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

Xiangli Qing; Lin Wang; Shuangshuang Fang; Yanran Ban; Zhuotai Zhong; Weiqi Sun; Chenhui Zhang; Tao Zhang; Yang Yang; Wei Wei

doi:10.2147/JIR.S441231

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

J Inflamm Res. 2024 Feb 29:17:1389-1396. doi: 10.2147/JIR.S441231. eCollection 2024.

Authors

Xiangli Qing^{1

2}, Lin Wang¹, Shuangshuang Fang¹, Yanran Ban^{1

3}, Zhuotai Zhong¹, Weiqi Sun¹, Chenhui Zhang⁴, Tao Zhang¹, Yang Yang¹, Wei Wei¹

Affiliations

¹ Department of Gastroenterology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China.
² School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People's Republic of China.
³ Graduate School of Beijing University of Chinese Medicine, Beijing, People's Republic of China.
⁴ Department of General Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People's Republic of China.

Abstract

Background: 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: Mendelian randomization; antidiabetic drugs; inflammatory bowel disease.

Grants and funding

This study was funded by the National Natural Science Foundation of China (U22A20375) and the Science & Technology Innovation Project of China Academy of Chinese Medical Sciences (CI2021A03319).