Genetic analysis confirms a link between gastrointestinal disorders and endometriosis

Endometriosis is a gynecological disorder with a definitive diagnosis based on the presence of “lesions” (tissue fragments resembling the endometrial lining of the uterus). 2 Patients typically report a diverse range of symptoms including pain at time of menstruation, chronic pelvic pain, abdominal bloating, and pain with defecation. The fact that some of these symptoms are the same as those associated with gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS) and irritable bowel disease (IBD), can lead to delays in diagnosis and difficulties designing effective clinical management plans. Studies in Australia were the first to report evidence that the risk of developing endometriosis could be associated with specific genetic subtypes. 3 More recently, the application of methods to identify single-nucleotide polymorphisms (SNPs) in genome-wide association studies (GWASs) using data from hundreds of thousands of individuals with diagnosed endometriosis, which were compared to age-/ethnic-matched controls, has identified SNPs that appear overrepresented in patients. 4 That the GWASs are providing insights into mechanisms that may contribute to the etiology of endometriosis has been backed up by the apparent association of SNPs with signaling pathways involving steroid hormones and inflammatory responses, both of which have been validated in cell, tissue, and animal model studies. 4 In this issue of Cell Reports Medicine , Yang et al. further add to our understanding of the genetic causes of endometriosis and its associated symptoms with new information that provides evidence that endometriosis shares genetic risk factors with several common GI disorders. 1 The results extend those of a genetic analysis of shared risk factors between depression and endometriosis, where “abnormality of the gastric mucosa” showed a statistical enrichment. 5 Importantly, the study by Yang et al. goes beyond the usual GWAS analysis by application of Mendelian randomization with insights on the rates of co-morbidity based on data held in the UK Biobank backed up by medication usage in the UK and Australia. The UK Biobank was launched in 2006 as a project designed to provide longitudinal data from 500,000 individuals recruited between the ages of 40 and 69. To conduct analysis of the rates of co-morbidity between endometriosis and GI disorders, the numbers of women with self-reported or diagnosed endometriosis were compared to those diagnosed with each of the common GI disorders: IBS, IBD, GORD (gastro-esophageal reflux disease), PUD (peptic ulcer disease), and combined GORD/PUD (GPM). In this dataset, there were 5,392 cases of endometriosis (adenomyosis excluded) with larger numbers of women with IBS (16,330) and GORD (22,383). They used this dataset to answer two complementary questions: were women with endometriosis more/less likely to have a diagnosis of one or more of the GI disorders, and were women with any of these five disorders more/less likely to have endometriosis? The results showed clear evidence of co-morbidity: women with endometriosis were 2× as likely to suffer from IBS and 1.4× more likely to be diagnosed with GORD than those not recorded as having endometriosis. The reciprocal finding was also true—women with IBS were 2× more likely to have a diagnosis of endometriosis. The results for PUB and IBD were not as strong, and this was also the case when genetic correlations were examined. To follow up on these epidemiological findings, the authors turned to large GWAS datasets exploring shared genetic correlations complemented by Mendelian randomization to provide an estimate of causal relationships. The GWAS analysis backed up the findings from the UK Biobank with significant genetic correlations between IBS, GORD, and the combined GPM (GORD/PUD) subtype but, interestingly, no positive correlation between endometriosis and IBD was found. IBS and GPM have previously been reported to be genetically correlated, so to avoid this influencing their results they conducted extra tests on the data. A criticism of GWAS analyses is that the identification/location of disease-associated SNPs needs to be complemented by additional evidence before inferences on their impact on disease etiology/severity can be drawn. A strength of this study is the different approaches the authors have taken to increase the power of genes/pathways identified using their genetic toolkit by searching databases containing medication usage and complementing this with searching databases of drugs that might target the products of genes identified in potential pathways shared by endometriosis and GI disorders. Some genes identified by the combined GWAS/cross-trait meta-analysis and co-localization approach had previously been identified in endometriosis but not IBS or other GI disorders. Several of these are associated with the well-established role(s) of estrogen and inflammatory processes, 2 including RERG . 6 Data from the UK Biobank also found evidence of parallels with endometriosis with significantly higher use of hormone therapies among women with IBS, GORD, and PUD but not IBD, consistent with the co-morbidity findings. Other notable novel findings included four regions shared by endometriosis and IBS/GPM ( SEMA3F , RAB5B , CCKBR [cholecystokinin type 2 receptor], and PDE4B [phosphodiesterase-4]) previously identified by GWASs as linked to GI disorders but not formally linked to endometriosis. The translational potential of the approaches described in this study is backed up by the identification of drugs designed to target the proteins encoded by CCKBR and PDE4B . CCKBR drugs are already being used for treatment of PUD and GORD and are considered an attractive therapeutic opportunity for management of chronic pain—something clearly pertinent to patients with endometriosis. 7 PDE4 is considered a promising target for modulating immune cell function, and a number of drugs targeting the activity of the protein have been developed and tested in clinical trials for respiratory, skin, and neurological disorders. 8 To date, clinical trials suggest that their use as treatment for symptoms of IBS is promising, but a review of 5 trials involving women with endometriosis concluded that there was still insufficient evidence with respect to fertility and pain outcomes. 9 In conclusion, the new insights in this study will be of interest to anyone seeking better ways to improve diagnosis and treatment of the distressing symptoms associated with both endometriosis and GI disorders. They are complemented by the evidence of a link between the gut microbiome/metabolites and the pain experience in women (the so-called “gut-brain axis” 10 ) and confirm endometriosis patient experience that has highlighted IBS-like symptoms.