Genetic Risk Stratification and Prevention of CAD: An Idea Whose Time Is Now.

Abstract

The latter part of the 20th century was the golden age for genetics, as it focused on linkage analysis in families and discovered genes responsible for >4000 single gene disorders (1). Cardiovascular success included familial hypertrophic cardiomyopathy and atrial fibrillation, as well as Wolff–Parkinson–White, the long QT, and Brugada syndromes (1). A notable feature of the 21st century will be the breakthrough in genetics of polygenic disorders. In the year 2007, we and the Icelandic group simultaneously and independently discovered the first genetic risk variant (9p21) for coronary artery disease (CAD).2 This was followed closely by successes of the Wellcome Trust Group and many other investigators (2). An international collaboration was established to analyze and perform genome-wide association studies for CAD with a sample size of over 200000 cases and controls, referred to as the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. This collaboration provided the necessary expertise, resources, and sample size to identify over 60 genetic variants predisposing to CAD with more to come (2). All these variants are genome-wide significant ( P < 5 × 10−8) and have been replicated in independent populations. This information provided proof of concept for the observations made by epidemiologists decades ago, namely, 40% to 60% of risk for CAD is inherited. Genetic risk variants for CAD, as for all polygenic disorders, have several features in common: they occur commonly, each variant imparts only minimal risk, they occur primarily in nonprotein coding regions of the genome, and the total risk burden for CAD is proportional to the number of independent genetic risk variants rather than the intensity of any one variant. CAD, a pandemic disease, is the number one killer in men and women in the US and throughout the world (2). Someone born today in the …