Genetically predicted sex hormone binding globulin and ischemic heart disease in men and women: a univariable and multivariable Mendelian randomization study

Jie V Zhao,C Mary Schooling

doi:10.1038/s41598-021-02510-w

Jie V Zhao, C Mary Schooling

Open Access

https://doi.org/10.1038/s41598-021-02510-w

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Abstract

Men are more vulnerable to ischemic heart disease (IHD) than women, possibly due to testosterone. Correspondingly, 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. To assess the sex-specific role of SHBG in IHD, in univariable Mendelian randomization (MR), we used sex-specific, genome-wide significant genetic variants to predict SHBG, and examined their association with IHD 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. Genetically predicted SHBG was associated with lower IHD risk in men [odds ratio (OR) 0.78 per standard deviation, 95% confidence interval (CI) 0.70 to 0.87], and the association was less clear in women. The estimates were similar in Japanese. The inverse association remained after controlling for testosterone in men (OR 0.79, 95% CI 0.71 to 0.88). SHBG might lower the risk of IHD in men, with a role independent of testosterone. Exploring intervention strategies that increase SHBG is important for targeting IHD treatments.

Highlights

Men are more vulnerable to ischemic heart disease (IHD) than women, possibly due to testosterone
In univariable Mendelian randomization (MR), after excluding pleiotropic SNPs related to Low density lipoprotein (LDL)-cholesterol or lipoprotein (a), we used 343 genome-wide significant SNPs for sex hormone binding globulin (SHBG) in men and 330 SNPs for SHBG in women (Supplementary Tables S2 and S3)
One SNP was associated with alcohol drinking and related to LDL-cholesterol, so it was excluded in main analysis (Supplementary Tables S4 and S5). 4 SNPs were related to body mass index (BMI) in men and 2 SNPs were related to BMI in women (Supplementary Tables S2 and S3), which were excluded in sensitivity analysis

Summary

Introduction

Men are more vulnerable to ischemic heart disease (IHD) than women, possibly due to testosterone. To assess the sex-specific role of SHBG in IHD, in univariable Mendelian randomization (MR), we used sex-specific, genome-wide significant genetic variants to predict SHBG, and examined their association with IHD in the UK Biobank. No large RCT examining the effect of SHBG on IHD overall or by sex exists In this situation where experimental evidence is unavailable, a Mendelian Randomization (MR) study design has been increasingly used in recent years as an alternative way to provide unconfounded e stimates[24]. We used univariable MR to examine the role of genetically predicted SHBG in IHD in men and women separately, by applying published, sex-specific, genome-wide significant genetic variants predicting SHBG14 to sex-specific genetic associations with IHD in men and women from the UK B iobank[33]. To examine the role of SHBG independent of testosterone, we used multivariable MR to control for bioavailable testosterone

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