Sex-Specific Basal Metabolic Rate and NAFLD Risk: The Multi-Population Observational and Mendelian Randomization Study

Background: The impact of basal metabolic rate (BMR) on non-alcoholic fatty liver disease (NAFLD) is still not fully understood, particularly regarding potential sex differences. We aimed to explore population-specific associations using data from health examinations, NHANES 2017– 2020, and genome-wide association studies (GWASs). Methods: 30,845 Chinese from health examinations and 5019 US adults from NHANES were analyzed. BMR was estimated using the Mifflin-St Jeor equation. Multivariable-adjusted logistic regression and restricted cubic splines (RCS) were applied. To determine the causality, a two-sample MR study was conducted among Europeans using GWASs data for BMR (IEU OpenGWAS) and NAFLD (FinnGen). Odds ratios (ORs) with 95% confidence intervals (CIs) were reported. Results: In Chinese, ORs (95% CIs) for NAFLD across ascending quartile groups of BMR were 1 (reference), 1.17 (1.03– 1.33), 1.83 (1.60– 2.09), and 5.98 (4.92– 7.28). The corresponding ORs (95% CIs) were 2.00 (1.67– 2.39), 2.71 (2.24– 3.29), and 4.91 (3.97– 6.10) for males, and 1.64 (1.41– 1.92), 1.93 (1.64– 2.27), and 4.04 (3.41– 4.81) for females. In the NHANES, weighted ORs (95% CIs) for NAFLD across quartile groups were 1 (reference), 1.84 (0.95– 3.54), 4.98 (2.28– 10.89), and 16.10 (6.69– 38.72), with similar associations across sexes. Significant sex differences in BMR-NAFLD associations ( P for interaction < 0.05) were observed in the Chinese, but not in the US population. RCS revealed nonlinear dose-response relationships in both sexes within the Chinese population. Two-sample MR confirmed a causal effect with OR (95% CI) of 1.59 (1.24– 2.03). Conclusion: A higher BMR is an independent and causally relevant risk factor for NAFLD. The observed sex effect modification in the Chinese population suggests that population-specific management strategies may be warranted.