BACKGROUND: Circulating levels of homocysteine and folate are inconsistently associated with the risk of non-alcoholic fatty liver disease (NAFLD) in observational studies.
OBJECTIVE: We conducted a meta-analysis and Mendelian randomization (MR) analyses to examine these associations.
METHODS: We performed a meta-analysis of observational studies identified from three databases to evaluate the associations of serum homocysteine and folate levels with NAFLD from inception to 07 April 2022. We conducted MR analyses to strengthen the causal inference in these associations. Independent single-nucleotide polymorphisms without linkage disequilibrium (r2 <0.01) and strongly (P < 5×10-8) associated with serum homocysteine (n=13) and folate (n=2) concentrations were selected as instrumental variables from two meta-analyses of genome-wide association studies (GWAS) of 44,147 and 37,645 individuals of European ancestry, respectively. Data on NAFLD were obtained from a GWAS of 8,434 NAFLD cases and 770,180 controls of European ancestry. We further included four liver enzymes as secondary outcomes from GWAS of 361,194 individuals with European descent.
RESULTS: Twenty-two observational studies comprising 30,368 participants were included in the meta-analysis. There was a positive association between serum homocysteine and NAFLD risk (n=20, odds ratio [OR] 1.96, 95% confidence interval [CI] 1.57, 2.45) and an inverse association between serum folate and NAFLD risk (n=12, OR 0.75, 95% CI 0.58, 0.99). In MR analysis, the OR of NAFLD was 1.17 (95% CI 1.01, 1.36) and 0.75 (95% CI 0.55, 1.02) per 1-SD increment of genetically predicted circulating levels of homocysteine and folate, respectively. Each 1-SD increase of genetically predicted circulating homocysteine and folate conferred a change in alanine aminotransferase levels of 0.62 (95% CI 0.20, 1.04) and -0.84 (95% CI -0.14, -1.54) U/L, respectively.
CONCLUSIONS: This study suggests a potential role of circulating homocysteine and possibly folate in NAFLD, which calls for future clinical exploration of the possibility of lowering homocysteine levels to prevent NAFLD. Systematic review registration: registered at https://www.crd.york.ac.uk/prospero/ as CRD42021296434.
Elsevier, 2022. Vol. 116, no 6, p. 1595-1609, article id nqac285
Mendelian randomization, folate, homocysteine, meta-analysis, nonalcoholic fatty liver disease