Background: Menarche timing may not be directly associated with the risk of coronary artery disease (CAD). Therefore, we investigated the roles of metabolic factors in explaining the effect of age at menarche on CAD risk. Methods: We identified women with age at menarche and CAD by using three analytical methods: Mendelian randomization (MR), logistic regression analysis, and Cox proportional hazard regression. The first two analyses were performed in the Taiwan Biobank (N = 71,923) study, and the last analysis was performed in the Chin-Shan Community Cardiovascular Cohort study (N = 1,598). We further investigated the role of metabolic factors in mediating the effect of age at menarche on CAD risk by using three complementary methods with mediation analyses. Results: One standard deviation of earlier age at menarche was associated with a 2% higher CAD risk [odds ratio = 1.02, 95% confidence interval (CI) = 1.001–1.03] in the MR analysis, an 11% higher risk (odds ratio = 1.11, 95% CI = 1.02–1.21) in the logistic regression analysis, and a 57% higher risk (hazard ratio = 1.57, 95% CI = 1.12–2.19) in the Cox proportional hazard regression. All the analyses consistently supported the role of systolic blood pressure in mediating this effect. The MR results indicated that 29% (95% CI = 26%–32%) of the effect of genetically predicted earlier age at menarche on CAD risk was mediated by genetically predicted systolic blood pressure. Conclusion: The results obtained using different analytical methods suggest that interventions aimed at lowering systolic blood pressure can reduce the cases of CAD attributable to earlier age at menarche.
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