Association between circulating biomarkers and non-alcoholic fatty liver disease: An integrative Mendelian randomization study of European ancestry

Abstract

Background and aim

Circulating biomarkers provide potential diagnostic or prognostic information on disease presentation, progression or both. Early detection of circulating risk biomarkers is critical for non-alcoholic fatty liver disease (NAFLD) prevention. We aimed to systematically assess the potential causal relationship of genetically predicted 60 circulatory biomarkers with NAFLD using a two-sample Mendelian randomization (MR) design.

Methods and results

We extracted instrumental variables for 60 circulating biomarkers, and obtained genome-wide association data for NAFLD from 3 sources [(including Anstee, FinnGen and UK Biobank (N ranges: 19264–377988)] among individuals of European ancestry. Our primary method was inverse-variance weighted (IVW) MR, with a series of additional and sensitivity analyses to test the hypothesis of MR. MR results showed that genetically predicted higher density lipoprotein-cholesterol (odds ratio (OR) = 0.86, 95% confidence interval (CI): 0.77–0.96) and vitamin D (OR = 0.39, 95% CI: 0.19–0.78) levels decreased the risk of NAFLD, whereas genetically predicted higher alanine (OR = 1.68, 95% CI: 1.21–2.33), histidine (OR = 1.21, 95% CI: 1.00–1.46), lactate (OR = 2.64, 95% CI: 1.09–6.39), triglycerides (OR = 1.16, 95% CI: 1.05–1.13), ferritin (OR = 1.17, 95% CI: 1.01–1.37), serum iron (OR = 1.23, 95% CI: 1.07–1.41) and transferrin saturation (OR = 1.16, 95% CI: 1.05–1.29), component 4 (OR = 1.10, 95% CI: 1.01–1.20), interleukin-1 receptor antagonist (OR = 1.12, 95% CI: 1.04–1.21) and interleukin-6 (OR = 1.62, 95% CI: 1.14–2.30) levels increased the risk of NAFLD.

Conclusions

The findings might aid in elucidating the underlying processes of these causal relationships and provide strong evidence for focusing on high-risk populations and the therapeutic management of specific biomarkers.