肠道菌群与乳腺癌风险:双向两样本孟德尔随机化研究  

Gut microbiota and risk of breast cancer:a bidirectional two-sample Mendelian randomization study

作　　者：马鸿轩 张玉元 翁思远 徐辉 巴瑀皓 刘姝彤 刘灶渠 韩新巍[2] Ma Hongxuan;Zhang Yuyuan;Weng Siyuan;Xu Hui;Ba Yuhao;Liu Shutong;Liu Zaoqu;Han Xinwei(Department of Kidney Transportation,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China;Department of Interventional Radiology,the First Affiliated Hospital of Zhengzhou University,Interventional Institute of Zhengzhou University,Interventional Treatment and Clinical Research Center of Henan Province,Zhengzhou 450052,China;Department of Clinical Medicine,Zhengzhou University,Zhengzhou 450052,China;Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences,Beijing 100005,China)

机构地区：[1]郑州大学第一附属医院肾移植科,郑州450052 [2]郑州大学第一附属医院介入科,郑州大学介入研究所,河南省介入治疗临床研究中心,郑州450052 [3]郑州大学临床医学系,郑州450052 [4]中国医学科学院基础医学研究所,北京100005

出　　处：《中华微生物学和免疫学杂志》2025年第2期125-134,共10页Chinese Journal of Microbiology and Immunology

基　　金：河南省重大科技项目(221100310100)。

摘　　要：目的利用双向两样本孟德尔随机化(Mendelian randowization,MR)方法探究肠道菌群与乳腺癌及其亚型发病风险之间的因果关联。方法获取欧洲最大的肠道菌群全基因组关联研究(genome-wide association studies,GWAS)数据作为暴露,乳腺癌协会联盟(Breast Cancer Association Consortium,BCAC)的乳腺癌GWAS数据作为结局,进行双向两样本MR分析。采用逆方差加权(inverse-variance weighted,IVW)、加权中值、MR Egger回归法和MR-PRESSO进行MR分析。反向MR分析和分层分析以评估逆向因果关系和对乳腺癌亚型的影响。结果阿德勒克罗伊茨菌属(Adlercreutzia)(IVW OR=0.92,95%CI:0.87~0.98,P=0.01)和副拟杆菌属(Parabacteroides)(IVW OR=0.87,95%CI:0.79~0.96,P=0.007)对乳腺癌具有显著的保护作用,而塞利单胞菌属(Sellimonas)(IVW OR=1.05,95%CI:1.01~1.09,P=0.01)与乳腺癌风险显著相关。此外,脱硫弧菌属(Desulfovibrio)(IVW OR=0.94,95%CI:0.88~1.00,P=0.04)和瘤胃球菌科(UCG013菌属)(IVW OR=0.92,95%CI:0.86~0.99,P=0.03)显示出对乳腺癌提示性保护作用。分层分析发现阿德勒克罗伊茨菌属对乳腺癌的保护作用在雌激素受体(estrogen receptor,ER)阳性亚型中仍然存在,而脱硫弧菌属在ER阴性亚型中存在。塞利单胞菌属与ER阳性乳腺癌的风险增加有因果关系。在分子机制上,阿德勒克罗伊茨菌属功能基因CACNA1S高表达与乳腺癌预后良好相关,塞利单胞菌属功能基因ERBB4高表达与乳腺癌预后不良相关。结论本研究支持几个肠道菌群在乳腺癌中的因果效应并揭示了潜在分子机制,这可能为早期临床预防和治疗提供了新的潜在靶点。未来需要进一步探究肠道菌群如何影响乳腺癌的发展。Objective To investigate the potential causal relationships between gut microbiota composition and the risk of developing various subtypes of breast cancer by using bidirectional two-sample Mendelian randomization(MR).MethodsThe research utilized genome-wide association studies(GWAS)data on gut microbiota from the MiBioGen database and GWAS data on breast cancer from the Breast Cancer Association Consortium(BCAC).In this MR study,inverse variance weighted(IVW),weighted median,MR Egger,and MR-PRESSO methods were used.Additionally,reverse MR and stratified analyses were conducted to assess reverse causality and the impact on different subtypes of breast cancer.Results Adlercreutzia(IVW OR=0.92,95%CI:0.87-0.98,P=0.01)and Parabacteroides(IVW OR=0.87,95%CI:0.79-0.96,P=0.007)exhibited a statistically significant protective effect on breast cancer.Conversely,Sellimonas(IVW OR=1.05,95%CI:1.01-1.09,P=0.01)was significantly associated with an increased risk of breast cancer.Desulfovibrio(IVW OR=0.94,95%CI:0.88-1.00,P=0.04)and Ruminococcaceae(UCG013)(IVW OR=0.92,95%CI:0.86-0.99,P=0.03)presented suggestive protective effects against breast cancer.Furthermore,stratified analysis revealed that the protective effect of Adlercreutzia against breast cancer persisted in the estrogen receptor(ER)-positive subtypes,while Desulfovibrio persisted in the ER-negative subtypes.Sellimonas was causally associated with the risk of ER-positive subtypes.CACNA1S was identified as the functional gene of Adlercreutzia,and associated with favorable prognosis in breast cancer,while ERBB4 was identified as the functional gene of Sellimonas and associated with poor prognosis in breast cancer.ConclusionsThis study identifies the causal relationships between gut microbiota and breast cancer,suggesting a novel target for early clinical intervention and treatment,with potential implications for future functional analysis.

关 键 词：肠道菌群 乳腺癌 因果关系 孟德尔随机化 单核苷酸多态性 

分 类 号：R73[医药卫生—肿瘤]