Insights from genomic studies on the role of sex steroids in the aetiology of endometriosis

Abstract

Endometriosis is a chronic neuro-inflammatory disorder the defining feature of which is the growth of tissue (lesions) that resemble the endometrium outside the uterus. Estimates of prevalence quote rates of ~10% of women of reproductive age, ~190 million women world-wide. Genetic, hormonal and immunological factors have all been proposed as contributing to risk factors associated with the development of lesions. Twin studies report the heritable component of endometriosis as ~50%. Genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that appear over-represented in patients with endometriosis, particularly those with more extensive disease (stage III/IV). In different sample populations there has been replication of SNPs near genes involved in oestrogen and other steroid regulated pathways including ESR1 (oestrogen receptor alpha), GREB1, HOXA10, WNT4 and MAPK kinase signalling. Comparisons with GWAS conducted on other patient cohorts have found links with reproductive traits (age at menarche) and disorders (fibroids, endometrial and ovarian cancer) and common co-morbities (migraine, depression, asthma). In summary, genetic analyses have provided new insights into the hormone-regulated pathways that may contribute to increased risk of developing endometriosis some of which may act in early life. New studies are needed to clarify the relationship between the many SNPs identified, the genes that they regulate and their contribution(s) to development of different forms of endometriosis. It is hope that more advanced methods allowing integration between GWAS, epigenetic and tissue expression data will improve risk analysis and reduce diagnositic delay.

A GREB1-steroid receptor feedforward mechanism governs differential GREB1 action in endometrial function and endometriosis

“…The Genome-Wide Association Studies (GWAS) have documented Single Nucleotide Polymorphisms (SNPs) in patients with endometriosis, predominantly in the stage III/IV cases. In different sample populations, there has been replication of SNPs near genes involved in estrogen and other steroid regulated pathways including ESR1 and GREB1 47 . The multiple SNPs of GREB1 constitutes most consistently associated gene with endometriosis population 27 , 28 , 47 – 50 .…”

“…In different sample populations, there has been replication of SNPs near genes involved in estrogen and other steroid regulated pathways including ESR1 and GREB1 47 . The multiple SNPs of GREB1 constitutes most consistently associated gene with endometriosis population 27 , 28 , 47 – 50 . Considering the reported SNPs of GREB1 in endometriosis 27 , 28 , 47 – 50 , it is intriguing to test the impact of these SNPs on GREB1 interaction with steroid hormone receptors.…”

“…The multiple SNPs of GREB1 constitutes most consistently associated gene with endometriosis population 27 , 28 , 47 – 50 . Considering the reported SNPs of GREB1 in endometriosis 27 , 28 , 47 – 50 , it is intriguing to test the impact of these SNPs on GREB1 interaction with steroid hormone receptors. Examining the functional relevance of these individual SNPs of GREB1 in endometriosis disease progression is of our immediate future focus.…”

Microbiome: The impact of the microbiota–gut–brain axis on endometriosis-associated symptoms: mechanisms and opportunities for personalised management strategies

“…The exact cause of endometriosis is currently undetermined, although evidence shows genetic changes may increase risk of developing the disorder (Saunders, 2022, Zondervan et al, 2018.…”

“…For example, whilst pain (cyclical or constant) and infertility are common symptoms, patients with endometriosis often present at clinics reporting a range of other problems. These include mood disorders (anxiety, depression) and symptoms affecting their digestive system, such as abdominal bloating and those mirroring irritable bowel syndrome (IBS) (Saunders andHorne, 2021, Saunders andHorne, 2023).…”