Clinical and Translational Research
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Feb 16, 2024; 12(5): 891-902
Published online Feb 16, 2024. doi: 10.12998/wjcc.v12.i5.891
Serum urate is associated with an increased risk of inflammatory bowel disease: A bidirectional Mendelian randomization study
Song Zhang, Xue Fang, Le Kang, Xiang-Yu Sui, Miao Liu, Yu-Jia Luo, Shuo Fu, Zhao-Shen Li, Sheng-Bing Zhao, Yu Bai
Song Zhang, Xue Fang, Le Kang, Xiang-Yu Sui, Miao Liu, Yu-Jia Luo, Shuo Fu, Yu Bai, Department of Gastroenterology, Changhai Hospital, Shanghai 200433, China
Zhao-Shen Li, Sheng-Bing Zhao, Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai 200433, China
Zhao-Shen Li, Sheng-Bing Zhao, Digestive Endoscopy Center, Changhai Hospital, Naval/Second Military Medical University, Shanghai 200433, China
Zhao-Shen Li, Sheng-Bing Zhao, National Clinical Research Center for Digestive Diseases, Shanghai 200433, China
Co-first authors: Song Zhang and Xue Fang.
Co-corresponding authors: Sheng-Bing Zhao and Yu Bai.
Author contributions: Zhang S, Zhao SB and Bai Y designed the research; Zhang S, Kang L and Luo YJ performed the research; Zhang S, Fang X, Kang L and Luo YJ analyzed the data; Sui XY, Liu M and Fu S visualized the data; Zhang S, Fang X, Kang L, Sui XY, Zhao SB and Bai Y wrote the paper; Fang X, Zhao S and Bai Y received the funding; Li ZS, Zhao SB and Bai Y supervised the research.
Supported by National Natural Science Foundation of China, No. 82170567, No. 81873546, No. 82170568, and No. 82300627; Program of Shanghai Academic/Technology Research Leader, No. 22XD1425000; The "Shu Guang" project of Shanghai Municipal Education Commission and Shanghai Education Development Foundation, No. 19SG30, China; Deep Blue Project of Naval Medical University (Pilot Talent Plan); The Chenguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission, No. 22CGA42; The Shanghai Sailing Program, No. 23YF1458600; and Shanghai Natural Science Foundation, No. 23ZR1478700.
Institutional review board statement: The study did not include human trials.
Institutional animal care and use committee statement: All animal experimental procedures were approved and conducted in accordance with the guidelines of the Animal Care Committee of Navy Medical University (CHEC(A.E.)2023-046).
Informed consent statement: All data used in the current manuscript was available online, thus the Signed Informed Consent Form(s) or Document(s) was not applied for the current manuscript.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: The data underlying this article are available in individual referenced papers, the Finngen database (https://r7.finngen.fi/) and the IEU OpenGWAS project (https://gwas.mrcieu.ac.uk/).
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yu Bai, MD, PhD, Academic Research, Associate Professor, Researcher, Department of Gastroenterology, Changhai Hospital, No. 168 Changhai Road, Yangpu District, Shanghai 200433, China. changhaibaiyu@smmu.edu.cn
Received: December 9, 2023
Peer-review started: December 9, 2023
First decision: December 14, 2023
Revised: January 1, 2024
Accepted: January 23, 2024
Article in press: January 23, 2024
Published online: February 16, 2024
ARTICLE HIGHLIGHTS
Research background

Inflammatory bowel disease (IBD), mainly consisted of Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease. As a vital antioxidant, urate can decrease oxidative stress in vivo, which may be associated with IBD state. However, the causality between IBD and urate levels has not been investigated.

Research motivation

Previous studies indicated uric acid-to-creatinine ratio and urate were positively correlated with the disease activity of CD and UC. Despite the existing findings demonstrated the bidirectional associations between urate levels and IBD, including UC and CD, the causality association between them remains unclear. This study seeks to investigate the causal association between IBD and urate through Mendelian randomization (MR) study, which may shed crucial new insight into treating and preventing IBD. In specific, IBD patients may benefit from monitoring and reducing serum urate levels.

Research objectives

The study aims to investigate the bidirectional causal relationship between urate levels and IBD by performing MR analysis, to better understand the gene susceptibility of urate levels and IBD.

Research methods

Single nucleotide polymorphisms retrieved from genome-wide association studies (GWASs) was selected as instrument variants. Summary GWAS statistics for instrument-outcome associations were retrieved from three separate databases for IBD (UK Biobank, FinnGen database and a large GWAS meta-analysis) and one for urate levels (a large GWAS meta-analysis). Inverse-variance-weighted was performed to investigate the bidirectional causal relationship, and other sensitivity analysis were conducted to strengthen the results. Meta-analysis was conducted to merge the data from separate outcome databases using a fixed-effects model.

Research results

The current study found that the genetic susceptibility to urate levels was associated with increased UC risk [odds ratio (OR): 1.95, 95% confidence interval (CI): 1.86-2.05], and animal studies confirmed the positive association between urate levels and UC. Additionally, 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.

Research conclusions

This study identified urate levels might be risk factors for UC, whereas genetically predicted IBD was inversely associated with urate levels. The current results shed new insight into prevention and treatment of IBD.

Research perspectives

Although the current study investigated the causal relationship between urate levels and UC, which was further verified by animal studies, the precise mechanism by which high urate levels affects the development of UC remains unknown. More basic and clinical studies should be conducted for identification of key regulators and molecules during the process.