Association of Antidiabetic Drug Target Genes with Inflammatory Bowel Disease: A Mendelian Randomization Study

Abstract

Xiangli Qing,1,2 Lin Wang,1 Shuangshuang Fang,1 Yanran Ban,1,3 Zhuotai Zhong,1 Weiqi Sun,1 Chenhui Zhang,4 Tao Zhang,1 Yang Yang,1 Wei Wei1 1Department of Gastroenterology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China; 3Graduate School of Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 4Department of General Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of ChinaCorrespondence: Wei Wei, Department of Gastroenterology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China, Email [email protected]: An unmet medical need for the treatment of inflammatory bowel disease (IBD) exists. A part of antidiabetic drugs had potential effects on IBD in various observational research.Objective: To investigate the potential of antidiabetic drugs on IBD.Methods: We undertook a summary-data-based Mendelian randomization (SMR) using the expression quantitative trait loci (eQTL) expressed in the blood or colon and a two sample Mendelian randomization (TSMR) utilizing single nucleotide polymorphism (SNP) of antidiabetic drug target genes mediated by blood glucose traits. Participants encompassed patients with IBD (25,042 cases/34,915 controls), UC (12,366 cases/33,609 controls), and CD (12,194 cases/28,072 controls). Data on eQTL in the blood or the colon were from the eQTLGen consortium (31,684 individuals) or GTEx Consortium V8, respectively. SMR was performed by SMR software (20,220,322); the primary method for TSMR was inverse-variance weighted (IVW) or Wald ratio through R studio (2023.06.0+421). Sensitivity analyses were carried out.Results: A 1-SD upper expression of the KCNJ11 gene (target gene of sulfonylureas) in the blood reduced the risk of CD (OR per 1-SD = 0.728, 95% CI = 0.586– 0.903, P = 0.004) according to the result of SMR. ABCC8 (target gene of sulfonylureas) expressed in the colon did not affect CD, UC, or IBD. T2D-mediated KCNJ11 has a protective effect on CD (OR = 0.475, 95% CI = 0.297– 0.761, P = 0.002). Gene predicted no relationship between T2D and CD.Conclusion: Sulfonylureas (SUs) may have side effects on CD. This work provides some suggestions for the selection of antidiabetic drugs in patients with CD.Keywords: antidiabetic drugs, inflammatory bowel disease, Mendelian randomization

Keywords

• antidiabetic drugs
• inflammatory bowel disease
• mendelian randomization