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Article(id=1240375112952762667, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240375105386238038, articleNumber=null, orderNo=null, doi=10.20043/j.cnki.MPM.202311476, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1700755200000, receivedDateStr=2023-11-24, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773658071982, onlineDateStr=2026-03-16, pubDate=1711296000000, pubDateStr=2024-03-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773658071982, onlineIssueDateStr=2026-03-16, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773658071982, creator=13701087609, updateTime=1773658071982, updator=13701087609, issue=Issue{id=1240375105386238038, tenantId=1146029695717560320, journalId=1227665162245664772, year='2024', volume='51', issue='6', pageStart='961', pageEnd='1152', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773658070179, creator=13701087609, updateTime=1773658539618, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1240377074414833974, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240375105386238038, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1240377074414833975, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240375105386238038, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1012, endPage=1016, ext={EN=ArticleExt(id=1240375113263141175, articleId=1240375112952762667, tenantId=1146029695717560320, journalId=1227665162245664772, language=EN, title=Causal associations of female estrogen with the risk of incidence and mortality of breast cancer: a Mendelian randomization study, columnId=1228016568949474136, journalTitle=Modern Preventive Medicine, columnName=Child and Adolescent Health, Maternal and Child Health, runingTitle=null, highlight=null, articleAbstract=
Objective

To investigate the causal association between estrogen and breast cancer incidence and mortality risk.

Methods

Using summary data from genome-wide association studies, with estradiol representing estrogen, genetic variants associated with estradiol were utilized as instrument variables.Employing the univariate Mendelian randomization method, the causal association between estradiol and the risk ofincidence (4 outcomes), as well as the risk of mortality (6 outcomes) of female breast cancer and its subtypes, were assessed by the inverse variance-weighted method.

Results

The results revealed that elevated levels of estradiol (≥175 pmol/L)were associated with an increased risk of overall breast cancer (OR=1.43,95% CI:1.27-1.60,P=2.92×10-9), estrogen receptor-negative breast cancer (OR=1.41, 95% CI:1.25-1.60, P=2.16×10-8), and estrogen receptor-positive breast cancer (OR=1.49, 95% CI:1.29-1.72, P=6.92×10-8) incidence. However, there was no evidence that elevated levels of estradiol were the risk factors for triple-negative breast cancer incidence. Moreover, overall breast cancer and its subtypes mortality risks were not shown to be causally related to estradiol.

Conclusion

Elevated estrogen levels (≥175 pmol/L) are associated with an increased risk of overall breast cancer, estrogen receptor-negative breast cancer, and estrogen receptor-positive breast cancer incidence.

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目的

探索雌激素与女性乳腺癌发病和死亡风险的关系。

方法

使用公开发表的全基因组关联研究汇总数据，以雌二醇代表雌激素，将与雌二醇相关的遗传位点作为工具变量，采用单变量孟德尔随机化（逆方差加权法）方法，评估雌激素（雌二醇）与女性乳腺癌及其亚型的发病风险（4项指标）和死亡风险（6项指标）间的因果关联。

结果

雌二醇水平较高（≥175 pmol/L）会增加乳腺癌（不分型）的发病风险（OR=1.43，95% CI：1.27~1.60，P=2.92×10-9）；雌二醇水平较高也是雌激素受体阴性乳腺癌（OR=1.41，95% CI：1.25~1.60，P=2.16×10-8）与雌激素受体阳性乳腺癌（OR=1.49，95% CI：1.29~1.72，P=6.92×10-8）发病的危险因素；未发现雌二醇与三阴性乳腺癌发病风险的因果关联；未发现雌二醇与乳腺癌及其亚型死亡风险的因果关联。

结论

雌激素水平较高（≥175 pmol/L）是乳腺癌（不分型）、雌激素受体阴性与雌激素受体阳性乳腺癌发病的危险因素。

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朱彩蓉，E-mail：
, copyrightStatement=本刊刊出的所有文章不代表中华预防医学会和本刊编委会的观点，除非特别声明。, copyrightOwner=中华预防医学会和四川大学华西公共卫生学院, extLink=null, articleAbsUrl=null, sourceXml=yxwwPoHr90uIpBV/AEra/Q==, magXml=GHdT0HUCYSFji/ZNSkkrzg==, pdfUrl=null, pdf=EZgwTjHI0/QRJGL7zQgCWw==, pdfFileSize=601883, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=L8gOEXDvx1b74Ef64Gj8kA==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=Imq7vTlJ8KcA1tvzAVyKrA==, mapNumber=null, authorCompany=null, fund=null, authors=

李增俊（1997—），男，硕士在读，研究方向：孟德尔随机化方法在流行病学领域的应用

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李增俊（1997—），男，硕士在读，研究方向：孟德尔随机化方法在流行病学领域的应用

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注：TN：三阴性乳腺癌；ER-：雌激素受体阴性乳腺癌；ER+：雌激素受体阳性乳腺癌。

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注：TN：三阴性乳腺癌；ER-：雌激素受体阴性乳腺癌；ER+：雌激素受体阳性乳腺癌。

, figureFileSmall=xuyFSqWT9UwG16pl+ImBKw==, figureFileBig=QJGe4qL7JSXc3v0oY4JbiQ==, tableContent=null), ArticleFig(id=1240746306700899099, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375112952762667, language=EN, label=Table 1, caption=

Data sources for estradiol and breast cancer GWAS

, figureFileSmall=null, figureFileBig=null, tableContent=
变量发表年份人群性别样本量PMID
暴露
雌二醇2021欧洲人女不低于检测下限：37 461；低于检测下限：126 52434 255 042
结局
乳腺癌发病风险
乳腺癌（不分型）2020欧洲人女病例组：133 348；对照组：113 78931 605 532
TN2020欧洲人女病例组：8 602；对照组：91 47731 605 532
ER-2017欧洲人女病例组：21 468；对照组：105 97429 059 683
ER+2017欧洲人女病例组：69 501；对照组：105 97429 059 683
乳腺癌死亡风险
5年死亡，ER-2021欧洲人女死亡例数：638；总病例数：6 41134 407 845
5年死亡，ER+2021欧洲人女死亡例数：773；总病例数：27 34034 407 845
15年死亡，乳腺癌（不分型）2021欧洲人女死亡例数：7 531；总病例数：91 68634 407 845
15年死亡，TN2021欧洲人女死亡例数：677；总病例数：5 63134 407 845
15年死亡，ER-2021欧洲人女死亡例数：907；总病例数：6 85234 407 845
15年死亡，ER+2021欧洲人女死亡例数：2 298；总病例数：30 13734 407 845
), ArticleFig(id=1240746306843505448, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375112952762667, language=CN, label=表1, caption=

雌二醇与乳腺癌GWAS汇总数据信息

, figureFileSmall=null, figureFileBig=null, tableContent=
变量发表年份人群性别样本量PMID
暴露
雌二醇2021欧洲人女不低于检测下限：37 461；低于检测下限：126 52434 255 042
结局
乳腺癌发病风险
乳腺癌（不分型）2020欧洲人女病例组：133 348；对照组：113 78931 605 532
TN2020欧洲人女病例组：8 602；对照组：91 47731 605 532
ER-2017欧洲人女病例组：21 468；对照组：105 97429 059 683
ER+2017欧洲人女病例组：69 501；对照组：105 97429 059 683
乳腺癌死亡风险
5年死亡，ER-2021欧洲人女死亡例数：638；总病例数：6 41134 407 845
5年死亡，ER+2021欧洲人女死亡例数：773；总病例数：27 34034 407 845
15年死亡，乳腺癌（不分型）2021欧洲人女死亡例数：7 531；总病例数：91 68634 407 845
15年死亡，TN2021欧洲人女死亡例数：677；总病例数：5 63134 407 845
15年死亡，ER-2021欧洲人女死亡例数：907；总病例数：6 85234 407 845
15年死亡，ER+2021欧洲人女死亡例数：2 298；总病例数：30 13734 407 845
), ArticleFig(id=1240746306927391538, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375112952762667, language=EN, label=Table 2, caption=

Basic information on estradiol instrumental variables

, figureFileSmall=null, figureFileBig=null, tableContent=
SNP所在基因EAOAβ P值R2F值
rs16991615MCM8AG0.130.024.67×10-81.82×10-414.92
rs45446698CYP3A7GT-0.210.037.62×10-122.86×10-423.43
), ArticleFig(id=1240746307036443448, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375112952762667, language=CN, label=表2, caption=

雌二醇工具变量基本信息

, figureFileSmall=null, figureFileBig=null, tableContent=
SNP所在基因EAOAβ P值R2F值
rs16991615MCM8AG0.130.024.67×10-81.82×10-414.92
rs45446698CYP3A7GT-0.210.037.62×10-122.86×10-423.43
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女性雌激素与乳腺癌发病和死亡风险因果关联的孟德尔随机化研究
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李增俊 1 , 林奕蝶 1 , 陈海畅 1 , 田韫菏 1 , 赵健 2 , 朱彩蓉 1
现代预防医学 | 儿少卫生与妇幼保健 2024,51(6): 1012-1016
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现代预防医学 | 儿少卫生与妇幼保健 2024, 51(6): 1012-1016
女性雌激素与乳腺癌发病和死亡风险因果关联的孟德尔随机化研究
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李增俊1, 林奕蝶1, 陈海畅1, 田韫菏1, 赵健2, 朱彩蓉1
作者信息
  • 1.四川大学华西公共卫生学院/华西第四医院流行病学与卫生统计学系，四川 成都 610041
  • 2.南方科技大学公共卫生及应急管理学院

    • 李增俊（1997—），男，硕士在读，研究方向：孟德尔随机化方法在流行病学领域的应用

通讯作者:

朱彩蓉，E-mail：
Causal associations of female estrogen with the risk of incidence and mortality of breast cancer: a Mendelian randomization study
Zeng-jun LI1, Yi-die LIN1, Hai-chang CHEN1, Yun-he TIAN1, Jian ZHAO2, Cai-rong ZHU1
Affiliations
  • West China School of Public Health / West China Fourth Hospital, Sichuan University, Chengdu, Sichuan 610041, China
出版时间: 2024-03-25 doi: 10.20043/j.cnki.MPM.202311476
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摘要
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目的

探索雌激素与女性乳腺癌发病和死亡风险的关系。

方法

使用公开发表的全基因组关联研究汇总数据，以雌二醇代表雌激素，将与雌二醇相关的遗传位点作为工具变量，采用单变量孟德尔随机化（逆方差加权法）方法，评估雌激素（雌二醇）与女性乳腺癌及其亚型的发病风险（4项指标）和死亡风险（6项指标）间的因果关联。

结果

雌二醇水平较高（≥175 pmol/L）会增加乳腺癌（不分型）的发病风险（OR=1.43，95% CI：1.27~1.60，P=2.92×10-9）；雌二醇水平较高也是雌激素受体阴性乳腺癌（OR=1.41，95% CI：1.25~1.60，P=2.16×10-8）与雌激素受体阳性乳腺癌（OR=1.49，95% CI：1.29~1.72，P=6.92×10-8）发病的危险因素；未发现雌二醇与三阴性乳腺癌发病风险的因果关联；未发现雌二醇与乳腺癌及其亚型死亡风险的因果关联。

结论

雌激素水平较高（≥175 pmol/L）是乳腺癌（不分型）、雌激素受体阴性与雌激素受体阳性乳腺癌发病的危险因素。

孟德尔随机化  /  雌激素  /  乳腺癌亚型  /  乳腺癌发病风险  /  乳腺癌死亡风险
Objective

To investigate the causal association between estrogen and breast cancer incidence and mortality risk.

Methods

Using summary data from genome-wide association studies, with estradiol representing estrogen, genetic variants associated with estradiol were utilized as instrument variables.Employing the univariate Mendelian randomization method, the causal association between estradiol and the risk ofincidence (4 outcomes), as well as the risk of mortality (6 outcomes) of female breast cancer and its subtypes, were assessed by the inverse variance-weighted method.

Results

The results revealed that elevated levels of estradiol (≥175 pmol/L)were associated with an increased risk of overall breast cancer (OR=1.43,95% CI:1.27-1.60,P=2.92×10-9), estrogen receptor-negative breast cancer (OR=1.41, 95% CI:1.25-1.60, P=2.16×10-8), and estrogen receptor-positive breast cancer (OR=1.49, 95% CI:1.29-1.72, P=6.92×10-8) incidence. However, there was no evidence that elevated levels of estradiol were the risk factors for triple-negative breast cancer incidence. Moreover, overall breast cancer and its subtypes mortality risks were not shown to be causally related to estradiol.

Conclusion

Elevated estrogen levels (≥175 pmol/L) are associated with an increased risk of overall breast cancer, estrogen receptor-negative breast cancer, and estrogen receptor-positive breast cancer incidence.

Mendelian randomization  /  Estrogen  /  Breast cancer subtypes  /  Breast cancer incidence  /  Breast cancer mortality
李增俊, 林奕蝶, 陈海畅, 田韫菏, 赵健, 朱彩蓉. 女性雌激素与乳腺癌发病和死亡风险因果关联的孟德尔随机化研究. 现代预防医学, 2024 , 51 (6) : 1012 -1016 . DOI: 10.20043/j.cnki.MPM.202311476
Zeng-jun LI, Yi-die LIN, Hai-chang CHEN, Yun-he TIAN, Jian ZHAO, Cai-rong ZHU. Causal associations of female estrogen with the risk of incidence and mortality of breast cancer: a Mendelian randomization study[J]. Modern Preventive Medicine, 2024 , 51 (6) : 1012 -1016 . DOI: 10.20043/j.cnki.MPM.202311476
正文
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乳腺癌（breast cancer）严重威胁女性健康[1]，2020年GLOBOCAN数据显示[2]，乳腺癌全球发病数达2 261 419例，全球死亡数达684 996例，占女性癌症死亡病例的六分之一。
动物实验提示雌激素可能通过刺激乳腺细胞生长和分化，影响基因表达等机制导致乳腺癌发生[3-4]，观察性研究也提示血浆雌激素浓度升高与女性乳腺癌发病风险增加有关[5-7]，但雌激素与乳腺癌患者死亡风险的关联研究存在不一致。以血浆中生物活性最强的雌激素——雌二醇[8]为例，Duggan等人发现雌二醇水平与女性乳腺癌患者的死亡风险无关[9]，而Kensler等人则认为较高浓度的乳腺癌诊断前雌二醇水平与乳腺癌患者死亡风险较高有关[10]。此外，不同乳腺癌亚型的发生机制可能存在差异[11]：一项细胞实验显示，雌激素受体（estrogen receptor，ER）与雌激素结合生成复合物，增加细胞DNA受损风险[7]，进而影响雌激素受体阳性（estrogen receptor-positive，ER+）乳腺癌亚型的发生发展；而一项综述表明降低雌激素水平无法预防雌激素受体阴性（estrogen receptor-negative，ER-）乳腺癌亚型发病[12]。
虽然大量观察性研究探索了雌激素与乳腺癌发病及死亡的关联[5,9,13]，但关于两者因果关联的证据较少。公开发表的全基因组关联研究（genome-wide association study，GWAS）数据，使采用孟德尔随机化[14]（Mendelian randomization，MR）进行因果关联分析成为可能。Nounu等人基于MR方法的研究提示雌二醇水平升高是乳腺癌（不分型）及ER+亚型发病的危险因素[15]。但该研究使用的有关雌二醇的GWAS数据样本量较小，其代表性可能不足，且该研究未对雌二醇与乳腺癌死亡的因果关联进行探索。
因此，本研究使用可获得的样本量更大的GWAS数据，基于MR的方法，以雌二醇代表雌激素，探索雌激素与乳腺癌及其分型的发病和死亡风险的因果关联，为乳腺癌发生和预后提供因果关联证据。
1 数据与方法
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1.1 数据来源
雌二醇的遗传数据来自于一项公开发表的GWAS数据[16]，总样本量为163 985。该GWAS通过logistic回归计算获得，调整了年龄、性别、是否接受过激素替代疗法、是否使用过口服避孕药、活产次数、更年期状态等。此外，该数据中雌二醇为二分类变量，即不低于与低于检测下限（175 pmol/L）。
乳腺癌发病及死亡风险遗传关联数据来自乳腺癌协会联盟[17-19]。乳腺癌发病风险GWAS采用logistic回归计算获得，数据包括133 348例对照与113 789例病例，并调整了年龄、国家等协变量。乳腺癌细胞中主要包括ER、孕激素受体（progesterone receptor，PR）和人类表皮生长因子受体2（human epidermal receptor 2，HER2）[20]三种受体表达类型。本研究采用乳腺癌（不分型）、ER-、ER+以及三阴性（triple-negative，TN）乳腺癌（ER、PR和HER2表达均为阴性的乳腺癌）发病风险的4项指标。
乳腺癌死亡风险数据总病例数达91 686例，以乳腺癌患者作为研究对象，采用Cox比例风险回归模型计算基因型与乳腺癌特异性死亡率相关的风险比（hazard ratio，HR），调整了诊断年龄、肿瘤特征、以及与定义肿瘤分型所无关的治疗方式[18]。本研究采用5年与15年乳腺癌及其分型死亡风险数据等6项指标。
雌二醇、乳腺癌发病风险以及死亡风险数据均来自于欧洲女性人群。本研究使用的GWAS数据详细信息见表1。
1.2 研究方法
1.2.1 研究设计
本研究以雌二醇作为暴露，以乳腺癌及其亚型发病风险的4项指标、死亡风险的6项指标，共10项指标作为结局，使用两样本MR方法估计雌二醇对各结局的因果效应，研究设计见图1。MR方法基于三个基本假设[21]，本研究通过设置严格的阈值，选择与雌二醇水平相关的单核苷酸多态性（single nucleotide polymorphism，SNP）作为工具变量，以满足“关联性”假设；在工具变量选择时，筛选与混杂因素相关的SNPs并剔除，以满足“独立性”假设；为避免工具变量通过其他途径影响结局，在进行MR分析时，可进行水平多效性分析[22]，或排除具有多效性的工具变量以满足“排他性”假设。
1.2.2 工具变量选择
MR方法采用SNP作为工具变量。在雌二醇的GWAS数据中，选取具有全基因组意义的SNP（P<5×10-8）作为雌二醇的工具变量。使用来自于欧洲人群的千人基因组计划数据集作为参考面板，进行了严格的连锁不平衡（linkage disequilibrium，LD）分析，以确保工具变量之间的独立性。采用PLINK软件中的计算方法，设置LD范围在10 000 kb之内，连锁不平衡参数r2<0.001。若在结局的GWAS中没有与暴露的工具变量相匹配的SNP时，可以使用与该工具变量高度LD的SNP进行替代，范围在1 000 kb之内，r2>0.80，通过在线平台LDlink（https://ldlink.nci.nih.gov/tab=ldproxy）进行查找。
同时在PhenoScanner在线平台（http://www.phenoscanner.medschl.cam.ac.uk/）中对各SNP所关联的性状进行检索，如若SNP与混杂因素相关，则将该SNP剔除。本研究仅将成年人身体质量指数（body mass index，BMI）[23-24]作为混杂因素进行查找。
1.2.3 弱工具变量检验
通过计算F统计量，检测工具变量是否存在弱工具变量偏倚。工具变量F> 10，则认为存在弱工具变量的可能性较小[25-26]。计算公式如下：
其中，β为SNP对暴露的遗传效应估计值，MAF为较小的等位基因频率，N为暴露的GWAS样本量，SEβ为SNP对暴露的遗传效应估计值的标准误差，R2表示暴露的SNP所解释的变异比例，k表示工具变量的数量。
1.2.4 分析方法
当只有1个SNP满足工具变量筛选条件时，使用Wald比值法进行暴露对结局的因果效应的估计，即用此工具变量对暴露的效应值除以工具变量对结局的效应值。当有多个SNP满足工具变量筛选条件时，采用基于逆方差加权法（inverse-variance weighted，IVW）的MR分析作为分析方法，即对单个SNP计算的Wald 比值进行加权，探索暴露对结局的因果效应[27]。
1.3 分析软件
MR分析通过R软件（4.3.1版本）的“TwoSampleMR”程序包实现，森林图通过“forestplot”软件包绘制。
2 结果
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2.1 工具变量选择结果
根据工具变量筛选条件，最终纳入的SNP信息见表2。共有2个SNP满足要求。F统计量结果显示所有SNP均满足F>10，存在弱工具变量的可能性较小。
2.2 分析结果
2.2.1 雌激素与乳腺癌及其亚型发病风险的分析结果
IVW分析结果见图2。结果显示雌激素水平较高（≥175 pmol/L）是乳腺癌（不分型）（OR=1.43，95% CI：1.27~1.60，P=2.92×10-9）发病的危险因素。以乳腺癌亚型发病为结局的分析结果显示，雌激素水平高与ER-乳腺癌（OR=1.41，95% CI：1.25~1.60，P=2.16×10-8）和ER+乳腺癌（OR=1.49，95% CI：1.29~1.73，P=6.92×10-8）发病风险存在因果关联。未发现雌激素与TN乳腺癌（OR=1.17，95% CI：0.88~1.56，P=0.28）的发病风险之间的因果关联。
2.2.2 雌激素与乳腺癌及其亚型患者死亡风险的分析结果
IVW分析结果见图3，在6个与乳腺癌患者死亡相关的结局中，未发现遗传预测的雌激素与乳腺癌患者死亡风险的因果关联。
3 讨论
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本研究结果提示雌激素水平较高（≥175 pmol/L）是乳腺癌（不分型）（OR=1.43，P=2.92×10-9），ER-乳腺癌（OR=1.41，P=2.16×10-8）和ER+乳腺癌（OR=1.49，P=6.92×10-8）发病的危险因素，但与TN乳腺癌发病不存在因果关联。未发现雌激素与乳腺癌患者死亡风险的因果关联。
雌激素水平较高是乳腺癌（不分型）与ER+乳腺癌发病的危险因素。Fuhrman等人发现内源性游离雌激素增加与绝经后乳腺癌（不分型）风险增加显著相关[5]，这与本研究结论一致。雌激素是ER+乳腺癌生长的主要调节因子，能够与ER结合形成复合物并进入细胞核，调节基因表达并促进乳腺细胞的增殖和生长[28]，从而增加乳腺癌的风险。
雌激素水平较高也是ER-乳腺癌发病的危险因素。先前的MR研究显示雌二醇与ER-乳腺癌发病风险的因果关联OR值为1.01[15]，方向与本研究一致，但由于该GWAS样本量较小且存在弱工具变量，因此结论无统计学意义。而本研究使用的工具变量经过严格筛选，其中rs45446698位点能够影响内源性激素代谢[29]；rs16991615也已被认为能够独立影响雌激素水平[30]，工具变量可靠。既往实验研究发现，经过雌激素处理的乳腺癌细胞能够更快地从分裂间期进入分裂期，该过程受到线粒体调控，不依赖于ER信号通路[31]。此外，实验性研究提示雌激素水平升高能够诱导正常组织中PR表达[28]，雌激素可能通过PR途径对乳腺癌发病造成影响[32]。雌激素与TN乳腺癌发病不存在因果关联，未能控制PR表达可能是雌激素对ER-乳腺癌与TN乳腺癌因果效应不同的原因之一。
雌激素水平与乳腺癌及其亚型患者死亡风险的关联不明确。本研究结果提示雌激素水平与乳腺癌及其亚型患者死亡风险无因果关联，结论仅得到一项队列研究的支持[9]。虽然另外3项队列研究[10,33-34]中雌激素测量于乳腺癌患者治疗的不同阶段，但均提示雌激素水平与乳腺癌死亡风险有关联。考虑到观察性研究的固有缺陷，以及本研究中乳腺癌亚型死亡风险相关GWAS数据的死亡例数较小，提示雌激素水平与乳腺癌及其亚型患者死亡风险的关联需要进一步探索。
本研究具有以下优点：（1）采用MR方法，利用最新的GWAS数据系统全面地探索了雌激素与乳腺癌及其亚型发病、死亡的因果关联，结果不易受到混杂与反向因果的影响[35]。（2）本研究采取严格的工具变量筛选流程，SNP经过PhenoScanner检索，工具变量可靠。
本研究也存在局限性：（1）仅使用欧洲女性数据进行分析，因此将该结论推广至其他人种时还需要证据支持[36]。（2）由于测量方式的限制，本研究的雌二醇为二分类数据（不低于检测下限与低于检测下限）。然而，女性雌激素的水平呈周期性变化，根据月经周期阶段不同而波动[35]。本研究采用的雌激素水平为某一时间点测量数据，可能对女性整个月经周期雌激素水平的代表性有限。（3）数据无法区分不同PR状态，未进一步分析雌激素对PR相关乳腺癌因果效应。（4）由于工具变量数量较少，结果对于SNPs的选择比较敏感，采用共定位分析[38]能够进一步排除非共定位导致工具变量违背基本假设的情形。而本研究未能采用共定位分析评估工具变量与暴露和结果之间的关系。
基金
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  • 四川省科技计划项目(2021JDR0189)
  • 中国主要恶性肿瘤的危险因素监测及控制关键技术研究(2016YFC1302505-2)
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2024年第51卷第6期
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doi: 10.20043/j.cnki.MPM.202311476
  • 接收时间：2023-11-24
  • 首发时间：2026-03-16
  • 出版时间：2024-03-25
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  • 收稿日期：2023-11-24
基金
四川省科技计划项目(2021JDR0189)
中国主要恶性肿瘤的危险因素监测及控制关键技术研究(2016YFC1302505-2)
作者信息
    1.四川大学华西公共卫生学院/华西第四医院流行病学与卫生统计学系，四川 成都 610041
    2.南方科技大学公共卫生及应急管理学院

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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