Non-linear association of serum molybdenum and linear association of serum zinc with nonalcoholic fatty liver disease: Multiple-exposure and Mendelian randomization approach

The homeostasis imbalance of metals is closely associated with nonalcoholic fatty liver disease (NAFLD). A total of 1594 and 566 Chinese Han men were enrolled in cross-sectional and longitudinal analyses, respectively. We measured the serum concentrations of 22 metals by ICP-MS. The traditional and the LASSO regression methods were used to construct multiple-metals models, respectively. We performed Mendelian randomization (MR) analysis to confirm the causal relationship between NAFLD and metals using three NAFLD-related SNPs as instrumental variable. After adjustment in the six-metal model, only depressed molybdenum and elevated zinc were associated with a higher NAFLD risk, in both cross-sectional and longitudinal analyses. In the twelve-metal model, similar results were still observed. Moreover, dose-response relationships were non-linear for molybdenum and positively linear for zinc with NAFLD risk. In MR analysis, no causal associations were found from NAFLD to molybdenum and zinc. Our results support that serum molybdenum levels were non-linearly associated with NAFLD risk in Chinese men, whereas serum zinc levels showed a positively linear association. Moreover, MR analysis indicated the changes in serum molybdenum and zinc levels might be not caused by NAFLD, further confirmed our findings in cross-sectional and longitudinal analyses.