• Amit V Khera, Connor A Emdin, Isabel Drake, Pradeep Natarajan, Alexander G Bick, Nancy R Cook, Daniel I Chasman, Usman Baber, Roxana Mehran, Daniel J Rader, Valentin Fuster, Eric Boerwinkle, Olle Melander, Marju Orho-Melander, Paul M Ridker, and Sekar Kathiresan.
• From the Center for Human Genetic Research and Cardiology Division, Massachusetts General Hospital (A.V.K., P.N., S.K.), and the Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital (N.R.C., D.I.C., P.M.R.), Boston, and the Program in Medical and Population Genetics, Broad Institute, Cambridge (A.V.K., C.A.E., A.G.B., S.K.) - all in Massachusetts; the Department of Clinical Sciences, Lund University, Malmö, Sweden (I.D., O.M., M.O.-M.); the Cardiovascular Institute, Mount Sinai Medical Center, Icahn School of Medicine at Mount Sinai, New York (U.B., R.M., V.F.); Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (D.J.R.); and the University of Texas Health Science Center School of Public Health, Houston (E.B.).
• N. Engl. J. Med. 2016 Dec 15; 375 (24): 234923582349-2358.

BackgroundBoth genetic and lifestyle factors contribute to individual-level risk of coronary artery disease. The extent to which increased genetic risk can be offset by a healthy lifestyle is unknown.MethodsUsing a polygenic score of DNA sequence polymorphisms, we quantified genetic risk for coronary artery disease in three prospective cohorts - 7814 participants in the Atherosclerosis Risk in Communities (ARIC) study, 21,222 in the Women's Genome Health Study (WGHS), and 22,389 in the Malmö Diet and Cancer Study (MDCS) - and in 4260 participants in the cross-sectional BioImage Study for whom genotype and covariate data were available. We also determined adherence to a healthy lifestyle among the participants using a scoring system consisting of four factors: no current smoking, no obesity, regular physical activity, and a healthy diet.ResultsThe relative risk of incident coronary events was 91% higher among participants at high genetic risk (top quintile of polygenic scores) than among those at low genetic risk (bottom quintile of polygenic scores) (hazard ratio, 1.91; 95% confidence interval [CI], 1.75 to 2.09). A favorable lifestyle (defined as at least three of the four healthy lifestyle factors) was associated with a substantially lower risk of coronary events than an unfavorable lifestyle (defined as no or only one healthy lifestyle factor), regardless of the genetic risk category. Among participants at high genetic risk, a favorable lifestyle was associated with a 46% lower relative risk of coronary events than an unfavorable lifestyle (hazard ratio, 0.54; 95% CI, 0.47 to 0.63). This finding corresponded to a reduction in the standardized 10-year incidence of coronary events from 10.7% for an unfavorable lifestyle to 5.1% for a favorable lifestyle in ARIC, from 4.6% to 2.0% in WGHS, and from 8.2% to 5.3% in MDCS. In the BioImage Study, a favorable lifestyle was associated with significantly less coronary-artery calcification within each genetic risk category.ConclusionsAcross four studies involving 55,685 participants, genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease. Among participants at high genetic risk, a favorable lifestyle was associated with a nearly 50% lower relative risk of coronary artery disease than was an unfavorable lifestyle. (Funded by the National Institutes of Health and others.).

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