背景:子宫内膜异位症被认为是一种复杂的妇科疾病,可引起严重的疼痛和不孕症,影响所有育龄女性的6-10%。子宫内膜异位症是子宫内膜组织,通常排列在子宫内部,其他组织中的沉积物。子宫内膜异位症的病因和发病机制仍不明确。尽管有辩论,人们普遍认为子宫内膜异位症是一种慢性炎症性疾病,子宫内膜异位症患者似乎处于高凝状态。凝血系统在止血和炎症反应中起重要作用。因此,本研究的目的是使用公开的GWAS汇总统计数据来检验凝血因子与子宫内膜异位症风险之间的因果关系.
方法:探讨凝血因子与子宫内膜异位症发病风险之间的因果关系。我们使用了一个双样本孟德尔随机化(MR)分析框架.遵循一系列质量控制程序,以选择与暴露密切相关的合格工具变量(vWF,ADAMTS13,aPTT,FVIII,FXI,FVII,FX,ETP,PAI-1蛋白C,和纤溶酶)。使用了两个独立的欧洲血统子宫内膜异位症GWAS汇总统计数据:UKBiobank(4354例和217,500例对照)和FinnGen(8288例和68,969例对照)。我们分别在英国生物银行和FinnGen进行了MR分析,接下来是荟萃分析。Cochran的Q测试,MR-Egger截距测试,留一法敏感性分析用于评估异质性,水平多效性,和子宫内膜异位症中SNP的稳定性。
结果:我们在英国生物库对11种凝血因子进行的双样本MR分析显示,基因预测的血浆ADAMTS13水平对降低子宫内膜异位症风险具有可靠的因果效应。在FinnGen中观察到ADAMTS13的负因果效应和vWF对子宫内膜异位症的正因果效应。在荟萃分析中,因果关系仍然显著,效应大小较强.MR分析还确定了ADAMTS13和vWF对子宫内膜异位症不同亚型的潜在因果效应。
结论:我们基于来自大规模人群研究的GWAS数据的MR分析显示ADAMTS13/vWF与子宫内膜异位症风险之间存在因果关系。这些发现表明,这些凝血因子参与子宫内膜异位症的发展,并可能代表治疗这种复杂疾病的潜在治疗目标。
Endometriosis is recognized as a complex gynecological disorder that can cause severe pain and infertility, affecting 6-10% of all reproductive-aged women. Endometriosis is a condition in which endometrial tissue, which normally lines the inside of the uterus, deposits in other tissues. The etiology and pathogenesis of endometriosis remain ambiguous. Despite debates, it is generally agreed that endometriosis is a chronic inflammatory disease, and patients with endometriosis appear to be in a hypercoagulable state. The coagulation system plays important roles in hemostasis and inflammatory responses. Therefore, the purpose of this
study is to use publicly available GWAS summary statistics to examine the causal relationship between coagulation factors and the risk of endometriosis.
To investigate the causal relationship between coagulation factors and the risk of endometriosis, a two-sample Mendelian randomization (MR) analytic framework was used. A series of quality control procedures were followed in order to select eligible instrumental variables that were strongly associated with the exposures (vWF,
ADAMTS13, aPTT, FVIII, FXI, FVII, FX, ETP, PAI-1, protein C, and plasmin). Two independent cohorts of European ancestry with endometriosis GWAS summary statistics were used: UK Biobank (4354 cases and 217,500 controls) and FinnGen (8288 cases and 68,969 controls). We conducted MR analyses separately in the UK Biobank and FinnGen, followed by a meta-analysis. The Cochran\'s Q test, MR-Egger intercept test, and leave-one-out sensitivity analyses were used to assess the heterogeneities, horizontal pleiotropy, and stabilities of SNPs in endometriosis.
Our two-sample MR analysis of 11 coagulation factors in the UK Biobank suggested a reliable causal effect of genetically predicted plasma ADAMTS13 level on decreased endometriosis risk. A negative causal effect of
ADAMTS13 and a positive causal effect of vWF on endometriosis were observed in the FinnGen. In the meta-analysis, the causal associations remained significant with a strong effect size. The MR analyses also identified potential causal effects of
ADAMTS13 and vWF on different sub-phenotypes of endometrioses.
Our MR analysis based on GWAS data from large-scale population studies demonstrated the causal associations between
ADAMTS13/vWF and the risk of endometriosis. These findings suggest that these coagulation factors are involved in the development of endometriosis and may represent potential therapeutic targets for the management of this complex disease.