Genetics of coronary artery disease in the 21st century.

Coronary artery disease (CAD) is still the number-one killer in the world, and clinical trials indicate that it is preventable. Mortality and morbidity can be reduced by at least 30% to 40% by treating known risk factors. Genetic susceptibility is claimed to account for 50% of predisposition. The challenge of preventing CAD in this century, as claimed by some investigators, will require a more comprehensive prevention and treatment of environmental and genetic risk factors. Part of that challenge has been met by genome-wide association studies, which have identified 36 genetic variants with increased risk for CAD. All of these genetic variants have reached genome-wide significance (5 × 10(-8) ) and replicate in independent populations with large sample sizes. More than 50% of these variants occur in >50% of the population, with 10 occurring in >75% of the population. The challenge and the opportunity lie in the observation that >66% of these risk variants do not mediate their risk through known conventional risk factors. These results suggest that genetic predisposition for CAD is conferred by common DNA variants and many factors contributing to the pathogenesis of CAD are yet to be determined. Comprehensive prevention of CAD will most likely require combating genetic and environmental risk factors. We are on the cusp of genetic screening, and new therapeutic targets are becoming available to manage both genetic and environmental risk factors for CAD.