Serum urate is associated with an increased risk of inflammatory bowel disease: A bidirectional Mendelian randomization study

Abstract

Background: Previous studies have indicated bidirectional associations between urate levels and inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). However, it remains unclear whether the observations are causal because of confounding factors.

Aim: To investigate the causal associations between urate levels and IBD using bidirectional Mendelian randomization (MR).

Methods: Independent genetic variants for urate levels and IBD were selected as instrumental variables from published genome-wide association studies (GWASs). Summary statistics for instrument-outcome associations were retrieved from three separate databases for IBD (the UK Biobank, the FinnGen database and a large GWAS meta-analysis) and one for urate levels (a large GWAS meta-analysis). MR analyses included the inverse-variance-weighted method, weighted-median estimator, MR-Egger and sensitivity analyses (MR-PRESSO). A meta-analysis was also conducted to merge the data from separate outcome databases using a fixed-effects model.

Results: Genetically higher serum urate levels were strongly associated with an increased risk of UC [odds ratio (OR): 1.95, 95% confidence interval (CI): 1.86-2.05] after outlier correction, and the ORs (95%CIs) for IBD and CD were 0.94 (95%CI: 0.86-1.03) and 0.91 (95%CI: 0.80-1.04), respectively. Animal studies have confirmed the positive association between urate levels and UC. Moreover, genetically predicted IBD was inversely related to urate levels (OR: 0.97, 95%CI: 0.94-0.99). However, no association was observed between genetically influenced UC or CD and urate levels.

Conclusion: Urate levels might be risk factors for UC, whereas genetically predicted IBD was inversely associated with urate levels. These findings provide essential new insight for treating and preventing IBD.

Keywords: Antioxidant; Inflammatory bowel disease; Mendelian randomization; Single nucleotide polymorphism; Urate levels.

Figure 1

Overview of study design. IBD: Inflammatory bowel disease; SNP: Single-nucleotide polymorphisms; UC: Ulcerative colitis; CD: Crohn’s disease; UA: Ursolic acid; MR: Mendelian randomization.

Figure 2

Association of urate levels and inflammatory bowel disease in Mendelian randomization analyses (inverse-variance weighted estimate). Estimated odds ratios (OR) represent the effect of per log-OR increase in urate levels on inflammatory bowel disease (IBD), using inverse-variance weighted analysis, per outcome database separately. The meta-analyses combined the three databases (genome-wide association studies meta-analysis by Liu et al[19] and the FinnGen and UK Biobank databases) for UC and the former two databases for IBD and Crohn’s disease (UK Biobank data were not available) using a fixed-effects model. IBD: Inflammatory bowel disease; UA: Ursolic acid; UC: Ulcerative colitis; SNP: Single-nucleotide polymorphisms; CD: Crohn’s disease; CI: Confidence interval; IVW: Inverse-variance weighted.

Figure 3

Scatter plot of Mendelian randomization analyses from urate levels to inflammatory bowel disease in each database. The X-axes indicate the single-nucleotide polymorphisms (SNPs) of urate levels, while the Y-axes indicate the SNPs of inflammatory bowel disease from different outcome databases. The black dots represent the genetic instruments included in the current Mendelian randomization (MR) analyses. The five colors represent five different genetic estimates: Red: Inverse-variance weighted; Blue: Weighted-median estimator; Green: MR Egger. IBD: Inflammatory bowel disease; SNP: Single-nucleotide polymorphisms.

Figure 4

Association of inflammatory bowel disease and urate levels in Mendelian randomization analyses (inverse-variance weighted estimate). Estimated odds ratio (OR) represent the effect of per log-OR increase in inflammatory bowel disease on urate levels, using inverse-variance weighted analysis with a fixed-effects model. IBD: Inflammatory bowel disease; UC: Ulcerative colitis; CD: Crohn’s disease; CI: Confidence interval; SNP: Single-nucleotide polymorphisms; UA: Ursolic acid; IVW: Inverse-variance weighted.

Figure 5

Scatter plot of the association of inflammatory bowel disease with urate levels. The detailed description is the same as in Figure 3. IBD: Inflammatory bowel disease; SNP: Single-nucleotide polymorphisms.

Figure 6

Dextran sulfate sodium contributed to increase of inflammation in inflammatory bowel disease mice. C57BL/6 mice were administered dextran sulfate sodium (DSS) (2%) for 7 d (and a control group was provided with water only for comparison) and 2 d for water. A-E: DSS group (n = 5) exhibited a significant aggravation of inflammatory bowel disease-associated changes in of body weight (A), disease activity index (B), colon length (C), inflammatory infiltration (D) and increased levels of interleukin (IL)-6, IL-1β and tumor necrosis factor-α (E); F: Compared with control group (n = 5), DSS group demonstrated increased levels of urate levels. DSS: Dextran sulfate sodium; NC: Control group; IL: Interleukin; TNF: Tumor necrosis factor; DAI: Disease activity index. ^aP < 0.05; ^bP < 0.01; ^cP < 0.001.