Genetic Evidence for the Associations of Alcohol Intake Frequency and Dietary Salt Intake with Non-Alcoholic Fatty Liver Disease Risk and Hepatic Steatosis: A Mendelian Randomization Study.

Objective

Non-Alcoholic Fatty Liver Disease (NAFLD) poses a significant global health burden, yet causal relationships with modifiable dietary factors remain incompletely defined. This Mendelian Randomization (MR) study evaluated the causal associations between dietary exposures and NAFLD risk, as well as related hepatic traits.

Methods

We performed univariable, Bayesian Weighted MR (BWMR), and Multivariable MR (MVMR) analyses using genetic variants as instrumental variables. Data from 335,394 to 462,630 European-ancestry individuals (IEU OpenGWAS) were analyzed for 20 dietary exposures. Outcomes included NAFLD diagnosis, liver volume, liver fat content, and percent liver fat. Primary analysis used Inverse-Variance Weighted (IVW) regression, supplemented by sensitivity analyses (MR-Egger, MR-PRESSO) to assess pleiotropy and heterogeneity.

Results

Genetically predicted higher alcohol intake frequency (OR = 1.348, 95% CI = 1.110-1.638, P = 0.003) and salt added to food (OR = 1.544, 95% CI = 1.160-2.054, P = 0.003) significantly increased NAFLD risk in IVW analysis. These findings were robust in BWMR and MVMR analyses adjusting for potential confounders. Cheese (OR = 0.718) and dried fruit intake (OR = 0.406) showed protective associations. Alcohol frequency positively correlated with liver volume (β = 0.152, P = 0.002), while added salt was associated with increased liver volume (β = 0.244, P = 0.002) and liver fat content (β = 0.196, P = 0.038). Sensitivity analyses revealed no significant horizontal pleiotropy (MR-Egger intercept P > 0.05) or heterogeneity affecting primary results.

Discussion

We identified alcohol intake frequency and dietary salt as genetically determined risk factors for NAFLD through MR analysis, while suggesting potential protective associations of cheese and dried fruit intake. By integrating BWMR and MVMR approaches with hepatic steatosis indices, we further revealed positive correlations between these exposures and liver volume/fat content, providing evidence-based dietary insights for NAFLD prevention.

Conclusion

This MR study provides genetic evidence supporting potential causal associations of alcohol consumption frequency and dietary salt intake with NAFLD risk. It further associates these exposures with adverse changes in liver morphology and fat content. These findings highlight the importance of moderating the frequency of alcohol intake and salt consumption in NAFLD prevention strategies.