|(A;C)||1.5||Slight (~1.2x) increase in endometriosis risk|
|(C;C)||1.5||Slight (~1.4x) increase in endometriosis risk|
[PMID 23104006] Genome-wide association meta-analysis identifies new endometriosis risk loci
Summary of trait
Endometriosis is a disorder in which the endometrium, which lines the inside of a woman’s uterus grows outside the uterus (etopic). It affects 6% - 10% of women of reproductive age. In a patient with endometriosis, the endometrial tissue behaves normally, whereby during a menstrual cycle, it would thicken, break down and bleed out. Being outside the uterus, the broken down endometrial tissue cannot leave the body. This blood will irritate surrounding tissue, causing scar tissue and adhesions and may potentially bind organs together. Endometriosis may involve ovaries, bowel or tissue lining pelvis. Cysts (or endometriomas) may form if endometriosis involves ovaries [PMID 22819144]. The exact cause of endometriosis is unknown, but the most widely accepted theory is the retrograde menstruation theory, proposed by Sampson in the 1920s [PMID 19969738]. This theory is able to explain the presence of endometrial fragments in the peritoneal cavity.
Symptoms of endometriosis include dysmenorrhea or menstrual cramps, whereby it is typically described as more painful that the usual menstrual pain. Other symptoms include painful intercourse, painful bowel movements or urination during periods, heavy periods or infertility. There is evidence suggesting that endometriosis could be genetically linked [PMID 23104006].
Summary of Studies
Through a genome-wide association (GWAS) meta-analysis of 4604 endometriosis cases and 9393 controls, involving both Japanese and Europeans (Australians and British), Nyholt et al identified SNP rs10859871 to be significantly associated with endometriosis in 2012 [PMID 23104006]. This is the first time rs10859871 has been identified to be associated with endometriosis, along with 6 other SNPs. rs10859871 is at 12q22, 17kb upstream of the vezatin (VEZT) gene. In their studies, the authors combined data from United Kingdom, Australia and Japan for meta-analysis to identify SNPs that are associated with endometriosis and is consistent between Europeans and Japanese. GWAS meta-analysis identified rs10859871 as one of the SNPs that achieved genome wide significance and is associated with endometriosis in both European and Japanese populations, with a P value of 5.5 × 10−9 and a p value of 3.7 × 10−7 for a more severe stage of endometriosis. The risk allele is C with an odds ratio of 1.18 (95% confidence interval = 1.12–1.25) [PMID 23104006].
In a separate study conducted by Pagliardini et al, the authors came to the same conclusion that the SNP at rs10859871 was significantly associated with endometriosis. In their study the authors used laparoscopy to identify 305 cases and 285 controls, and also included 2425 blood donor healthy controls. All subjects are of Italian heritage [PMID 25678572]. Here, the authors reported the odds ratio when compared to the blood donor healthy controls to be 1.43, with a 95% confidence interval of 1.20 – 1.71 and P = 6.9 × 10−5 and odds ratio when compared to laparoscopic controls to be 1.53, 95% confidence interval of 1.24–2.02 and P = 2.1 × 10−4. When they combined their data with the data obtained by Rahmioglu et al, an odds ratio of 1.19 was obtained, with P = 7.9 × 10−20.), with C being the risk allele.
Data obtained by both authors are consistent with each other, in that when compared to healthy controls, the odds ratio is approximately 1.18. This odds ratio is further confirmed by GWAS studies by other authors [PMID 24676469].
What’s known about the SNP
SNP rs10859871 is located near VEZT (vezatin).
VEZT encodes transmembrane protein vezatin, which forms part of the E-cadherin-catenin complex at adherens junctions and is also expressed in the actin cytoskeleton in most epithelial cells. When there is a loss of function in mouse embryos, the resulting loss or instability of actin cytoskeleton adherens junctions caused implantation failure and embryo death, suggesting the need for vezatin during implantation and embryogenesis [PMID 17379651].
VEZT has been postulated to be involved in endometriosis based on the hypothesis that alterations in the expression of adhesion molecules have been observed in eutopic and ectopic cells from endometriosis patients. Therefore, VEZT is associated to endometriosis based on the fact that cell adhesion and migration is observed in the pathogenesis of endometriosis [PMID 25678572].
Based on a study in gastric cancer patients, it has been hypothesize that VEZT also plays a role in lymphatic metastasis and cancer invasion [PMID 24069310].
Considerations for diagnosis/ treatment
Endometriosis has been associated with many other SNPs (e.g. rs10965235, rs12700667, rs7521902 etc), in addition to rs10859871 and the odds ratio for the risk allele in all these SNPs are all less than 2 (relatively small odds). Consolidating GWAS data obtained by research groups in different countries, heterogeneity in genome wide significant SNPs are observed [PMID 24676469]. For instance, rs10965235 achieved genome wide significance in Uno et al’s paper using a Japanese population (OR = 1.44, P = 5.57 × 10-12)  but could not be replicated by Painter et al using European data sets [PMID 21151130] [PMID 21497341], nor another study using a much smaller Japanese population [PMID 20844546].
Therefore, the presence of the risk allele should not affect diagnosis/ treatment significantly.
[PMID 26337243] Independent Replication and Meta-Analysis for Endometriosis Risk Loci
[PMID 28901453] The role of gene polymorphisms in endometriosis.
[PMID 30010178] The assessment of GWAS - identified polymorphisms associated with infertility risk in Polish women with endometriosis.
[PMID 32143537] Genetic Characterization of Endometriosis Patients: Review of the Literature and a Prospective Cohort Study on a Mediterranean Population.