Saturday, July 12, 2014

Genetics and Endometriosis

Is there a genetic component to endometriosis? Current research says yes, although there are other factors that come into play.

"Multifactorial or polygenic disorders, such as endometriosis, are determined by multiple genes with allelic variations. Early studies by the groups of Simpson and Lamb [2,3] suggested that endometriosis has a heritable component. Endometriosis is a common, chronic, inflammatory and estrogen-dependent gynecological disease that develops as a consequence of a combination of genetic predisposition and environmental factors."

"Endometriosis is a benign disease with high prevalence in women of reproductive age estimated between 10 and 15% and is associated with considerable morbidity. Its etiology and pathogenesis are controversial but it is believed to involve multiple genetic, environmental, immunological, angiogenic, and endocrine processes. Altered expressions of growth factors, cytokines, adhesion molecules, matrix metalloproteinases, and enzymes for estrogen synthesis and metabolism have been frequently observed in this condition. The possibility of genetic basis of endometriosis is demonstrated in studies of familial disease, in which the incidence of endometriosis is higher for first-degree relatives of probands as compared to controls....

"This condition is considered as benign disorder, but exhibits cellular proliferation, cellular invasion, and neo angiogenesis. The glandular epithelium occasionally exhibits cytological atypia and/or hyperplasia (3) as well as DNA aneuploidy (4). The malignant potential of the endometriotic epithelial cells has been suggested in some cases considering the monoclonal methylation pattern of the HUMARA alleles and their invasive and metastatic ability in vitro (5, 6). In this context, previous studies supported the hypothesis that progression of endometriotic lesions to frank malignancy can occur although with a very rare incidence (711). However, the significance of the so-called malignant potential of endometriotic cells is controversial since monoclonal cells growth pattern was described in various benign lesions (5).

"There is strong evidence that the endometrium of women with endometriosis has an increased capacity to proliferate, implant, and grow in the peritoneal cavity (2). Morphological studies of tissue sections have demonstrated that the endometriotic glands have a wide range of morphologic development presenting a pattern ranging from poorly to highly differentiated glandular structures. Such morphological variations occur from gland to gland even within cellular areas in the same gland (19). Adequate morphological changes of the endometriotic glands were found in implants only during the proliferative phase of the menstrual cycle, whereas secretory changes were completely missing during the luteal phase (19). These changes include histological differentiation and induction of secretory proteins such as prolactin (PRL) (20), insulin-like growth factor binding protein-1 (IGF-BP1) (21), and extracellular matrix proteins such as fibronectin (22). In addition, several markers are aberrantly expressed in endometriotic cells in comparison to the normal cell elements, including the gap junction connexins (Cx) (23), β-cadherins (24), metalloproteinases (25), and P450 aromatase (26). Altogether, these features indicate a high degree of dedifferentiation in comparison to the normal situation....

"From the collected molecular data, it is evident that one or several genes may be disrupted by mutations or loss of DNA sequences in this condition. Loss of some protein functions may effect the regulation of several emerging down stream pathways, including the EGFR-axis, E-cadherin dynamics, transcriptional regulation, cell cycle regulation (proliferation/apoptosis), and cell adhesion. Divergences from mature endometrial epithelium to endometriotic epithelium must involve abnormal gene expression, which may directly cause or reinforce the alterations caused by changes of one or several genes undergoing germinal alterations. Within this context, the treatment strategies of endometriosis centered mainly toward ovarian function suppression and indirect limitation of cell growth and activity of endometriosis remain insufficient (73, 74).

"Future studies should concentrate on modifying and extending the use of the molecular biology techniques. Cytogenetic analysis with improved culture techniques of endometriotic tissue, capable of simulating the normal endometriotic environment, may help to prevent selective in vitro growth pressures. CGH and cDNA microarray studies has only been used to date on a limited number of primary endometriotic samples, yet has given us important informations (41, 75). Gene expression profiling, allelotyping, and FISH studies need to investigate the various types of endometriotic samples and more regions of the genome. As techniques are improving and examination of archival material is now possible it should be easier to correlate clinical data with the phenotypical features and genotype of primary lesions. This will certainly yield informations important for the early diagnosis and prognosis of patients.
"Finally, the anatomical and the immuno-histochemical features of the ectopic organic structures identified in fetal female reproductive tract suggest that endometriotic as well as neoplastic disease in adult women may develop on the basis of misplaced endometrial glands and/or embryonic cell remnants."
"Endometriosis is a benign gynecological disease characterized by the presence and growth of endometrial cells outside the uterus. Genetic, endocrine, immunological, and environmental factors have been suggested in its pathogenesis. A great number of studies have related genetic polymorphisms as a factor that contributes to the development of endometriosis. This review presents a detailed description of the contribution of genetic polymorphisms in genes that regulate vascular function and tissue remodeling in endometriosis (alpha 2-HS glycoprotein [AHSG], epidermal growth factor receptor [EGFR], vascular endothelial growth factor [VEGF], endostatin, plasminogen activator inhibitor 1 [PAI-1], angiotensin I-converting enzyme [ACE], and matrix metalloproteinases [MMPs]). Some polymorphisms of the VEGF (-460 C/T, +405 G/C, +936 C/T), PAI, MMP-1, 2, and 3 genes were widely studied, while polymorphisms of the AHSG, EGF, endostatin, and VEGF (-1154 G/A, -2578 A/C) genes were not. In this latter case, additional studies are required to confirm the findings of the few studies that have analyzed these single nucleotide polymorphisms (SNPs). Additionally, studies that found a positive or negative association of SNP with endometriosis emphasize the relevance of studies with a large number of control cases to confirm their findings. The haplotype analysis was performed only for the VEGF (-460, +405, -1154 and -2578), ACE (-240/2350) and MMP-1, 2, 3, and 9 genes, and in most of them, there was no association with endometriosis. Of the eight works that analyzed haplotypes of the VEGF gene, five did not associate them with endometriosis. Haplotypes of ACE and MMP-2 genes were not associated with endometriosis, while those of MMP-1, 3, and 9 genes were related to a high risk for the disease." lots more details at
"They have identified two new genetic variants that increase the risk of developing the disease, particularly moderate-severe stages.... The first is a variant on chromosome 7 believed to be involved in regulating nearby genes, probably those involved in the development of the womb and its lining. The second variant was found on chromosome 1, close to the gene WNT4. This is important for hormone metabolism and the development of the female reproductive tract, especially the ovaries, making it an important biological candidate for involvement in endometriosis.

"Our study is a breakthrough because it provides the first strong evidence that variations in DNA make some women more likely to develop endometriosis," says Dr Zondervan. "We now need to understand the effect of these variations on cells and molecules in the body.""
"We conducted a genome-wide association meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese1 and European2 ancestry. We show that rs12700667 on chromosome 7p15.2, previously found to associate with disease in Europeans, replicates in Japanese (P = 3.6 × 10−3), and we confirm association of rs7521902 at 1p36.12 near WNT4. In addition, we establish an association of rs13394619 in GREB1 at 2p25.1 with endometriosis and identify a newly associated locus at 12q22 near VEZT (rs10859871). Excluding cases of European ancestry of minimal or unknown severity, we identified additional previously unknown loci at 2p14 (rs4141819), 6p22.3 (rs7739264) and 9p21.3 (rs1537377). All seven SNP effects were replicated in an independent cohort and associated at P <5 × 10−8 in a combined analysis. Finally, we found a significant overlap in polygenic risk for endometriosis between the genome-wide association cohorts of European and Japanese descent (P = 8.8 × 10−11), indicating that many weakly associated SNPs represent true endometriosis risk loci and that risk prediction and future targeted disease therapy may be transferred across these populations."