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

https://doi.org/10.1016/j.rbmo.2019.11.003Get rights and content

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.

Introduction

Endometriosis is one of the most common chronic gynaecological conditions, characterized by the presence of endometrial-like tissue that undergoes proliferation, bleeding and regeneration outside the uterine cavity (Mathew et al., 2016). Its prevalence in women of reproductive age is 2–10%, and is as high as 35–50% in women with pain and/or infertility (Baranov et al., 2015; Fassbender et al., 2015).

There are different theories of the possible causes of the disease but the exact mechanisms are still unknown. Treatment encompasses the removal of ectopic endometrial lesions by invasive surgery. Definitive diagnosis is currently made through surgical inspection and histological assessment of the removed endometriotic implants. However, the invasiveness of this diagnostic approach leads to the diagnosis often being delayed for many years, with an estimated average of up to 5–10 years (Soliman et al., 2017). Reducing the time to diagnosis would enhance the quality of life of affected women by making the available medical or surgical options more successful with earlier intervention. There is a strong international recognition that accurate minimally invasive diagnostic markers and more effective disease-modifying agents are needed for this commonly occurring disease (D'Hooghe et al., 2019; Rogers et al., 2017).

Women with endometriosis often present with other comorbidities, i.e. co-occurrence of one or more additional diseases. However, epidemiological data concerning the incidence of endometriosis and its comorbidity with various chronic conditions are often fragmented (Surrey et al., 2018), which adds even more complexity to the study of this co-occurrence. It seems that it could hold a strong relationship with complex immune disorders, since patients with endometriosis are at higher risk of autoimmune diseases, gynaecological cancers, asthma/atopic diseases, cardiovascular and inflammatory bowel diseases (Kvaskoff et al., 2015; Shigesi et al., 2019; Sinaii et al., 2002; Yuan et al., 2018). In fact, it is well known that endometriosis shares some characteristics with autoimmune diseases, such as Graves’ disease, polyclonal B-cell activation, abnormal function of T and B cells, inflammatory tissue damage (Yuk et al., 2016), altered immune surveillance or a heightened humoral immune response (Kvaskoff et al., 2015), and with ovarian cancer, such as invasion, unrestrained growth or neoangiogenesis (Samimi et al., 2019; Tarín et al., 2015). Altogether, these observations suggest that different diseases co-occurring with endometriosis could be genetically and clinically linked.

The objective of the present study was to identify the overlap between the molecular processes and biological functions underlying endometriosis and its comorbidities, which could explain the co-occurrence of these diseases with endometriosis and could lead to identification of potential specific biomarkers of this chronic disease.

Section snippets

Systematic search of the literature

A systematic review of the literature up to May 2018 in PubMed was performed to create a complete list of clinical conditions comorbid with endometriosis. The systematic review was independently conducted by two researchers (E.V. and S.A.) in agreement with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) (Moher et al., 2009) (see the protocol at PROSPERO: www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018095469).

The term ‘endometriosis’

Identification of conditions comorbid with endometriosis and gene-based dendrogram

The flow chart of the systematic review of the literature is presented in Supplemental Figure 1. Reasons for first exclusion after abstract evaluation included non-human studies, non-English-language papers, non-available abstract, or articles reporting either a negative or non-existent relationship between endometriosis and comorbid diseases. After exclusion of duplicates and removal of all potentially not eligible studies, a total of 50 publications was selected to search for disease terms,

Discussion

The systematic literature search of all diseases co-occurring with endometriosis identified a common molecular signature between endometriosis and its comorbidities that could explain their co-occurrence and propose informative biomarkers for endometriosis. This approach has indeed been successful in unravelling the molecular basis and biomarker discovery in other complex disorders such as bipolar disorder, type 2 diabetes mellitus, asthma and autism (Aguilar et al., 2017; Díaz-Beltrán et al.,

Acknowledgements

This work was supported by the Spanish Ministry of Education, Culture and Sport (grant FPU15/01193); the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (FEDER), grants RYC-2016-21199 and ENDORE SAF2017-87526; Programa Operativo FEDER Andalucía (B-CTS-500-UGR18); the Junta de Andalucía [BIO-302]; the University of Jaén [PAIUJA-EI_CTS02_2017]; the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of

Eva Vargas is a PhD student at the Department of Experimental Biology, University of Jaen, Jaen, Spain. She is currently engaged in computational biology studies of female infertility, sterility and embryo implantation.

Key Message

The study of endometriosis and its comorbidities under a systems biology approach may lead to a better understanding of the molecular basis underlying this gynaecological condition as well as the identification of putative associated biomarkers.

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    Eva Vargas is a PhD student at the Department of Experimental Biology, University of Jaen, Jaen, Spain. She is currently engaged in computational biology studies of female infertility, sterility and embryo implantation.

    Key Message

    The study of endometriosis and its comorbidities under a systems biology approach may lead to a better understanding of the molecular basis underlying this gynaecological condition as well as the identification of putative associated biomarkers.

    These authors contributed equally to this work.

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