Association between leptin and NAFLD: A Two-Sample Mendelian randomization study

Abstract

Abstract Background Nonalcoholic fatty liver disease (NAFLD) etiology involves a complex interaction of genetic and environmental factors. Previous observational studies have suggested that increased leptin levels may be associated with a low risk of developing NAFLD, but the causal relationship remains unclear. Due to advances in genome-wide association studies (GWAS) and the discovery of Mendelian randomization (MR), we aimed to investigate the causal effect of leptin and NAFLD using MR analysis. Methods We performed a two-sample Mendelian randomization analysis (TSMR) using summary GWAS data from leptin (up to 50,321 individuals) and NAFLD (894 cases and 217,898 controls) in a European population. Genetic instrumental variables (InstrumentalVariables, IVs) that satisfied the three core assumptions of Mendelian randomization were selected. TSMR analysis was performed using the Inverse Variance Weighted (IVW) method, MR-Egger regression method, and Weighted Median (WM) method. To ensure the accuracy and stability of the study results, heterogeneity tests, multiple validity tests, and sensitivity analyses were conducted. Results The results of TSMR correlation analysis between NAFLD and leptin were IVW (OR: 0.3032; 95% CI 0.1181–0.7783; P = 0.0131), WM method (OR: 0.2816; 95% CI 0.0931–0.8678; P = 0.0273), MR-Egger regression method (P = 0.6955), and Among them, the IVW method and WM method showed P > 0.05, and the results were statistically significant. In addition, TSMR correlation analysis between NAFLD and circulating leptin levels adjusted for Body Mass Index (BMI) resulted in IVW (OR: 0.4416; 95% CI 0.2807–0.6948; P = 0.0004), WM method (OR: 0.4194; 95% CI 0.2279–0.7720; P = 0.0052), MR-Egger regression method (OR: 0.2023; 95% CI 0.0541–0.7562; P = 0.0389), P > 0.05, and the results were statistically significant. It is further demonstrated that increased leptin is causally associated with reduced risk of NAFLD, and leptin may serve as a protective factor for NAFLD. Conclusions In this study, we explored the causal association between leptin and NAFLD from a genetic perspective based on the GWAS database using TSMR analysis. Further studies are needed to explain the underlying mechanisms.