A genetic risk score for CAD, psychological stress, and their interaction as predictors of CAD, fatal MI, non-fatal MI and cardiovascular death

BACKGROUND: Psychological stress is an independent risk factor for cardiovascular disease (CVD), but the mechanism by which stress is associated with CVD is not entirely understood. Although genetic factors are implied in both stress responsivity and cardiovascular reactivity, no studies to date have investigated their interactions with stress for cardiovascular end points. The objective was to elucidate the association and interactions between a genetic risk score (GRS), individual genetic variants and stress for three cardiovascular end points: coronary artery disease (CAD), fatal myocardial infarction (MI), non-fatal MI, and cardiovascular death. METHODS AND FINDINGS: 18,559 participants from the Malmö Diet Cancer Study, a population-based prospective study, were included in the analyses. Cox proportional hazards regression models were used and adjusted for a large number of known predictors of cardiovascular end points. Mean follow-up time in years was 14.6 (CAD; n = 1938), 14.8 (fatal MI; n = 436), 14.8 (non-fatal MI; n = 1108), and 15.1 (cardiovascular death; n = 1071) respectively. GRS was significantly associated with increased risks of CAD (top quartile hazard ratio [HR], 1.72; 95% confidence interval [CI], 1.51-1.96), fatal MI (top quartile HR, 1.62; 95%CI, 1.23-2.15), non-fatal MI (top quartile HR, 1.55; 95%CI, 1.31-1.84), and cardiovascular death (top quartile HR, 1.29; 95%CI, 1.08-1.53). Stress was not independently associated with any end point and did not interact with GRS. Four individual genetic variants interacted unfavorably with stress for end points with mortality outcomes. CONCLUSION: A GRS composed of 50 SNPs and predictive of CAD was found for the first time to also strongly predict fatal MI, non-fatal MI and cardiovascular death. A stress-sensitive component of the GRS was isolated on the basis of individual genetic variants that interacted unfavorably with stress.