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.