PMID- 38313367 OWN - NLM STAT- MEDLINE DCOM- 20240206 LR - 20240301 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 15 DP - 2024 TI - Causal linkage between type 2 diabetes mellitus and inflammatory bowel disease: an integrated Mendelian randomization study and bioinformatics analysis. PG - 1275699 LID - 10.3389/fendo.2024.1275699 [doi] LID - 1275699 AB - BACKGROUND: Observational studies have indicated associations between type 2 diabetes mellitus (T2DM) and both colorectal cancer (CRC) and inflammatory bowel disease (IBD). However, the underlying causality and biological mechanisms between these associations remains unclear. METHODS: We conducted a bidirectional Mendelian randomization (MR) analysis employing summary statistics from genome-wide association studies involving European individuals. The inverse variance weighting (IVW) method was the primary method used to assess causality. Additionally, we applied MR Egger, Weighted median, Simple mode, and Weighted mode to evaluate the robustness of the results. Outliers were identified and eliminated using the MR-PRESSO, while the MR-Egger intercept was used to assess the horizontal pleiotropic effects of single nucleotide polymorphisms (SNPs). The heterogeneity was evaluated using the Cochrane Q test, and sensitivity analysis was performed using leave-one-out method. The F statistic was calculated to evaluate weak instrumental variable bias. Finally, a pilot bioinformatics analysis was conducted to explore the underlying biological mechanisms between T2DM and IBD/UC. RESULTS: The IVW results demonstrated that T2DM significantly reduced risks of IBD (OR=0.885, 95% CI: 0.818-0.958, P=0.002) and ulcerative colitis (UC) (OR=0.887, 95% CI: 0.812-0.968, P=0.007). Although the 95% CIs of MR Egger, Weighted median, Simple mode, and Weighted mode were broad, the majority of their estimates were consistent with the direction of IVW. Despite significant heterogeneity among SNPs, no horizontal pleiotropy was observed. The leave-one-out analysis showed that the causality remained consistent after each SNP was removed, underscoring the reliability of the results. Reverse MR analysis indicated that genetic susceptibility to both CRC and IBD had no significant effect on the relative risk of T2DM. Ten hub genes were identified, which mainly enriched in pathways including maturity onset diabetes of the young, thyroid cancer, gastric acid secretion, longevity regulating pathway, melanogenesis, and pancreatic secretion. CONCLUSION: The presence of T2DM does not increase the risk of CRC or IBD. Moreover, T2DM might reduce risk of IBD, including UC. Conversely, the occurrence of CRC or IBD does not influence the risk of T2DM. The association between T2DM and IBD/UC may be related to the changes in multiple metabolic pathways and CTLA-4-mediated immune response. CI - Copyright (c) 2024 Xiao, Wu, Yi, You, Li and Xiao. FAU - Xiao, Xiang AU - Xiao X AD - TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Wu, Xuanyu AU - Wu X AD - TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Yi, Lu AU - Yi L AD - TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - You, Fengming AU - You F AD - TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China. AD - Cancer Institute, Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Li, Xueke AU - Li X AD - TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China. FAU - Xiao, Chong AU - Xiao C AD - TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China. AD - Cancer Institute, Chengdu University of Traditional Chinese Medicine, Chengdu, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20240119 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 SB - IM MH - Humans MH - *Diabetes Mellitus, Type 2/epidemiology/genetics MH - Genome-Wide Association Study MH - Mendelian Randomization Analysis MH - Reproducibility of Results MH - *Inflammatory Bowel Diseases/genetics MH - *Colitis, Ulcerative MH - Computational Biology PMC - PMC10836595 OTO - NOTNLM OT - Crohn's disease OT - bidirectional Mendelian randomization OT - colorectal cancer OT - inflammatory bowel disease OT - single nucleotide polymorphisms OT - type 2 diabetes mellitus OT - ulcerative colitis COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2024/02/05 06:42 MHDA- 2024/02/06 06:42 PMCR- 2024/01/01 CRDT- 2024/02/05 04:40 PHST- 2023/08/11 00:00 [received] PHST- 2024/01/05 00:00 [accepted] PHST- 2024/02/06 06:42 [medline] PHST- 2024/02/05 06:42 [pubmed] PHST- 2024/02/05 04:40 [entrez] PHST- 2024/01/01 00:00 [pmc-release] AID - 10.3389/fendo.2024.1275699 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2024 Jan 19;15:1275699. doi: 10.3389/fendo.2024.1275699. eCollection 2024.