ROLE OF GENETICS IN CORONARY ARTERY DISEASE (CAD) - MANAGEMENT AND PREVENTION

Abstract

The incidence of Coronary artery disease (CAD) decreased significantlyfollowing implementation of primary and secondary prevention strategies likepromotion of healthy life style, cessation of smoking, positive changes in nutritionand more emphasis on physical activity besides effective medical treatment like1,2 platelet inhibitors and Statins in the later part of last century. Improvedapplication of established primary prevention strategies undoubtedly has thepotential to further reduce the incidence of CAD.

The exact mechanism linking genetic variation at 9p21 to the risk of CAD remains uncertain, although several sets ofobservations at the population level and in the laboratory have helped to point to the possibilities. Firstly, exactly same variantshave been linked to extra cardiac atherosclerosis like carotid plaque, ischemic stroke, and peripheral arterial disease,suggesting that the locus predisposes to atherosclerosis in all vascular beds. Secondly, same variants have been linked to both19 abdominal aortic and intracranial arterial aneurysms, implying that the cells that are affected are in the vessel wall of the artery.Thirdly, evidence suggests that the SNPs in the high-risk region disrupt or create transcription factor binding sites that alter theexpression levels, or the relative abundance of different transcripts of the noncoding ribonucleic acid, ANRIL, which in turnaffects the expression levels of CDKN2B and/or 2A. The protein products of these 2 genes, p15INK4a and p16 INK4a, then alterthe function of macrophages and/or vascular smooth muscle cells, facilitating the formation of atherosclerotic plaque. Fourthly,animal model studies suggest that these effects could involve increased proliferation and reduced apoptosis of resident19 macrophages and/or vascular smooth muscle cells.

To conclude, we are entering a new exciting era as we can use genetic risk variants for the prevention and management ofcoronary artery disease (CAD). Current knowledge pertaining to 60 susceptibility loci identified for CAD confirms theimportance of established risk factors and many novel causal pathways. This will surely improve our understanding of geneticbasis of CAD and hopefully open the door to development of new therapeutic agents in the future. Mendelian randomizationstudies have enhanced our understanding of causal relationship between CAD-related traits. This has further highlighted thepotential benefits of long-term modifications of risk factors. Genetic risk scores of CAD are important both as prognostic andpredictive markers. This may also change the approach to delivery of established prevention strategies.