Polygenic Risk and Coronary Artery Disease Severity.

ABSTRACT

BACKGROUND: Coronary atherosclerotic burden and adverse coronary heart disease events are related phenotypes with likely shared genetic cause. METHODS: We analyzed 6021 patients with available coronary angiography, genotyping, and exome sequencing data. We tested for associations of polygenic risk scores for coronary heart disease (PRSCHD) with multiple measures of coronary artery disease (CAD) severity. We assessed the interplay between PRSCHD and pathogenic/likely pathogenic variants in 3 familial hypercholesterolemia genes. We performed mediation analyses to explore whether CAD severity mediated the association of PRSCHD with prevalent coronary heart disease and incident myocardial infarction. RESULTS: A 1-SD increase in PRSCHD was associated with multiple measures of CAD severity, including the log Gensini score (ß, 0.31 [95% CI, 0.28-0.33]). Carrying a pathogenic/likely pathogenic familial hypercholesterolemia variant was associated with a higher log Gensini score after adjustment for PRSCHD (ß, 0.21 [95% CI, 0.03-0.38]). PRSCHD was associated with incident myocardial infarction over a mean follow-up of 9.2 years (hazard ratio, 1.20 [95% CI, 1.13-1.27]; P=5×10-10), and the Gensini score mediated 90% of this association. CONCLUSIONS: PRSCHD was associated with multiple measures of CAD severity. The association of PRSCHD with incident myocardial infarction was almost fully mediated by CAD severity, indicating a considerable genetic overlap between the 2 phenotypes.