Xiao Xiang, Wu Xuanyu, Yi Lu, You Fengming, Li Xueke, Xiao Chong
TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Cancer Institute, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Front Endocrinol (Lausanne). 2024 Jan 19;15:1275699. doi: 10.3389/fendo.2024.1275699. eCollection 2024.
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.
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 test, and sensitivity analysis was performed using leave-one-out method. The 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.
The IVW results demonstrated that T2DM significantly reduced risks of IBD (=0.885, 95% : 0.818-0.958, =0.002) and ulcerative colitis (UC) (=0.887, 95% : 0.812-0.968, =0.007). Although the 95% s 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.
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.
观察性研究表明2型糖尿病（T2DM）与结直肠癌（CRC）和炎症性肠病（IBD）之间存在关联。然而，这些关联背后的因果关系和生物学机制仍不清楚。
我们利用涉及欧洲个体的全基因组关联研究的汇总统计数据进行了双向孟德尔随机化（MR）分析。逆方差加权（IVW）方法是用于评估因果关系的主要方法。此外，我们应用MR Egger、加权中位数、简单模式和加权模式来评估结果的稳健性。使用MR-PRESSO识别并消除异常值，同时使用MR-Egger截距来评估单核苷酸多态性（SNP）的水平多效性效应。使用Cochrane检验评估异质性，并使用留一法进行敏感性分析。计算统计量以评估弱工具变量偏差。最后，进行了一项初步的生物信息学分析，以探索T2DM与IBD/UC之间潜在的生物学机制。
IVW结果表明，T2DM显著降低了IBD（=0.885，95%可信区间：0.818-0.958，=0.002）和溃疡性结肠炎（UC）（=0.887，95%可信区间：0.812-0.968，=0.007）的风险。尽管MR Egger、加权中位数、简单模式和加权模式的95%可信区间较宽，但其大多数估计值与IVW的方向一致。尽管SNP之间存在显著异质性，但未观察到水平多效性。留一法分析表明，在每个SNP被去除后，因果关系仍然一致，这突出了结果的可靠性。反向MR分析表明，CRC和IBD的遗传易感性对T2DM的相对风险没有显著影响。确定了10个枢纽基因，它们主要富集在包括青年发病的成年型糖尿病、甲状腺癌、胃酸分泌、长寿调节途径、黑色素生成和胰腺分泌等途径中。
T2DM的存在不会增加CRC或IBD的风险。此外，T2DM可能会降低IBD（包括UC）的风险。相反，CRC或IBD的发生不会影响T2DM的风险。T2DM与IBD/UC之间的关联可能与多种代谢途径的变化和CTLA-4介导的免疫反应有关。
