Serum folate levels and risk of metabolic dysfunction-associated steatotic liver disease: results from a cross-sectional study and Mendelian randomization analysis.

Background: Evidence from observational studies on the association between folate and metabolic dysfunction-associated steatotic liver disease (MASLD) is conflicting.

Aims: This study aimed to investigate the association between serum folate concentration and MASLD and further assess the causal relationship using Mendelian randomization (MR) analysis.

Methods: To investigate the causal relationship between serum folate and MASLD, we conducted a cross-sectional study that selected 1,117 participants from the 2017-2020 National Health and Nutrition Examination Survey (NHANES). The association between serum folate level and the risk of MASLD was evaluated under a multivariate logistic regression model. In addition, we conducted a two-sample MR study using genetic data from a large genome-wide association study (GWAS) to compare serum folate level (37,465 individuals) and MASLD (primary analysis: 8,434 cases/770,180 controls; Secondary analysis:1,483 cases/17,781 controls) were performed to infer causal relationships between them. Inverse variance weighted (IVW) was used as the primary method of MR Analysis.

Results: The results from the NHANES database showed that Tertile 3 group (Tertile 3: ≥ 48.6 nmol/L) had a significantly lower risk (OR = 0.58, 95% CI: 0.38-0.88,  = 0.010) of MASLD than Tertile 1 group (Tertile 1: < 22.3 nmol/L) after complete adjustments. However, in the IVW of MR analysis, there was no causal relationship between serum folate level and MASLD risk in the primary analysis (OR = 0.75, 95% CI: 0.55-1.02,  = 0.065) and secondary analysis (OR = 0.83, 95% CI: 0.39-1.74,  = 0.618).

Conclusion: In observational analyses, we observed an inverse association between higher serum folate concentrations and a reduced risk of MASLD. Our MR study generated similar results, but the association failed to reach the significance threshold of < 0.05, suggesting that our MR study does not support a causal relationship between serum folate levels and MASLD risk. Additional research involving a larger number of cases would contribute to enhancing the confirmation of our preliminary findings.