The Genetic Basis of Endometriosis: Evidence from a Systematic Review and MetaAnalysis

Objectives: To examine the genetic factors associated with the development and progression of endometriosis. To gain insight into how these factors influence disease susceptibility among women with similar risk profiles, enhance risk stratification, improve the potential for personalized treatment, and identify new therapeutic targets. Evidence Review: The systematic review was conducted using PubMed, the Cochrane Library, Scopus, Medline (via EBSCO), CINAHL Ultimate (via EBSCO), and Google Scholar. The review included primary case-control studies that examined genetic traits, gene mutations, gene expression patterns, or inheritance patterns associated with endometriosis in women of reproductive age (15-49 years) from inception to 20 March 2025. Studies were excluded if they involved animal models, cell lines, adenomyosis, ovarian cancer, drugs, or addressed issues not linked to genetics or inheritance patterns. In addition, case reports, reviews, systematic reviews, and meta-analyses were excluded. Two independent reviewers, working autonomously, performed study screening and eligibility assessment to ensure an objective and thorough process. The Modified Newcastle-Ottawa Scale was used to assess the risk of bias. A total of 44 studies were included in the meta-analysis examining the association between genetic variants and 25,347 endometriosis patients compared with 47,312 controls. Data synthesis was carried out using a combination of random-effects meta-analysis, narrative synthesis, and functional enrichment analysis. Results: Fifty-two studies were included in the analysis of genetic variants and gene expression patterns. Meta-analysis of genetic variant studies (n=44) showed a significant association with endometriosis risk, with a pooled odds ratio of 1.50 (95% confidence interval (CI) 1.22–1.86; I² = 82.1%). Quantitative synthesis of the gene expression studies (n=8) yielded an overall effect estimate of standardised mean difference (SMD) of 0.78 (95% confidence interval (CI) −3.49 to 5.05; I² = 98.4%). Analysis indicated gene expression was heterogeneous, with qualitative assessment showing a wide range of genes recurrently dysregulated across studies. Functional pathway analysis highlighted extracellular signalling, inflammation, cellular stress responses, and growth-factor-dependent pathways as central processes implicated in the pathophysiology of endometriosis.研究目标：探究与子宫内膜异位症（endometriosis）发生及进展相关的遗传因素，解析此类因素在具有相似风险特征的女性群体中对疾病易感性的影响机制，以此优化风险分层、提升个性化治疗的可行性，并识别全新的治疗靶点。 证据综述：本系统综述检索了PubMed、Cochrane图书馆、Scopus、Medline（通过EBSCO平台）、CINAHL Ultimate（通过EBSCO平台）及Google Scholar数据库，检索时限为建库至2025年3月20日，纳入对象为针对15~49岁育龄女性开展的、探讨与子宫内膜异位症相关的遗传特征、基因突变、基因表达模式或遗传模式的原创性病例对照研究。排除标准包括涉及动物模型、细胞系、子宫腺肌病、卵巢癌、药物相关研究，以及未探讨遗传或遗传模式相关问题的研究；同时排除病例报告、综述类文章、系统综述及荟萃分析。由两名独立研究者自主完成文献筛选与纳入评估，以保障流程的客观性与全面性。采用改良纽卡斯尔-渥太华量表（Modified Newcastle-Ottawa Scale）评价偏倚风险。最终纳入44项研究开展荟萃分析，探讨遗传变异与子宫内膜异位症的关联，涉及25347例子宫内膜异位症患者及47312例对照。数据合成采用随机效应模型荟萃分析、叙述性合成及功能富集分析相结合的方法。 研究结果：本分析共纳入52项关于遗传变异与基因表达模式的研究。针对遗传变异研究（n=44）的荟萃分析显示，其与子宫内膜异位症风险存在显著关联，合并比值比为1.50（95%置信区间（CI）：1.22~1.86；I²=82.1%）。针对基因表达研究（n=8）的定量合成结果显示，标准化均数差（standardised mean difference, SMD）的总体效应估计值为0.78（95%置信区间（CI）：-3.49~5.05；I²=98.4%）。分析表明基因表达存在异质性，定性评估显示多项研究中均有大量基因反复出现表达失调。功能通路分析显示，细胞外信号传导、炎症反应、细胞应激反应及生长因子依赖通路是子宫内膜异位症病理生理学中的核心过程。