Modification of coronary artery disease clinical risk factors by coronary artery disease polygenic risk score

Background: The extent to which the relationships between clinical risk factors and coronary artery disease (CAD) are altered by CAD polygenic risk score (PRS) is not well understood. Here, we determine whether the interactions between clinical risk factors and CAD PRS further explain risk for incident CAD. Methods: Participants were of European ancestry from the UK Biobank without prevalent CAD. An externally trained genome-wide CAD PRS was generated and then applied. Clinical risk factors were ascertained at baseline. Cox proportional hazards models were fitted to examine the incident CAD effects of CAD PRS, risk factors, and their interactions. Next, the PRS and risk factors were stratified to investigate the attributable risk of clinical risk factors. Findings: A total of 357,144 individuals of European ancestry without prevalent CAD were included. During a median of 11.1 years of follow-up (interquartile range 10.4–14.1 years), CAD PRS was associated with 1.35-fold (95% confidence interval [CI] 1.332–1.368) risk per SD for incident CAD. The prognostic relevance of the following risk factors was relatively diminished for those with high CAD PRS on a continuous scale: type 2 diabetes (hazard ratio [HR]_interaction 0.91, 95% CI_interaction 0.88–0.94), increased body mass index (HR_interaction 0.97, 95% CI_interaction 0.96–0.98), and increased C-reactive protein (HR_interaction 0.98, 95% CI_interaction 0.96–0.99). However, a high CAD PRS yielded joint risk increases with low-density lipoprotein cholesterol (HR_interaction 1.05, 95% CI_interaction 1.04–1.06) and total cholesterol (HR_interaction 1.05, 95% CI_interaction 1.03–1.06). Conclusion: The CAD PRS is associated with incident CAD, and its application improves the prognostic relevance of several clinical risk factors. Funding: P.N. (R01HL127564, R01HL151152, and U01HG011719) is supported by the National Institutes of Health.