Triglyceride glucose index as a causal risk factor for metabolic dysfunction-associated fatty liver disease: evidence from the National Health and Nutrition Examination Survey 2017-2020 and Mendelian randomization.

Background/aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a global health burden increasing liver-related mortality. Existing cross-sectional studies lack causal evidence between the triglyceride glucose (TyG) index and MAFLD. Utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 and Mendelian randomization, this study aimed to investigate the causal association between the TyG index and MAFLD.

Methods: On the basis of the 2017-2020 NHANES data, baseline characteristics of MAFLD cases and the control group were comparatively analyzed. Multivariate logistic regression evaluated the association between the TyG index and MAFLD, with restricted cubic splines (RCS) employed for nonlinear relationship assessment. A two-sample Mendelian randomization analysis examined potential causal relationships, while comprehensive sensitivity analyses validated the robustness of the principal findings.

Results: Cross-sectional analysis revealed a significant positive linear association between the TyG index and MAFLD risk. After multivariable adjustment, the odds ratio (OR) was 2.30 [95% confidence interval (CI) = 1.71-3.10, P  < 0.001]. RCS analysis further confirmed a monotonic linear relationship between the TyG index and MAFLD risk. The test for nonlinearity was nonsignificant ( P  = 0.07), confirming a linear dose-response. Mendelian randomization analysis indicated that a genetically predicted 1-unit increase in TyG index was associated with 64% higher MAFLD risk (OR = 1.64, 95% CI = 1.07-2.50, P  = 0.02).

Conclusion: This study using cross-sectional data and Mendelian randomization confirms the TyG index as an independent causal risk factor for MAFLD, highlighting the need for early monitoring and intervention to inform precision prevention strategies.