No Evidence for a Causal Link between Serum Uric Acid and Nonalcoholic Fatty Liver Disease from the Dongfeng-Tongji Cohort Study

Abstract

Background and Aims. Elevated serum uric acid (SUA) is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD); however, whether this association is causal is undetermined. Methods. Each participant from the Dongfeng-Tongji cohort study based on 27,009 retirees was interviewed face-to-face following a clinical examination. Covariance, logistic regression analysis, and instrumental variables were used to assess associations between SUA and (severity of) NAFLD and the causal link. Results. Among 8,429 subjects free of NAFLD at baseline, 2,007 participants developed NAFLD after 5 years of follow-up. The multivariable-adjusted odds ratio (OR) for NAFLD for individuals in the fourth quartile of SUA level versus those in the first was 1.71 (95% CI: 1.45-2.01, $P$ for trend <0.001) and was more dramatic in women or normal-weight persons. Furthermore, SUA was materially associated with greater mean markers of hepatic necroinflammation and greater probabilities of fibrosis. In genetic analyses, both single nucleotide polymorphisms (rs11722228 to SLC2A9 and rs2231142 to ABCG2) were pronouncedly associated with increased SUA concentrations, ranging from 0.19 to 0.22 mg/dl. No significant associations were observed between SNPs and potential confounders. No association was observed between the SUA-increasing allele and NAFLD, with an OR of 0.98 (95% CI: 0.90-1.08) per genetic score. This was not significantly different ( $P=0.25$ ) from what was expected (1.03, 95% CI: 1.03-1.03). Conclusions. SUA was positively associated with NAFLD incidence especially in female and normal-weight individuals and the suspected progression risk of newly developed NAFLD. However, the Mendelian randomization analyses lend no causal evidence, suggesting high SUA as a marker and not a cause of NAFLD.