Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis

Abstract

<b>Objective</b>: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding. <p><b>Methods</b>: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (N=251,420 women and 212,049 men). Weighted-median, MR Egger, MR-PRESSO and radial MR from summary-level analyses were used for pleiotropy assessment. </p> <p><b>Results</b>: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.08-1.18 per 1-log unit increase in odds of type 2 diabetes) and men (OR 1.21, 95% CI 1.17-1.26 per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy, however, results were similar after correction for outlier SNPs.</p> <p><b>Conclusions</b>: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.</p>