Sasamoto Naoko, Ngo Long H, Vitonis Allison F, Dillon Simon T, Aziz Maryam, Shafrir Amy L, Missmer Stacey A, Libermann Towia A, Terry Kathryn L
Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA, USA.
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
EBioMedicine. 2025 May;115:105688. doi: 10.1016/j.ebiom.2025.105688. Epub 2025 Apr 11.
Endometriosis is a chronic inflammatory condition characterised by pain and infertility. We conducted a prospective study to elucidate the pathophysiological mechanisms underlying endometriosis development.
We examined the association between 1305 proteins measured by SomaScan proteomics and risk of endometriosis diagnosis in prospectively collected plasma from 200 laparoscopically-confirmed endometriosis cases and 200 risk-set sampling matched controls within the Nurses' Health Study II (NHSII) cohort. Using conditional logistic regression, we calculated odds ratios (OR) and 95% confidence intervals (CI) per one standard deviation increase in protein levels and area under the curve (AUC) to assess the multi-protein model in discriminating cases from controls. Analytical validation for three proteins was performed using immunoassays. Ingenuity Pathway Analysis and STRING analyses identified biological pathways and protein interactions.
Blood samples from cases were collected up to 9 years before diagnosis (median = 4 years). Among 61 individual proteins nominally significantly associated with risk of endometriosis diagnosis compared to controls, endometriosis cases had higher plasma levels of S100A9 (OR = 1.52, 95%CI = 1.19-1.94), ICAM2 (OR = 1.47, 95%CI = 1.17-1.85), HIST1H3A (OR = 1.42, 95%CI = 1.31-1.78), TOP1 (OR = 1.95, 95%CI = 1.24-3.06), CD5L (OR = 1.23, 95%CI = 1.00-1.51) and lower levels of IGFBP1 (OR = 0.70, 95%CI = 0.52-0.94). We further evaluated three of the proteins in an independent set of 103 matched case-control pairs within the NHSII cohort. Pathway analyses revealed upregulation of multiple immune-related pathways in blood samples collected years before endometriosis diagnosis.
In this prospective analysis using aptamer-based proteomics, we identified multiple proteins and biological pathways related to innate immune response upregulated years before endometriosis surgical diagnosis, suggesting the role of immune dysregulation in endometriosis development.
This study was supported by the Department of Defence, the 2017 Boston Center for Endometriosis Trainee Award. Investigators were supported by Aspira Women's Health and NIH which were not directly related to this project.
子宫内膜异位症是一种以疼痛和不孕为特征的慢性炎症性疾病。我们进行了一项前瞻性研究，以阐明子宫内膜异位症发生的病理生理机制。
在护士健康研究II（NHSII）队列中，我们检测了通过SomaScan蛋白质组学测量的1305种蛋白质与200例经腹腔镜确诊的子宫内膜异位症病例以及200例风险集抽样匹配对照的前瞻性采集血浆中子宫内膜异位症诊断风险之间的关联。使用条件逻辑回归，我们计算了蛋白质水平每增加一个标准差的比值比（OR）和95%置信区间（CI）以及曲线下面积（AUC），以评估多蛋白质模型区分病例与对照的能力。使用免疫测定法对三种蛋白质进行了分析验证。 Ingenuity Pathway Analysis和STRING分析确定了生物途径和蛋白质相互作用。
病例的血样在诊断前长达9年采集（中位数 = 4年）。与对照组相比，在名义上与子宫内膜异位症诊断风险显著相关的61种个体蛋白质中，子宫内膜异位症病例的血浆中S100A9水平较高（OR = 1.52，95%CI = 1.19 - 1.94）、ICAM2（OR = 1.47，95%CI = 1.17 - 1.85）、HIST1H3A（OR = 1.42，95%CI = 1.31 - 1.78）、TOP1（OR = 1.95，95%CI = 1.24 - 3.06）、CD5L（OR = 1.23，95%CI = 1.00 - 1.51），而IGFBP1水平较低（OR = 0.70，95%CI = 0.52 - 0.94）。我们在NHSII队列中另外103对匹配的病例对照中进一步评估了其中三种蛋白质。通路分析显示，在子宫内膜异位症诊断前数年采集的血样中多种免疫相关通路上调。
在这项使用适体蛋白质组学的前瞻性分析中，我们鉴定出了在子宫内膜异位症手术诊断前数年上调的与先天免疫反应相关的多种蛋白质和生物途径，提示免疫失调在子宫内膜异位症发生中的作用。
本研究由国防部、2017年波士顿子宫内膜异位症研究中心学员奖资助。研究人员得到了Aspira Women's Health和NIH的支持，与本项目无直接关联。
