A genetic basis for coronary artery disease.

CAD and cancer account for over one-half of all deaths in the world. It is claimed that the 21st century is the last century for CAD. This is, in part, because CAD is preventable based on randomized, placebo-controlled clinical trials, which show modifying known risk factors such as cholesterol is associated consistently with 40-60% reduction in morbidity and mortality from CAD. Comprehensive prevention will require modifying genetic risk factors that are claimed to account for 40-60% of predisposition to CAD. The 21st century is meeting this challenge with over 50 genetic risk variants discovered and replicated in large genome-wide association studies involving over 200,000 cases and controls. Similarly, 157 genetic variants have been discovered that regulate plasma lipids including, LDL-C, HDL-C, triglycerides, and total cholesterol. A major finding from these studies is that only 15 of the 50 genetic variants for CAD act through known risk factors. Hence, the pathogenesis of CAD in addition to cholesterol and other known risk factors is due to various other factors, many of which remain unknown. Secondly, genes regulating the plasma triglyceride levels are strongly associated with the pathogenesis of CAD. Thirdly, Mendelian randomization studies show no protection from genes that increase plasma HDL cholesterol. This is contrary to current opinion. These genetic risk variants have provided new targets for the development of novel therapies to prevent CAD. Already a new and potent drug has been developed targeting PCSK9, which is in phase 3 clinical trials and shows great efficacy and safety for prevention of CAD. The 21st century is looking very bright for the prevention of CAD.