抗糖尿病药物与女性恶性肿瘤的因果关联:一项两样本孟德尔随机化分析

doi:10.6040/j.issn.1671-7554.0.2024.1155

摘要/Abstract

摘要： 目的孟德尔随机化方法分析外源性胰岛素、二甲双胍、罗格列酮、格列齐特等抗糖尿病药物治疗与女性恶性肿瘤发病风险的因果关联。方法使用IEU OpenGWAS project公开发布的全基因组关联研究(genome-wide association analyses, GWAS)汇总数据进行孟德尔随机化分析,将4种常用抗糖尿病药物胰岛素、二甲双胍、罗格列酮和格列齐特作为暴露因素,女性恶性肿瘤作为结局变量。采用逆方差加权法(inverse variance weighting, IVW)、MR-Egger回归法和加权中位数法进行两样本孟德尔随机化分析,其中IVW法为主要分析方法。采用IVW、MR-Egger法对分析结果进行异质性检验,利用 MR-Egger 回归截距进行多效性分析,并使用留一法评估结果的可靠性和稳定性。结果胰岛素治疗与卵巢癌发病风险存在正向因果关联(OR=1.08,95%CI: 1.03~1.14;P=0.004),与宫颈癌(OR=6.14×10^-11,95%CI: 2.00×10^-19~1.88×10^-2;P=0.018)、子宫内膜癌(OR=1.86×10^-3,95%CI: 6.47×10^-6~0.533;P=0.029)、乳腺癌(OR=4.83×10^-4;95%CI: 2.02×10^-6 ~ 0.116;P=0.006)和人体表皮生长因子受体(human epidermal growth factor receptor, HER)(+)乳腺癌亚型(OR=2.4×10^-4;95%CI: 1.64×10^-7~0.351;P=0.025)发病风险则呈负向因果关联;二甲双胍治疗与HER(+)乳腺癌亚型呈负向因果关系(OR=2.14×10^-2;95%CI: 1.36×10^-3~0.337; P=0.006)。以上研究均未发现水平多效性。结论外源性胰岛素治疗会增加卵巢癌发病风险,但会降低宫颈癌、子宫内膜癌、乳腺癌以及HER(+)乳腺癌亚型发病风险;二甲双胍治疗可以降低HER+乳腺癌亚型发病风险。

关键词: 女性恶性肿瘤, 乳腺癌, 胰岛素, 二甲双胍, 孟德尔随机化

Abstract: Objective To investigate the causal associations between antidiabetic medications(exogenous insulin, metformin, rosiglitazone, and gliclazide)and the risk of malignant tumours in women using Mendelian randomisation. Methods Summary-level data from genome-wide association studies(GWAS)in the IEU OpenGWAS project were analyzed. Exposures included four antidiabetic drugs(insulin, metformin, rosiglitazone, and gliclazide), with female malignant tumours as the outcome. Two-sample Mendelian randomisation analyses were conducted using inverse variance weighting(IVW, primary method), MR-Egger regression, and weighted median approaches. Heterogeneity was assessed via IVW and MR-Egger, pleiotropy was evaluated using MR-Egger intercepts, and leave-one-out sensitivity analysis tested result robustness. Results This study showed a positive causal association between insulin treatment and the risk of ovarian cancer(OR=1.08,95%CI: 1.03-1.14; P=0.004), a negative causal association with the risk of cervical cancer(OR=6.14×10^-11,95%CI: 2.00×10^-19-1.88×10^-2; P=0.018), endometrial cancer(OR=1.86×10^-3,95%CI: 6.47×10^-6-0.533; P=0.029), breast cancer(OR=4.83×10^-4;95%CI: 2.02×10^-6-0.116; P=0.006), and HER(+)breast cancer subtype(OR=2.4×10^-4;95%CI: 1.64×10^-7-0.351; P=0.025), and a negative causal association between metformin treatment and human epidermal growth factor receptor(HER)(+)breast cancer subtypes(OR=2.14×10^-2;95%CI: 1.36×10^-3-0.337; P=0.006). No horizontal pleiotropy was found in any of the above studies. Conclusion Exogenous insulin increases ovarian cancer risk but reduces risks of cervical, endometrial, breast, and HER(+)breast cancers. Metformin lowers HER+ breast cancer risk.

Key words: Female malignant tumours, Breast cancer, Insulin, Metformin, Mendelian randomisation

中图分类号:

R737.3

王雪梅,杨豪,宋洋,程世超,张婷婷,王艳春. 抗糖尿病药物与女性恶性肿瘤的因果关联:一项两样本孟德尔随机化分析[J]. 山东大学学报 (医学版), 2025, 63(6): 67-77.

WANG Xuemei, YANG Hao, SONG Yang, CHENG Shichao, ZHANG Tingting, WANG Yanchun. Causal association of antidiabetic drugs with female malignant tumours: a two-sample Mendelian randomisation study[J]. Journal of Shandong University (Health Sciences), 2025, 63(6): 67-77.

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