Genetically Determined Reproductive Aging And Cardiovascular Risk Factors And Coronary Heart Disease Risk: A Two-Sample Mendelian Randomization Study

Introduction: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with an increased risk of coronary heart disease (CHD) in observational studies. Conversely, an adverse CHD risk factor profile has been suggested to accelerate menopause. We conducted a bidirectional Mendelian randomisation (MR) study to investigate the direction and evidence for a causal nature of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors. Genomic variants for age at natural menopause (ANM) have been implicated in genome stability, immune function and mitochondrial biogenesis, which are not sex-specific processes. We used ANM variants as a measure for genetically determined reproductive aging in women and also in men, since genome-wide association studies (GWAS) for reproductive aging traits in men are lacking. Hypothesis: Reproductive ageing is causally related to CHD in both women and men. Methods: We conducted a bidirectional two-sample Mendelian Randomization, using both cohort data as well as summary statistics, with four methods: simple median-based, weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression. Exposures: Genetically determined reproductive aging, CHD and CHD risk factors. Main outcomes: CHD, CHD risk factors and age at natural menopause. Results: Summary statistics were pooled from three studies with together 417,579 participants from European descent, including 49,150 CHD cases. Publicly available GWAS and EPIC-CVD were pooled for total cholesterol, high density lipoprotein cholesterol, triglycerides, HbA1c, and glucose. Across different MR methods genetically determined reproductive aging was not causally related to CHD risk in women (Relative Risk Estimate (RRE) IVW =0.99, 95% confidence interval (CI): 0.97;1.01), or any of the CHD risk factors. Also, no associations were found in men. Furthermore, CHD was not causally related to reproductive ageing. Conclusions: Reproductive aging is not causally related to CHD risk or CHD risk factors in women, nor in men. We found no evidence for a reverse association. The associations between early menopause and CHD risk in observational studies might be the result of residual confounding, reverse causation, or reflect a shared etiology that results in both earlier menopause and higher CHD risk.