PubMed · 7032299
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O Käser. 1981-12-15. Function-retaining or function-restoring gynecologic surgery.. https://doi.org/10.1016/s0002-9378(16)32677-1
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BACKGROUND: Endometriosis affects about 10% of women usually of reproductive age. It often has severe negative impacts on patients' quality of life, but the average time to a definitive diagnosis remains 7-9 years, and there are few effective therapeutic options. Relatively little is known about the genetic drivers of the disease even though its heritability is fairly high. A recent large genome wide association study (GWAS) meta-analysis identified 42 genomic loci associated with risk of endometriosis, but together these explain only 5% of disease variance. METHODS: We used the PrecisionLife® combinatorial analytics platform to identify multi-SNP disease signatures significantly associated with endometriosis in a white European UK Biobank (UKB) cohort. We assessed the reproducibility of these multi-SNP disease signatures as well as 35 of the 42 meta-GWAS SNPs in a multi-ancestry American endometriosis cohort from All of Us (AoU) after controlling for population structure. RESULTS: We identified 1,709 disease signatures, comprising 2,957 unique SNPs in combinations of 2-5 SNPs, that were associated with increased prevalence of endometriosis in UKB. Pathways enriched in the disease signatures included cell adhesion, proliferation and migration, cytoskeleton remodeling, angiogenesis as well as biological processes involved in fibrosis and neuropathic pain.We observed a significant enrichment of these signatures (58-88%, p<0.04) that are also positively associated with endometriosis in the AoU cohort, including one 2-SNP signature that is individually significant. Reproducibility rates were greatest for higher frequency signatures, ranging from 80-88% for signatures with greater than 9% frequency (p<0.01) in AoU. Encouragingly, the disease signatures also show high reproducibility rates in non-white European AoU sub-cohorts (66-76%, p<0.04 for signatures with greater than 4% frequency).A total of 195 unique SNPs mapping to 98 genes were identified in the high frequency reproducing signatures (>9%). Of these, 7 genes were previously identified in the endometriosis meta-GWAS study and 16 genes have a previous association with endometriosis. 75 novel genes were identified in this study.We characterized 9 novel genes that occur at the highest frequency in reproducing signatures and that do not contain any SNPs linked to known GWAS genes, providing new evidence for links between endometriosis and autophagy and macrophage biology. Reproducibility rates, ranging between 73% to 85%. are especially strong for the signatures that contain these 9 genes independently of any SNPs mapping to the meta-GWAS genes. CONCLUSION: Although using much smaller, less well-characterized datasets than the previous whole genome meta-GWAS study, combinatorial analysis has provided important new insights into the genetics and biology of endometriosis including reproducible biologically relevant genes that are overlooked by GWAS approaches.The 75 novel gene associations provide new insights and routes for study of the disease and potential new therapies. Several of the novel genes identified are credible targets for drug discovery, repurposing and/or repositioning. Using the disease signatures identified as genetic biomarkers in trials of candidates drugs targeting specific mechanisms will enable precision medicine-based approaches. We hope this will encourage new targeted therapy discovery efforts.
The pathogenesis of endometriosis is not known. The currently favoured theory is that viable endometrial cells, shed from the endometrium into the pelvic cavity by retrograde menstruation, reattach and invade other tissues. We used a collagen gel invasion assay to assess invasive potential of endometriotic cells. The invasion indices of cells from peritoneal endometriotic lesions and a metastatic bladder carcinoma cell line (EJ28) were similar (2.2-15.6 vs 8.4-11.6) whereas cells from normal endometrium and non-metastatic carcinoma cells (RT112) were non-invasive (indices < 1). Invasiveness of endometriotic cells might contribute to the pathogenesis of endometriosis.
The myometrium is usually thought of as a homogeneous mass of smooth muscle fibres. However, magnetic resonance studies of the uterus have revealed two distinct zones--the subendometrial myometrium or junctional zone and the outer myometrium. The junctional zone is not only structurally but also functionally different from the outer myometrium. For instance, myometrial contractions in a non-pregnant woman originate exclusively from the junctional zone, and their amplitude, frequency, and direction depend on the phase of the cycle. Irregular thickening of the junctional zone has been proposed as the magnetic resonance criterion for the diagnosis of diffuse adenomyosis. However, this magnetic resonance appearance relies on the disruption of the inner myometrial architecture secondary to smooth muscle hyperplasia but does not provide proof of mucosal invasion of the myometrium. We postulate that adenomyosis is a dichotomous disease characterised primarily by disruption of the inner myometrial architecture and function, with secondary infiltration of endometrial elements into the myometrium under certain circumstances. This hypothesis focuses on the inner myometrium and may explain the high incidence of superficial adenomyosis in dysfunctional uterine bleeding.