Inverse association between serum 25-hydroxyvitamin D and nonalcoholic fatty liver disease

Background & Aims
Serum 25-hydroxyvitamin D (S-25(OH)D) and nonalcoholic fatty liver disease (NAFLD) are correlated in many observational studies, whereas the causality of this association is uncertain, especially in European populations. We conducted a bidirectional Mendelian randomization study to determine the association between S-25(OH)D and NAFLD.

Seven and six independent genetic variants associated with S-25(OH)D and NAFLD at the genome-wide significance level, respectively, were selected as instrumental variables. Summary-level data for S-25(OH)D were obtained from the SUNLIGHT consortium including 79,366 individuals. Summary-level data for NAFLD were available from a genome-wide association meta-analysis (1483 cases and 17,781 controls), the FinnGen consortium (894 cases and 217,898 controls), and the UK Biobank study (275 cases and 360,919 controls). Summary-level data for four liver enzymes were obtained from the UK Biobank.

There were genetic correlations of S-25(OH)D with NAFLD and certain liver enzymes. Genetically predicted higher levels of S-25(OH)D were consistently associated with a decreased risk of NAFLD in the three sources. For one standard deviation increase in genetically predicted S-25(OH)D levels, the combined odds ratio of NAFLD was 0.78 (95% confidence interval (CI), 0.69, 0.89). Genetically predicted higher levels of S-25(OH)D showed a borderline association with aspartate aminotransferase levels (change -0.17, 95% CI, -0.36, 0.01). Genetic predisposition to NAFLD was not associated with S-25(OH)D (change 0.13, 95% CI, -0.26, 0.53).

Our findings have clinical implications as they suggest that increased vitamin D levels may play a role in NAFLD prevention in European populations.