Unraveling the Causal Nexus Between Reproductive Characteristics and Non-Alcoholic Fatty Liver Disease

Abstract

Abstract Background and Aim Non-alcoholic fatty liver disease (NAFLD), a prevalent global health concern, stems from intricate interactions between genetic and environmental factors. The primary aim of this study is to employs Mendelian randomization (MR) to investigate the causal relationship between key female reproductive characteristics—age at first birth (AFB), age at first sexual intercourse (AFS), and age at menarche (AAM)—and the risk of NAFLD. Methods: Genome-wide association data on AFB, AFS, AAM, and NAFLD were pooled for two-sample MR analysis. Instrumental variables were meticulously selected to meet MR assumptions. The primary analysis used the inverse variance weighting (IVW) approach, supplemented by MR-Egger regression and weighted median methods. Multivariate MR (MVMR) analysis considered confounding variables: educational attainment, BMI, and household income. Results: The MR analysis revealed significant causal associations between later AFB (OR 0.89; 95% CI: 0.83–0.96; P = 0.003), AFS (OR 0.64; 95% CI: 0.53–0.76; P = 1.47×10− 5), and AAM (OR 0.83; 95% CI: 0.75–0.91; P = 0.0002) with a reduced risk of NAFLD. MVMR, after accounting for confounders, sustained the significance of AFS (P = 0.003) and AAM (P = 0.02), with a weaker association for AFB (P = 0.3). Conclusion: This study provides compelling evidence that later reproductive events—later AFB, AFS, and AAM—are causally associated with a reduced risk of NAFLD. The observed associations persist even after adjusting for confounding variables. Further research is warranted to delve into the underlying mechanisms of this causality, emphasizing the importance of women's reproductive health awareness in mitigating NAFLD risk.