Cross-disorder analysis of endometriosis and its comorbid diseases reveals shared genes and molecular pathways and proposes putative biomarkers of endometriosis

Abstract

Research question: Women with endometriosis are considered to be at higher risk of several chronic diseases, such as autoimmune disorders, gynaecological cancers, asthma/atopic diseases and cardiovascular and inflammatory bowel diseases. Could the study of endometriosis-associated comorbidities help to identify potential biomarkers and target pathways of endometriosis? Design: A systematic review was performed to identify all possible endometriosis-associated comorbid conditions. Next, this list of disorders was coded into MeSH terms, and the gene expression profiles were downloaded from the Phenopedia database and subsequently analysed following a systems biology approach. Results: The results identified a group of 127 candidate genes that were recurrently expressed in endometriosis and its closest comorbidities and that were defined as ‘endometriosis sibling disorders’ (ESD). The enrichment analysis showed that these candidate genes are principally involved in immune and drug responses, hormone metabolism and cell proliferation, which are well-known hallmarks of endometriosis. The expression of ESD genes was then validated on independent sample cohorts (n = 207 samples), in which the involvement of 16 genes (AGTR1, BDNF, C3, CCL2, CD40, CYP17A1, ESR1, IGF1, IGF2, IL10, MMP1, MMP7, MMP9, PGR, SERPINE1 and TIMP2) in endometriosis was confirmed. Several of these genes harbour polymorphisms that associate to either endometriosis or its comorbid conditions. Conclusions: The study results highlight the molecular processes underlying the aetiopathogenesis of endometriosis and its comorbid conditions, and identify putative endometriosis biomarkers.