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中华肝脏外科手术学电子杂志

中华肝脏外科手术学电子杂志 ›› 2025, Vol. 15 ›› Issue (01) : 79 -88. doi: 10.3877/cma.j.issn.2095-3232.2026.01.013

临床研究

遗传学视角孟德尔随机化分析东亚人群肠道菌群与原发性肝癌因果关系
薛伟伟1, 杜凯豪1, 汪占金1, 东小鸽1, 何洁洁1, 罗兰明慧1, 蒋威1, 王展2,3,†()   
  1. 1　810000　西宁，青海大学临床医学院
    2　810000　西宁，青海大学附属医院肝胆胰外科
    3　810000　西宁，青海大学附属医院医工结合与转化应用部
  • 收稿日期:2025-08-12 出版日期:2025-02-10
  • 通信作者: 王展
  • 基金资助:
    国家自然科学基金(82160131); 中国科学院“西部之光”青年学者项目

Mendelian randomization analysis of causal relationship between gut microbiota and primary liver cancer in East Asian population from the genetic perspective

Weiwei Xue1, Kaihao Du1, Zhanjin Wang1, Xiaoge Dong1, Jiejie He1, Minghui Rolan1, Wei Jiang1, Zhan Wang2,3,†()   

  1. 1 Clinical Medical College of Qinghai University, Xining 810000, China
    2 Department of Hepatobiliary and Pancreatic Surgery, Qinghai University Affiliated Hospital, Xining 810000, China
    3 Transformation and Application of Engineering Medicine, Qinghai University Affiliated Hospital, Xining 810000, China
  • Received:2025-08-12 Published:2025-02-10
  • Corresponding author: Zhan Wang
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引用本文：

薛伟伟, 杜凯豪, 汪占金, 东小鸽, 何洁洁, 罗兰明慧, 蒋威, 王展. 遗传学视角孟德尔随机化分析东亚人群肠道菌群与原发性肝癌因果关系[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 15(01): 79-88.

Weiwei Xue, Kaihao Du, Zhanjin Wang, Xiaoge Dong, Jiejie He, Minghui Rolan, Wei Jiang, Zhan Wang. Mendelian randomization analysis of causal relationship between gut microbiota and primary liver cancer in East Asian population from the genetic perspective[J/OL]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2025, 15(01): 79-88.

目的

通过孟德尔随机化（MR）方法探究东亚人群肠道菌群（GM）与原发性肝癌（PLC）之间的潜在因果关系。

方法

本研究遵循STROBE-MR指南，采用基于相关性、独立性和排他性假设的MR分析。暴露数据来自3 432名中国人的全基因组关联研究（GWAS）汇总数据，涵盖500种GM特征。PLC的数据来自日本数据库（n=161 323）和IEU open GWAS平台（n=197 611）。综合运用了逆方差加权法（IVW）、加权中位数法、MR-Egger法以及贝叶斯加权MR等多种方法，评估GM与PLC之间的因果关系。

结果

特定GM如Selenomonas、Porphyromonas endodontalis、Gemella sanguinis和Clostridium butyricum与PLC风险的增加相关；而Alistipes shahii及Bifidobacterium catenulatum-Bifidobacterium pseudocatenulatum复合群可能具有保护作用。多种MR分析方法的应用增强了研究结果的可靠性和稳健性。

结论

本研究从遗传学的角度揭示GM在PLC发生发展中作用，并突出了肠道微生物群在PLC发病机制中的关键作用。

关键词: 肠道菌群, 原发性肝癌, 孟德尔随机化, 因果, 东亚
Objective

To investigate the potential causal relationship between gut microbiota (GM) and primary liver cancer (PLC) in East Asian population by Mendelian randomization (MR) analysis.

Methods

This study was conducted following the STROBE-MR guidelines. MR analysis was performed based on the assumptions of relevance, independence and exclusion restriction. The exposure data were collected from genome-wide association study (GWAS) summary statistics in 3 432 Chinese, covering 500 GM features. The data of PLC were obtained from Japanese Database (n=161 323) and IEU Open GWAS platform (n=197 611). The inverse variance weighted (IVW), weighted median, MR-Egger and Bayesian weighted MR methods were used to evaluate the causal relationship between GM and PLC.

Results

Specific GM such as Selenomonas, Porphyromonas endodontalis, Gemella sanguinis and Clostridium butyricum were associated the increased risk of PLC. However, Alistipes shahii and Bifidobacterium catenulatum-Bifidobacterium pseudotenatum complex might exert protective effects. The application of multiple MR analysis methods enhanced the reliability and robustness of the research results.

Conclusions

This study provides novel understanding of the role of GM in the incidence and progression of PLC from the genetic perspective and highlights the key role of GM in the pathogenesis of PLC.

Key words: Gut microbiome, Primary liver cancer, Mendelian randomization, Causality, East asia
表1 东亚人群GM与PLC因果关系MR研究的GWAS数据信息
变量 第一作者 年份 样本量(例) SNP数 种族 性别
GM Liu X[13] 2022 3 432 3 432 亚洲人 男女混合
肝癌 Ishigaki K[14] 2020 197 611 197 611 亚洲人 男女混合
肝癌 Sakaue S[15] 2021 161 323 161 323 亚洲人 男女混合
图1 东亚人群GM与PLC因果关系MR研究设计 注：MR为孟德尔随机化，IVW为逆方差加权法，weighted median为加权中位数法，MR-Egger为MR-Egger 回归方法，Simple Mode为简单模式法，Weighted Mode为加权模式法，MR-PRESSO为孟德尔随机化多态性残差和离群值检验，Cochran's Q为科克伦 Q检验，Leave-one-out为留一法，GM为肠道菌群
图2 东亚人群GM与PLC因果关系MR研究的阳性结果交集图 注：GM为肠道菌群，PLC为原发性肝癌，MR为孟德尔随机化，IVW为逆方差加权法，BWMR为贝叶斯加权孟德尔随机化，NBDC为日本国家生物科学数据中心，BBJ为日本生物银行
图3 东亚人群GM与PLC因果关系MR研究的6种阳性交集结果的IVW和BWMR结果 注：GM为肠道菌群，PLC为原发性肝癌，MR为孟德尔随机化，IVW为逆方差加权法，BWMR为贝叶斯加权孟德尔随机化，NBDC为日本国家生物科学数据中心，BBJ为日本生物银行
图4 BBJ中GM（log_s_Clostridium_butyricum）对PLC因果效应MR分析的散点图 注：BBJ为日本生物银行，SNP为单核苷酸多态性，exposure指暴露（GM），inverse-variance weighted为逆方差加权法，weighted median为加权中位数法，MR-Egger为MR-Egger 回归方法，simple mode为简单模式法，weighted weighted为加权模式法；散点图是暴露因素（肠菌）与结局（肝癌）因素之间的MR分析结果，每一个点代表了一个工具变量SNP，每个点上的线反映的是95%的置信区间，横坐标是SNP对暴露因素的效应，纵坐标是SNP对结局因素的效应，两个效应做比值，即暴露对结局的效应（斜率），若结果显示不同算法的线总体是同一方向的，则说明结果可靠；GM为肠道菌群，PLC为原发性肝癌，MR为孟德尔随机化
图5 BBJ中GM对PLC因果效应MR分析的留一法图 注：BBJ为日本生物银行，Leave-one-out为留一法，exposure指暴露（GM）；留一法图是逐步剔除每个SNP，计算剩余SNP的Meta效应，观察剔除每个SNP后结果是否发生变化，如图剔除每个SNP后，总体的误差线变化不大（均在0的右侧），说明结果可靠；SNP为单核苷酸多态性，GM为肠道菌群，PLC为原发性肝癌，MR为孟德尔随机化
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