胆囊癌（GBC）是一种罕见的消化道恶性肿瘤，其特点是预后极差。目前，关于2型糖尿病（T2D）与GBC之间的关系存在争议。此外，关于酒精摄入频率 (AIF)、初潮年龄 (AAM) 和 GBC 之间的因果关系，尚未得出明确的结论。本研究的目的是阐明 T2D、AIF、AAM 和 GBC 之间的因果关系。与暴露和结果相关的单核苷酸多态性 (SNP) 来源于综合流行病学单位 (IEU) 开放全基因组关联研究 (IEU) GWAS）数据库。具体来说，GBC的数据包括907名东亚人（所有病例的病理结果均已登记到日本生物银行）和425,707个SNP； T2D 包括 655,666 名欧洲人，拥有 5,030,727 个 SNP； AIF 由 462,346 名欧洲人和 9,851,867 名 SNP 组成； AAM 由 243,944 名欧洲人和 9,851,867 名 SNP 组成。暴露特征的测量统一从英国生物银行（UKB）数据库收集，并以标准差（SD）或对数形式的比值比（logOR）形式呈现。我们采用双样本孟德尔随机化 (MR) 分析来辨别 T2D、AIF、AAM 和 GBC 之间的因果关系。进行敏感性分析以识别和解决潜在的异质性、水平多效性和异常值。我们的研究结果表明，T2D 降低了 GBC 风险[比值比 (OR) =0.044；比值比 (OR) =0.044； 95%置信区间（CI）：0.004-0.55； P=0.015，逆方差加权（IVW）]。然而，AIF（OR = 0.158；95% CI：5.33E-05 至 466.84；P=0.65，IVW）、AAM（OR = 0.19；95% CI：0.0003-140.34；P=0.62、 IVW）和 GBC。敏感性分析未发现水平多效性、异质性或异常值的证据，表明我们结论的稳健性和可靠性。T2D 成为 GBC 的潜在保护因素，而 AIF 和 AAM 均未证明与 GBC 风险存在因果关系。调节葡萄糖代谢可能是预防 GBC.2024 Journal of Gastrointestinal Oncology 的方法之一。版权所有。

Gallbladder cancer (GBC) is a rare malignancy of the digestive tract, characterized by a remarkably poor prognosis. Currently, there is a controversy on the relationship between type 2 diabetes (T2D) and GBC. Additionally, no definitive conclusions were established regarding the causal relationships between alcohol intake frequency (AIF), age at menarche (AAM) and GBC. The objective of this study was to elucidate the causal association between T2D, AIF, AAM, and GBC.Single-nucleotide polymorphisms (SNPs) associated with exposures and outcomes were sourced from the Integrative Epidemiology Unit (IEU) Open Genome-Wide Association Study (GWAS) database. Specifically, the data of GBC comprised 907 East Asians (pathological results of all cases were registered into Biobank Japan) and 425,707 SNPs; T2D comprised 655,666 Europeans with 5,030,727 SNPs; AIF comprised 462,346 Europeans and 9,851,867 SNPs; AAM comprised 243,944 Europeans and 9,851,867 SNPs. The measurement of exposure traits is collected uniformly from the UK Biobank (UKB) database and presented in the form of standard deviation (SD) or the logarithmic form of the odds ratio (logOR). We employed a two-sample Mendelian randomization (MR) analysis to discern the causalities between T2D, AIF, AAM, and GBC. Sensitivity analyses were conducted to identify and address potential heterogeneity, horizontal pleiotropy, and outliers.Our findings indicated that T2D reduced GBC risk [odds ratio (OR) =0.044; 95% confidence interval (CI): 0.004-0.55; P=0.015, inverse variance-weighted (IVW)]. However, no causal relationship was observed between AIF (OR =0.158; 95% CI: 5.33E-05 to 466.84; P=0.65, IVW), AAM (OR =0.19; 95% CI: 0.0003-140.34; P=0.62, IVW), and GBC. Sensitivity analysis revealed no evidence of horizontal pleiotropy, heterogeneity, or outliers, suggesting the robustness and reliability of our conclusions.T2D emerged as a potentially protective factor against GBC, whereas neither AIF nor AAM demonstrated a causal relationship with GBC risk. Regulation of glucose metabolism may be one of the methods for preventing GBC.2024 Journal of Gastrointestinal Oncology. All rights reserved.