Genetically Predicted Sex Hormone Binding Globulin and Ischemic Heart Disease: A Sex-Specific Mendelian Randomization Study

Abstract

Background: Ischemic heart disease (IHD) is a leading contributor to global burden of disease. Men are more vulnerable to IHD than women, which could be partly due to sex hormones. Sex hormone binding globulin (SHBG) which lowers circulating testosterone might protect men against IHD. SHBG may also affect IHD independent of testosterone, which has not previously been examined. Methods: To assess the sex-specific role of SHBG in IHD, in univariable Mendelian randomization (MR), we used sex-specific, genome-wide significant genetic variants (343 for men and 328 for women) to predict SHBG, and examined their association with IHD (25,409 cases in men and 12,511 cases in women) in the UK Biobank. We also replicated using genetic instruments from Japanese men and applied to Biobank Japan. To assess the role of SHGB independent of testosterone in men, we used multivariable MR controlling for testosterone, additionally including 125 SNPs for free testosterone. Findings: Genetically predicted SHBG was associated with lower IHD risk in men (odds ratio (OR) 0.77 per standard deviation, 95% confidence interval (CI) 0.69 to 0.87), but not in women. The estimates were robust to different genetic instruments and similar in Japanese. The inverse association remained after controlling for testosterone in men (OR 0.78, 95% CI 0.70 to 0.87). Interpretation: SHBG might lower the risk of IHD in men, with a role independent of testosterone. Exploring intervention strategies that increase SHBG and understanding the underlying pathways is important for targeting IHD treatments to take account of sex disparity. Funding Information: None. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This research has been conducted using the UK Biobank Resource under Application number 42468. No original data were collected for the MR study. Ethical approval for each of the studies included in the investigation can be found in the original publications (including informed consent from each participant). The UK Biobank has already received ethical approval from the Research Ethics Committee and participants provided written informed consent. The analysis of other publicly available summary statistics does not require additional ethical approval.