Serum Uric Acid Levels and Nonalcoholic Fatty Liver Disease: A 2-Sample Bidirectional Mendelian Randomization Study

Background: Observational studies have shown that nonalcoholic fatty liver disease (NAFLD) is highly correlated with serum uric acid (SUA). However, these studies have an inherent risk of bias due to reverse causality. Here, we perform a Mendelian randomization (MR) study to investigate causality between SUA and NAFLD. Methods: We performed a 2-sample bidirectional MR analysis using summary-level data from genome-wide association studies of SUA (with up to 110 347 individuals) and NAFLD (1483 cases and 17781 controls) in European populations. First, 13 single nucleotide polymorphisms (SNPs) associated with SUA were selected as instruments to estimate the causal effect of elevated SUA levels on the risk of NAFLD using the inverse-variance weighted (IVW) method. Then we performed MR with 3 SNPs as genetic instruments for NAFLD. To test the reliability, further sensitivity analyses were also conducted. Results: Our MR analyses demonstrated that NAFLD was associated with SUA levels ([beta] = 0.032, P = 0.003). Similar results were obtained using other MR methods and in sensitivity analyses. Genetic predisposition to elevated SUA levels was not associated with NAFLD (IVW MR, odds ratio = 1.02, 95% CI: 0.90-1.15, P = 0.775). Similar results were obtained using other 4 pleiotropy robust MR methods and in sensitivity analyses, excluding 9 SNPs associated with potential confounders. Conclusions: Our study supports the causal increased SUA levels by NAFLD, while our study does not confirm a causal association for SUA levels on risk of NAFLD. Further study is needed to interpret the potential mechanisms. Key Words: uric acid, nonalcoholic fatty liver disease, NAFLD, Mendelian randomization