Polygenic Risk and Coronary Artery Disease Severity.

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 (PRS_CHD) with multiple measures of coronary artery disease (CAD) severity. We assessed the joint associations of PRS_CHD and pathogenic/likely pathogenic variants in 3 familial hypercholesterolemia genes, with CAD severity. We performed mediation analyses to explore whether CAD severity mediated the association of PRS_CHD with prevalent coronary heart disease and incident myocardial infarction.

Results: A 1-SD increase in PRS_CHD was associated with multiple measures of CAD severity, including the log Gensini score (β, 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 PRS_CHD (β, 0.21 [95% CI, 0.03-0.38]). A 1-SD increase in PRS_CHD 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: PRS_CHD was associated with multiple measures of CAD severity. The association of PRS_CHD with incident myocardial infarction was almost fully mediated by CAD severity, indicating a considerable genetic overlap between the 2 phenotypes.