Amit V. Khera, M.D., Connor A. Emdin, D.Phil., Isabel Drake, Ph.D., Pradeep Natarajan, M.D., Alexander G. Bick, M.D., Ph.D., Nancy R. Cook, Ph.D., Daniel I. Chasman, Ph.D., Usman Baber, M.D., Roxana Mehran, M.D., Daniel J. Rader, M.D., Valentin Fuster, M.D., Ph.D., Eric Boerwinkle, Ph.D., Olle Melander, M.D., Ph.D., Marju Orho-Melander, Ph.D., Paul M Ridker, M.D., and Sekar Kathiresan, M.D.
NEJM November 13, 2016DOI: 10.1056/NEJMoa1605086
Both genetic and lifestyle factors are key drivers of coronary artery disease, a complex disorder that is the leading cause of death worldwide.1 A familial pattern in the risk of coronary artery disease was first described in 1938 and was subsequently confirmed in large studies involving twins and prospective cohorts.2-6 Since 2007, genomewide association analyses have identified more than 50 independent loci associated with the risk of coronary artery disease.7-15 These risk alleles, when aggregated into a polygenic risk score, are predictive of incident coronary events and provide a continuous and quantitative measure of genetic susceptibility.16-24
Much evidence has also shown that persons who adhere to a healthy lifestyle have markedly reduced rates of incident cardiovascular events.25-30 The promotion of healthy lifestyle behaviors, which include not smoking, avoiding obesity, regular physical activity, and a healthy diet pattern, underlies the current strategy to improve cardiovascular health in the general population.31
Many observers assume that a genetic predisposition to coronary artery disease is deterministic.32 However, genetic risk might be attenuated by a favorable lifestyle. Here, we analyzed data for participants in three prospective cohorts and one cross-sectional study to test the hypothesis that both genetic factors and baseline adherence to a healthy lifestyle contribute independently to the risk of incident coronary events and the prevalent subclinical burden of atherosclerosis. We then determined the extent to which a healthy lifestyle is associated with a reduced risk of coronary artery disease among participants with a high genetic risk.