Population Studies The risk of endometriosis is seven times greater if a first-degree relative is affected by endometriosis (61). Because no specific Mendelian inheritance pattern is identified, multi-factorial inheritance is postulated. A relative risk for endometriosis of 7.2 was found in mothers and sisters, and a 75% (six in eight) incidence was noted in homozygotic twins of patients with endometriosis (62). In another study of twins, 51% of the variance of the latent liability to endometriosis may be attributable to additive genetic inﬂuences (63). Other investigators reported that 14 monozygotic twin pairs were concordant for endometriosis, and two pairs were discordant (64). Of these twin pairs, nine had moderate to severe endometriosis. A relationship was shown between endometriosis and systematic lupus erythematosus, dysplastic nevi, and a history of melanoma in women of reproductive age (65,66). Endometriosis is linked to the presence of individual human leukocyte antigens (67–69). Genome-wide association studies show that the risk of endometriosis is associated with a mutation on the short arm of chromosome 7 (7p15.2) in women of European ancestry and that this association is the strongest for moderate to severe disease (70).
A number of studies investigated genetic polymorphisms as a possible factor contributing to the development of endometriosis. About 50% of the studies in one review demonstrated positive correlations between different polymorphisms and endometriosis (71). This relation was seen most clearly in groups 1 (cytokines and inﬂammation), 2 (steroid-synthesizing enzymes and detoxifying enzymes and receptors), 4 (estradiol metabolism), 5 (other enzymes and metabolic systems), and 7 (adhesion molecules and matrix enzymes). Group 8 (apoptosis, cell-cycle regulation, and oncogenes) seemed to be negatively correlated with the disease, whereas groups 3 (hormone receptors), 6 (growth factor systems), and especially 9 (human leukocyte antigen system components) showed a relatively strong correlation. As many results were contradictory, the review concluded that genetic polymorphisms might have a limited value in assessing possible development of endometriosis (71). Future studies should include large numbers of women with laparoscopically and histologically confirmed endometriosis and women with a laparoscopically confirmed normal pelvis as controls, taking into account ethnic variability.
Aneuploidy Epithelial cells of endometriotic cysts are monoclonal on the basis of phosphoglycerate kinase gene methylation, and normal endometrial glands are monoclonal (72,73). In a comparison of endometriotic tissue with eutopic endometrium, ﬂow cytometric DNA analysis failed to show aneuploidy (74). Studies using comparative genomic hybridization, or multicolor in situ hybridization, showed aneuploidy for chromosomes 11, 16, and 17, increased heterogeneity of chromosome 17 aneuploidy, and losses of 1p and 22q (50%), 5p (33%), 6q (27%), 70 (22%), 9q (22%), and 16 (22%) of 18 selected endometriotic tissues (75–77). In another study, trisomies 1 and 7, and monosomies 9 and 17 were found in endometriosis, ovarian endometrioid adenocarcinoma, and normal endometrium (78). The proportions of aneusomic cells were significantly higher in ovarian endometriosis compared with extragonadal endometriosis and normal endometrium (p <0.001), suggesting a role of the ovarian stromal milieu in the induction of genetic changes, which may lead to invasive cancer in isolated cases (78).