtained from a single blood sample, does not need to be repeated in one’s lifetime. Furthermore, the genetic risk captured by the PRS is relatively independent of the conventional risk factors including family history. The current PRS was determined primarily in individuals of European decent which can be a limitation to its use in other ethnic groups. However, results of trials ongoing in several ethnic groups will soon be available. We propose primary prevention to be initiated early in life in individuals in the top 20% of the PRS. The test is relatively inexpensive and generic drug therapy is also inexpensive. The use of the PRS to risk stratify for CAD would be a paradigm shift for implementation of early primary prevention of CAD.