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

Abstract

Background Observational studies have shown that non-alcoholic 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 two-sample bidirectional MR analysis using summary-level data from genome-wide association studies (GWAS) 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 (β = 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 (OR) = 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 serum uric acid levels on risk of NAFLD. Further study is needed to interpret the potential mechanisms.

Associations of serum uric acid levels with liver disease‐related morbidity and mortality: A prospective cohort study of the UK Biobank

“…Furthermore, SUA levels are associated with the development of cirrhosis after adjustments for risk factors for chronic liver disease in a US nationwide cohort, 7 which was similar to the present findings for SLD. However, an MR study restricted to individuals of European ancestry does not confirm a causal association between SUA levels and the risk of NAFLD 18 . Correspondingly, causality was not discovered in the present study.…”

“…However, an MR study restricted to individuals of European ancestry does not confirm a causal association between SUA levels and the risk of NAFLD. 18 Correspondingly, causality was not discovered in the present study. The discrepancy between cohort studies and MR analyses may be because of the magnitude of exposure determined by genetic instruments not being equal to the exposure in observational studies, which generally leads to a null association in MR analysis.…”

“…To examine the causal effect of SUA on liver disease, one‐sample MR analyses in the UK Biobank were performed. We used 13 independent SNPs from 110 347 European individuals identified by Li et al, 18 which was estimated to explain 6.8% of the variance in SUA levels and satisfied three MR assumptions. We then calculated the weighted PRS (same methods as above) as a proxy instrumental variable, and the causal effect between exposure and outcome was obtained by two‐stage least squares.…”

Serum uric acid to creatinine ratio is associated with higher prevalence of NAFLD detected by FibroScan in the United States

“…Our findings are consistent with those of previous studies showing that serum uric acid levels were significantly associated with NAFLD prevalence. 24,25 A study based on the NHANES 1988-1994 in the United States also identified similar results between elevated uric acid level and ultrasound-diagnosed NAFLD in non-diabetic adults. 26 However, the effect of kidney function on the sUA level has been neglected in many studies, and sUA/Cr, a renal function-normalized index, might be a better biomarker.…”

Assessing the causal relationships between human blood metabolites and the risk of NAFLD: A comprehensive mendelian randomization study

“…Some MR studies have been performed to explore the relationship between exposure and NAFLD. However, the main focus was single exposures or common exposure factors, such as interleukin-6 (IL-6) ( Li et al, 2022a ), seven sleep characteristics ( Fan et al, 2022 ), serum uric acid levels ( Li et al, 2022b ), iron status ( He et al, 2022 ), and coronary artery disease ( Ren et al, 2022 ). Few studies have focused on blood metabolites and NAFLD.…”