Sexual Differences in Genetic Predisposition of Coronary Artery Disease

Abstract

Background - The genomic structure that contributes to the risk of coronary artery disease (CAD) can be evaluated as a risk score of multiple variants. However, sex differences have not been fully examined in applications of genetic risk score of CAD. Methods - Using data from the UK Biobank, we constructed a CAD genetic risk score based on all known loci, three mediating trait-based (blood pressure, lipids, body mass index) sub-scores, and a genome-wide polygenic risk score based on 1.1 million variants. The differences in genetic associations with prevalent and incident CAD between men and women were investigated among 317,509 unrelated individuals of European ancestry. We also assessed interactions with sex for 161 individual loci included in the comprehensive genetic risk score. Results - For both prevalent and incident CAD, the associations of comprehensive and genome-wide genetic risk scores were stronger among men than women. Using a score of 161 loci, we observed a 2.4 times higher risk for incident CAD comparing men with high genetic risk to men with low genetic risk, but an 80 percent greater risk comparing women with high genetic risk to women with low genetic risk. (interaction p=0.002). Of the three sub-scores, the blood pressure-associated sub-score exhibited sex differences (interaction p=0.0004 per SD increase in sub-score). Analysis of individual variants identified a novel gene-sex interaction at locus 21q22.11 . Conclusions - Sexual differences in genetic predisposition should be considered in future studies of coronary artery disease, and genetic risk scores should not be assumed to perform equally well in men and women.