Abstract
BACKGROUND: Endometriosis is a chronic inflammatory condition characterised by pain and infertility. We conducted a prospective study to elucidate the pathophysiological mechanisms underlying endometriosis development. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: 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.