Genetic Prediction of Age at Menarche, Age at Natural Menopause and Type 2 Diabetes: A Mendelian Randomization Study

Background and aims: The relationship between reproductive factors and type 2 dia-betes (T2D) is controversial; therefore, we explored the causal relationship of age at menarche (AAM), age at natural menopause (ANM), with the risk of T2D and glycemic traits using two -sample Mendelian randomization.Methods and results: We used publicly available data at the summary level of genome-wide as-sociation studies, where AAM (N = 329,345), ANM (N = 69,360), T2D (N = 464,389). The in-verse variance weighting (IVW) method was employed as the primary method. To demonstrate the robustness of the results, we also conducted various sensitivity analysis methods including the MR-Egger regression, the weighted median (WM) and the MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. After excluding IVs associated with confounders, we found a causal association between later AAM and reduced risk of T2D (OR 0.81 [95% CI 0.75, 0.87]; P = 2.20 x 10-8), lower levels of FI (6-0.04 [95% CI-0.06,-0.01]; P = 2.19 x 10-3), FPG (6-0.03 [95% CI-0.05,-0.007]; P = 9.67 x 10-5) and HOMA-IR (6-0.04 [95% CI-0.06,-0.01]; P = 4,95 x 10-3). As for ANM, we only found a causal effect with HOMA-IR (6-0.01 [95% CI-0.02,-0.0 05]; P = 1.77 x 10-3), but not with T2D.Conclusions: Our MR study showed a causal relationship between later AAM and lower risk of developing T2D, lower FI, FPG and HOMA-IR levels. This may provide new insights into the pre-vention of T2D in women.(c) 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Ital-ian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.