Abstract 23: Sexual Dimorphism In Genetic Associations Of Testosterone And Sex-hormone Binding Globulin With Coronary Heart Disease

Abstract

Introduction: Men have higher prevalence and mortality of coronary heart disease (CHD) than women. Sex differences in associations of testosterone (T) and sex-hormone binding globulin (SHBG) with CHD risk have been recognized. But mechanisms underlying sex differences in CHD are unknown. Hypothesis: Genetic regulations of T and SHBG may differ by sex; such genetic heterogeneity may contribute to sex differences in CHD. Methods: We carried out a sex-stratified genome-wide association study for T, SHBG, and CHD in 187,888 men and 221,014 women from the UK Biobank, to identify sex-specific ( P <5х10 -8 in one sex and P ≥5х10 -8 in the other) and sex-differed ( P <5х10 -8 in both sexes but effects differed significantly by sex) loci for each trait. Plasma T and SHBG were measured by immunoassay. Genetic correlations were estimated using linkage disequilibrium score regressions. We used cross-traits meta-analyses to identify loci that coregulate a biomarker (T or SHBG) and CHD. Results: The median T levels in men were 10-12 times higher than that in women across all age groups. Women had higher SHBG levels. We identified 344 sex-specific/sex-differed loci for T and 89 for SHBG ( Fig. A ). Genetic correlations between sexes were 0.02 for T, suggesting mostly sex-specific genetic regulation, and were 0.86 for SHBG and 0.94 for CHD, suggesting partially sex-differed genetic regulation. We observed a significant inverse genetic correlation between T and CHD in men ( r g =-0.15; P =1.4х10 -5 ) but not in women. The inverse genetic correlation between SHBG and CHD was stronger in women ( r g =-0.33; P =5.2х10 -11 ) than men ( r g =-0.18; P =2.8х10 -7 ). We identified 31 sex-specific loci coregulating T and CHD (26 for men and 5 for women), and 48 sex-specific loci coregulating SHBG and CHD (35 for men and 13 for women) ( Fig. B ). Tissue-specific gene expression regulations at some loci (e.g. LPA ) were also differed by sex ( Fig. C ). Conclusions: The between-sex heterogeneity in genetic coregulations of T and SHBG with CHD may contribute to the sex-differences in CHD etiology.