Li Ling, Li Fangxuan, Pan Zhanyu
Department of Integrated Traditional and Western Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
Department of Cancer Prevention, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Cancer Cell Int. 2025 Aug 4;25(1):295. doi: 10.1186/s12935-025-03929-1.
Our research aims to explore genetic correlation between T2D predisposition and risks of several cancers, which have been predominantly focused on populations of European ancestry. In an East Asian population, we leverage two-sample Mendelian Randomization to investigate the complex association between Type 2 Diabetes (T2D) and cancer susceptibility. This investigation utilizes genetic data summarized from three reputable sources: the Japanese ENcyclopedia of GEnetic associations by Riken (JENGER), the Asian Genetic Epidemiology Network (AGEN), and the Meta Analyses of Glucose and Insulin-related traits (MAGIC). We explored the associations between exposure datasets, which included T2D, glycated hemoglobin (HbA1c) and fasting glucose (FG) levels, and the risk of several prevalent cancers for the outcome datasets. By analyzing 174 SNPs associated with T2D, 15 SNPs related to FG, and 74 SNPs linked to HbA1c, we discovered a significant inverse relationship between T2D and the majority of cancers, including gastric (OR = 0.875, 95%CI: 0.825-0.928), breast (OR = 0.907, 95%CI: 0.850-0.967), esophageal (OR = 0.761, 95%CI:0.681-0.851), colorectal (OR = 0.877, 95%CI:0.834-0.923), hematological malignancy (OR = 0.837, 95%CI:0.752-0.933), lung (OR = 0.916, 95%CI:0.858-0.977), hepatocellular (OR = 0.865, 95%CI:0.787-0.951), prostate (OR = 0.862, 95%CI:0.812-0.914), and endometrial cancer (OR = 0.841). The power of gastric cancer, breast cancer, esophageal cancer, colorectal cancer and prostate cancer reached the desired 80%. Conversely, we did not observe a reverse correlation between T2D and specific cancers in the East Asian population. There is limited evidence that genetically predicted FG and HbA1c levels are associated with specific cancer. Moreover, conducting multivariable MR analysis did not alter the correlation between T2D and specific tumors. These findings explain the causal associations of genetic liability to T2D with various types of cancers in East Asian ancestry, and this association is not affected by glycemic biomarkers.
我们的研究旨在探索2型糖尿病易感性与几种癌症风险之间的遗传相关性，此前这主要集中在欧洲血统人群中。在东亚人群中，我们利用两样本孟德尔随机化方法来研究2型糖尿病（T2D）与癌症易感性之间的复杂关联。这项研究利用了来自三个著名来源汇总的遗传数据：日本理化学研究所的日本遗传关联百科全书（JENGER）、亚洲遗传流行病学网络（AGEN）以及葡萄糖和胰岛素相关性状的荟萃分析（MAGIC）。我们探讨了暴露数据集（包括T2D、糖化血红蛋白（HbA1c）和空腹血糖（FG）水平）与结局数据集中几种常见癌症风险之间的关联。通过分析与T2D相关的174个单核苷酸多态性（SNP）、与FG相关的15个SNP以及与HbA1c相关的74个SNP，我们发现T2D与大多数癌症之间存在显著的负相关，包括胃癌（比值比（OR）=0.875，95%置信区间（CI）：0.825 - 0.928）、乳腺癌（OR = 0.907，95%CI：0.850 - 0.967）、食管癌（OR = 0.761，95%CI：0.681 - 0.851）、结直肠癌（OR = 0.877，95%CI：0.834 - 0.923）、血液系统恶性肿瘤（OR = 0.837，95%CI：0.752 - 0.933）、肺癌（OR = 0.916，95%CI：0.858 - 0.977）、肝细胞癌（OR = 0.865, 95%CI：0.787 - 0.951）、前列腺癌（OR = 0.862，95%CI：0.812 - 0.914）和子宫内膜癌（OR = 0.841）。胃癌、乳腺癌、食管癌、结直肠癌和前列腺癌的检验效能达到了理想的80%。相反，在东亚人群中，我们未观察到T2D与特定癌症之间的反向关联。仅有有限的证据表明，基因预测的FG和HbA1c水平与特定癌症相关。此外，进行多变量孟德尔随机化分析并未改变T2D与特定肿瘤之间的相关性。这些发现解释了东亚血统人群中T2D遗传易感性与各类癌症之间的因果关联，且这种关联不受血糖生物标志物的影响。
