Abstract / Summary
Background: Among individuals with coronary artery disease (CAD), clinical risk factors are used to identify individuals warranting treatment intensification and enrich events in clinical trials. The extent to which genetic factors can augment this framework is not well understood. Methods: We deeply phenotyped sequenced participants with recurrent CAD within the Mass General Brigham Biobank and characterized their genetic risk by CAD polygenic risk score (PRS). We used multivariate logistic regression modeling to assess the association between genetic and clinical risk factors with recurrent events and evaluated cumulative incidence across a range of risk factors. Lastly, we conducted genome-wide association testing of recurrent CAD and effect size heterogeneity testing for lead variants for CAD susceptibility. Results: Among 7105 participants with prevalent CAD, 2574 (36%) developed recurrent events over a median follow-up of 15 [10–20] years. A CAD PRS was associated with increased risk of recurrent CAD (OR 1.25 per SD; 95% CI 1.19–1.31; P < 0.001) comparable to clinical risk factors. Among individuals at the top quintile of CAD PRS and high clinical risk, 39 (95% CI 36–42)% had recurrent events at five years post-study enrollment. On average, high genetic risk added 6.06 (3.60)% to the cumulative incidence of recurrent CAD across a range of clinical risk factors. Genetic variants associated with CAD susceptibility were weakly correlated with recurrence ( r = 0.31). Conclusions: High genetic susceptibility to CAD is a risk factor for disease recurrence independent of conventional clinical risk factors and may serve as a tool to augment secondary prevention guidelines.