氯吡格雷使用与原发性肝癌因果关系：基于孟德尔随机化研究

摘要/Abstract

摘要： 目的：采用双样本孟德尔随机化法分析氯吡格雷使用与肝细胞癌（HCC）、肝内胆管癌（ICC）和混合型肝细胞癌-胆管癌（cHCC-CCA））的因果关系。
方法：在GWAS catalog数据库中提取2018—2021年使用氯吡格雷（n=462 933）、HCC（n=161 323）、ICC（n=476 091）及cHCC-CCA（n=218 488）数据集。以逆方差加权法为主要方法评估氯吡格雷使用与HCC、ICC及cHCC-CCA的因果关系,用MR-Egger Q检验和IVW Q检验进行异质性分析,以漏斗图评估是否存在离群值,用留一法评估结果可靠性,采用 MR-Egger 截距检验评估结果是否存在水平多效性。
结果：本研究筛选出8个与氯吡格雷使用强相关的单核苷酸多态性（SNP）作为工具变量（IV）。逆方差加权法与中位数加权法分析结果显示患者使用氯吡格雷与HCC发生存在负相关关系（OR<1,P<0.05）,患者使用氯吡格雷与ICC及cHCC-CCA的发生均无关（均P>0.05）。异质性检验结果显示氯吡格雷使用与HCC的因果关系不存在异质性（P>0.05）,MR-Egger截距检测结果表明未检测到氯吡格雷使用与HCC存在水平多效性（P>0.05）。留一法评估结果显示逐一删除单个SNP后对孟德尔随机化分析结果无显著影响。漏斗图分析结果显示所选择的IV呈对称性分布,提示结果无明显的偏倚。
结论：氯吡格雷使用与HCC的风险降低有关,但未降低ICC和cHCC-CCA的风险。

关键词: 氯吡格雷, 肝细胞癌, 肝内胆管癌, 混合型肝细胞癌, 两样本孟德尔随机化

Abstract: Objective: To investigate the potential causal relationship between clopidogrel usage and the incidence of primary liver cancer, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular-cholangiocarcinoma (cHCC-CCA), using a two-sample Mendelian randomisation (MR) approach.
Methods: Data sets on clopidogrel use (n=462 933), HCC (n=161 323), ICC (n=476 091) and cHCC-CCA (n=218 488) were obtained from the GWAS catalog database from 2018 to 2021. The causal association of clopidogrel use with HCC, ICC and cHCC-CCA was assessed using inverse variance weighting as the primary method, heterogeneity analysed by MR-Egger Q test and IVW Q test, the presence of outliers assessed by funnel plots, reliability of the results assessed by leave-one-out rows, and horizontal multivariate validity tested by MR-Egger intercept test.
Results: In this study, eight SNPs strongly associated with clopidogrel use were screened as instrumental variables (IV). The results of the inverse variance weighted and median weighted analyses showed that there was a negative correlation between clopidogrel use in patients and the occurrence of HCC (OR<1, P<0.05), and there was no significant correlation between the use of clopidogrel in patients and the occurrence of both ICC and cHCC-CCA (P>0.05). The results of the heterogeneity test showed no heterogeneity in the causal relationship between clopidogrel use and HCC (P>0.05), and the results of the MR-Egger intercept test indicated that no horizontal pleiotropy was detected between clopidogrel use and HCC (P>0.05). The leave-one-out method of assessment showed no significant effect on the results of the Mendelian randomisation analysis after deleting individual SNPs one by one.The results of funnel plot analysis showed a symmetrical distribution of the selected IV, suggesting no significant bias in the results.
Conclusion: ClopidogrelusewasassociatedwithareducedriskofHCC, but did not reduce the risk of ICC and cHCC-CCA.

Key words: Clopidogrel, Hepatocellular carcinoma, Intrahepatic cholangiocarcinoma, Combined hepatocellular-cholangiocarcinoma, Two-sample Mendelian randomisation

阳唯, 杨淑红. 氯吡格雷使用与原发性肝癌因果关系：基于孟德尔随机化研究[J]. 肝癌电子杂志, 2026, 13(1): 33-38.

Yang Wei, Yang Shuhong. Clopidogrel use and primary liver cancer causality: a Mendelian randomisation-based study[J]. Electronic Journal of Liver Tumor, 2026, 13(1): 33-38.

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