Genetic and transcriptional characterization of a region on chromosome 7p15.2 that shows pleiotropy between endometriosis and fat distribution

Endometriosis is a common women's health problem characterised by the presence of deposits resembling endometrium (lining of the uterus) on ectopic sites in the pelvis, causing chronic inflammation, severe pelvic pain and reduced fertility. Family studies indicate that the disease can be inherited. In a recent study comparing genetic information from 5,675 women with endometriosis and 9,331 controls, we found a genetic variant on chromosome 7 associated with moderate-severe endometriosis. In an independent study involving 190,803 individuals, the same genetic region was found to be associated with fat distribution (waist-hip ratio). The signal is located between genes, and it is unclear how the variant - or those in its vicinity - act on transcription of DNA and ultimately on the development of endometriosis or differences in fat distribution. We are collecting endometriotic tissue, endometrium, subcutaneous abdominal fat and blood from women undergoing a laparoscopy for symptoms of endometriosis, or for tubal sterilisation. Using these samples, we will investigate whether DNA transcription in the region of interest is different between women with moderate-severe endometriosis and controls, and between tissues. We will also explore all known genetic variants in the region, and investigate how these affect transcription levels. Implicated variants will be investigated for association with endometriosis risk, and waist-hip ratio, in up to 10,936 women. The proposed work will provide crucial information on gene regulation in the implicated region and its effect on clinical phenotypes, information required for the translation of the genome-wide association findings into clinical meaningful results that can inform the development of new (non-invasive) diagnostic methods and identification of novel drug targets.

We have identified a pleiotropic signal in an inter-genic region of ~ 900 Kb on chromosome 7p15.2, from genome-wide association (GWA) studies of moderate-severe endometriosis and differential fat distribution (waist-hip ratio, adjusted for body mass index; WHR-adjBMI). Genome-wide expression analysis in subcutaneous adipose tissue identified a local transcript that was significantly associated with the WHR-adjBMI GWA SNP. It is unclear whether: 1) this transcript is differentially expressed in relevant tissues from women with endometriosis; 2) there are other associated known or novel transcripts in the region; and 3) which genetic variants in the region are involved in their regulation. We are collecting endometriotic tissue, endometrium, sc abdominal fat, and whole blood from women undergoing a laparoscopy for: a) symptoms suggestive of endometriosis; and b) sterilisation. We propose to assess differential expression of novel and known transcripts in the 1Mb region of interest in tissues from 100 stage B endometriosis cases and 200 controls, and investigate association with endometriosis and WHR-adjBMI. Genetic variants genotyped and imputed across the region will be tested for association with transcripts (eQTL analyses); eQTL variants significantly associated will be tested for association with phenotypes in 10,936 endometriosis cases and controls. The information to be gained from the proposed study is crucial for the understanding of the GWA findings and their translation into clinically meaningful results, which include the development of non-invasive diagnostic methods (biomarkers) for endometriosis and the development of novel treatments.

The beneficiaries of our proposed research are women with endometriosis and their families; employers; health care providers; and pharmaceutical industry. Endometriosis is a heritable chronic inflammatory disease and a major women's health problem, causing severe pelvic pain and reduced fertility, estimated to affect up to 10% of women of reproductive age. Characterised by the presence of endometrial-like tissue in sites outside the uterus, it can only be diagnosed reliably through surgery. As the cause remains unknown, treatment options are limited and are invasive. These include hormonal drugs to suppress ovarian function, surgical ablation of endometriotic lesions and, in the severest of cases, removal of the pelvic organs. Endometriosis has been shown to have a major impact on health-related quality of life and work productivity. Women may require multiple admissions for surgery and/or prolonged treatment with costly drugs with problematic side-effects. In 2002, the annual direct and indirect economic costs of endometriosis were estimated between $2.2 and $22 billion in the US alone.

Two independent GWASs have implicated an inter-genic region on 7p15.2 in the development of moderate-severe endometriosis and fat distribution. This is the first time a strong, replicated genetic association signal has been found for endometriosis, however, the mechanism through which this inter-genic region acts on endometriosis risk is unclear. Understanding how known and novel transcripts in this region are regulated by genetic variants is crucial for understanding their pleiotropic role in endometriosis pathogenesis and fat distribution, and for the translation of GWA findings into clinically meaningful results through the development of new, non-invasive diagnostic pathways and identification of new drug targets.