Background: Psychological stress is an independent risk factor for cardiovascular disease. Susceptibility to stress-mediated cardiovascular events differs between individuals, with genetic factors implied in both stress responsivity and cardiovascular reactivity.
Purpose: The aim of our study was to elucidate the association and interactions between a genetic risk score (GRS) consisting of 50 single nucleotide polymorphisms (SNP), individual genetic variants and psychological stress for three cardiovascular end points: coronary artery disease (CAD), fatal myocardial infarction (MI), and cardiovascular death.
Methods: A total of 18,559 participants from the Malmö Diet Cancer Study who had answered questions on stress, had provided complete genetic information, and without a history of prevalent CAD were included in the analyses. A composite categorical stress variable was constructed from 11 questions measuring job strain using the validated Swedish version of the Demand-Control Model, and one question assessing non-occupational stress.
Cox proportional hazards regression models were used and adjusted for a large number of known predictors of cardiovascular end points.
Results: Mean follow-up time was 14.6, 14.8, and 15.1 years for CAD (n=1938), fatal MI (n=436) and cardiovascular death (n=1071) respectively. Stress was not independently associated with any end point in the multivariable analyses whereas 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), and cardiovascular death (top quartile HR, 1.29; 95% CI, 1.08–1.53).
One-by-one analysis of the 50 SNPs indicated that four individual genetic variants interacted unfavourably with psychological stress. Post-hoc analyses showed that when constructing a stress-sensitive GRS comprised of these four SNPs, high psychological stress became significantly associated with fatal MI (HR, 2.47; 95% CI, 1.44–4.24) and cardiovascular death (HR, 1.77; 95% CI, 1.19–2.63) for individuals in the highest quartile of the stress-sensitive GRS.
Conclusion: A GRS composed of 50 SNPs and predictive of CAD was found for the first time to also strongly predict fatal MI and cardiovascular death. Our results point to a stress-sensitive component of the GRS which could be isolated based on individual genetic variants that interacted unfavourably with stress. Further research on stress-sensitive CAD genetic variants is warranted in order to understand stress-induced cardiovascular reactivity.