Key result
Genetically predicted elevated leptin levels were causally associated with a significantly reduced risk of nonalcoholic fatty liver disease (OR 0.3032).
Why the study?
Observational studies suggested increased leptin levels may associate with lower NAFLD risk, but whether a causal relationship exists remained unclear.
Does genetically predicted elevated leptin reduce the risk of NAFLD?
Observational (n=218,792)
Does genetically predicted elevated leptin reduce the risk of NAFLD?
Odds Ratio: 0.3032 (95% CI 0.1181–0.7783)
p-value: p=0.0131
Genetically predicted elevated leptin levels are causally associated with a reduced risk of NAFLD, suggesting leptin may serve as a protective factor.
Does not support leptin modulation for NAFLD; leaves open need for interventional confirmation of this genetic signal.
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.
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Guo et al. (2022) conducted an observational in Nonalcoholic fatty liver disease (NAFLD) (n=218,792). Genetically predicted elevated leptin levels vs. Genetically predicted lower leptin levels was evaluated on Risk of NAFLD (OR 0.3032, 95% CI 0.1181-0.7783, p=0.0131). Genetically predicted elevated leptin levels were causally associated with a significantly reduced risk of nonalcoholic fatty liver disease (OR 0.3032).
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