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

Overview

Journal J Inflamm Res

Publisher Dove Medical Press

Date 2024 Mar 13

PMID 38476469

Authors

Xiangli Qing

Lin Wang

Shuangshuang Fang

Yanran Ban

Zhuotai Zhong

Weiqi Sun

Chenhui Zhang

Tao Zhang

Yang Yang

Wei Wei

Affiliations

Soon will be listed here.

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 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. (target gene of sulfonylureas) expressed in the colon did not affect CD, UC, or IBD. T2D-mediated 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.

References

Rohm T, Meier D, Olefsky J, Donath M . Inflammation in obesity, diabetes, and related disorders. Immunity. 2022; 55(1):31-55. PMC: 8773457. DOI: 10.1016/j.immuni.2021.12.013. View

Le Berre C, Honap S, Peyrin-Biroulet L . Ulcerative colitis. Lancet. 2023; 402(10401):571-584. DOI: 10.1016/S0140-6736(23)00966-2. View

Chauquet S, Zhu Z, ODonovan M, Walters J, Wray N, Shah S . Association of Antihypertensive Drug Target Genes With Psychiatric Disorders: A Mendelian Randomization Study. JAMA Psychiatry. 2021; 78(6):623-631. PMC: 7948097. DOI: 10.1001/jamapsychiatry.2021.0005. View

Magliano D, Sacre J, Harding J, Gregg E, Zimmet P, Shaw J . Young-onset type 2 diabetes mellitus - implications for morbidity and mortality. Nat Rev Endocrinol. 2020; 16(6):321-331. DOI: 10.1038/s41574-020-0334-z. View

Radel J, Pender D, Shah S . Dipeptidyl Peptidase-4 Inhibitors and Inflammatory Bowel Disease Risk: A Meta-analysis. Ann Pharmacother. 2019; 53(7):697-704. DOI: 10.1177/1060028019827852. View

Mahajan A, Spracklen C, Zhang W, Ng M, Petty L, Kitajima H . Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. Nat Genet. 2022; 54(5):560-572. PMC: 9179018. DOI: 10.1038/s41588-022-01058-3. View

Huang W, Xiao J, Ji J, Chen L . Association of lipid-lowering drugs with COVID-19 outcomes from a Mendelian randomization study. Elife. 2021; 10. PMC: 8709572. DOI: 10.7554/eLife.73873. View

Liang H, OuYang Q . A clinical trial of combined use of rosiglitazone and 5-aminosalicylate for ulcerative colitis. World J Gastroenterol. 2008; 14(1):114-9. PMC: 2673374. DOI: 10.3748/wjg.14.114. View

Jess T, Jensen B, Andersson M, Villumsen M, Allin K . Inflammatory Bowel Diseases Increase Risk of Type 2 Diabetes in a Nationwide Cohort Study. Clin Gastroenterol Hepatol. 2019; 18(4):881-888.e1. DOI: 10.1016/j.cgh.2019.07.052. View

10.

Kobayashi T, Siegmund B, Le Berre C, Wei S, Ferrante M, Shen B . Ulcerative colitis. Nat Rev Dis Primers. 2020; 6(1):74. DOI: 10.1038/s41572-020-0205-x. View

11.

de Lange K, Moutsianas L, Lee J, Lamb C, Luo Y, Kennedy N . Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet. 2017; 49(2):256-261. PMC: 5289481. DOI: 10.1038/ng.3760. View

12.

Ng S, Shi H, Hamidi N, Underwood F, Tang W, Benchimol E . Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017; 390(10114):2769-2778. DOI: 10.1016/S0140-6736(17)32448-0. View

13.

Abrahami D, Douros A, Yin H, Yu O, Renoux C, Bitton A . Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study. BMJ. 2018; 360:k872. PMC: 5861502. DOI: 10.1136/bmj.k872. View

14.

Pedersen G, Brynskov J . Topical rosiglitazone treatment improves ulcerative colitis by restoring peroxisome proliferator-activated receptor-gamma activity. Am J Gastroenterol. 2010; 105(7):1595-603. DOI: 10.1038/ajg.2009.749. View

15.

Chen X, Kong J, Pan J, Huang K, Zhou W, Diao X . Kidney damage causally affects the brain cortical structure: A Mendelian randomization study. EBioMedicine. 2021; 72:103592. PMC: 8498227. DOI: 10.1016/j.ebiom.2021.103592. View

16.

Lewis J, Lichtenstein G, Deren J, Sands B, Hanauer S, Katz J . Rosiglitazone for active ulcerative colitis: a randomized placebo-controlled trial. Gastroenterology. 2008; 134(3):688-95. PMC: 2276587. DOI: 10.1053/j.gastro.2007.12.012. View

17.

Wang T, Yang J, Buse J, Pate V, Tang H, Barnes E . Dipeptidyl Peptidase 4 Inhibitors and Risk of Inflammatory Bowel Disease: Real-world Evidence in U.S. Adults. Diabetes Care. 2019; 42(11):2065-2074. PMC: 6804610. DOI: 10.2337/dc19-0162. View

18.

DeMarsilis A, Reddy N, Boutari C, Filippaios A, Sternthal E, Katsiki N . Pharmacotherapy of type 2 diabetes: An update and future directions. Metabolism. 2022; 137:155332. DOI: 10.1016/j.metabol.2022.155332. View

19.

Kang E, Han K, Chun J, Soh H, Park S, Im J . Increased Risk of Diabetes in Inflammatory Bowel Disease Patients: A Nationwide Population-based Study in Korea. J Clin Med. 2019; 8(3). PMC: 6463263. DOI: 10.3390/jcm8030343. View

20.

Fang S, Yarmolinsky J, Gill D, Bull C, Perks C, Davey Smith G . Association between genetically proxied PCSK9 inhibition and prostate cancer risk: A Mendelian randomisation study. PLoS Med. 2023; 20(1):e1003988. PMC: 9810198. DOI: 10.1371/journal.pmed.1003988. View