Genome-Wide European Ancestry Study Identifies Coronary Artery Disease-Associated Loci Through Gene-Sex Hormone Interaction.

Background: Although sex differences in coronary artery disease (CAD) risk have been observed, little is known about the role of sex hormones in CAD genetics. Accounting for sex hormone levels may help identify CAD-risk loci and extend our knowledge of its genetic architecture.

Methods And Results: A total of 365 662 individuals of European ancestry enrolled in the UK Biobank were considered. Genetic interaction of total testosterone, bioavailable testosterone, and SHBG (sex hormone-binding globulin) were evaluated. Gene-environment interactions in millions of samples software was used to conduct sex-stratified genome-wide interaction analysis with prevalent CAD as the outcome. Participant age at enrollment and principal components 1 to 10 were adjusted as covariates. We identified 45 loci in men and 8 loci in women that reached genome-wide significance ( < 5 × 10) for CAD. Ten of the loci identified (5 loci in both men and women) were through joint effects and would not have been picked up using a traditional genome-wide association study. Two of the joint effect loci in women were independently identified with significant single nucleotide polymorphism-total testosterone interactions.

Conclusions: This genome-wide gene-sex hormone interaction study identified genomic-risk loci that may contribute to the differential CAD risk between men and women, which otherwise would not have been discovered in a traditional genome-wide association study solely including marginal genetic effects.