Risk Factors For Endometriosis Research Articles

Adenomyosis and endometriosis in adolescents and young women with pelvic pain: prevalence and risk factors.

To evaluate the prevalence of ultrasound diagnosis of adenomyosis and endometriosis in young women complaining of pelvic pain and to find the symptoms and clinical characteristics associated with these diseases in young women. Cross-sectional study, including 100 young women (14-24 years) with a history of chronic pelvic pain. Women were asked detailed medical hystory and pain symptoms scores (Visual Analogue Scale) and underwent gynecological examination and ultrasound evaluation. The prevalence of endometriosis and adenomyosis in young women amounted to 25.0% and 46.0%, respectively. A significant correlation was found between ovarian endometriosis and adenomyosis. Dysmenorrhea and dyspareunia were risk factors for adenomyosis. Dyschezia, dyspareunia, chronic pelvic pain, presence of sonographic soft markers suggestive of pelvic adhesions, being a worker and having a previous surgery were risk factors for endometriosis. Young women (20-24 years) had a higher incidence of both adenomyosis and endometriosis than adolescents (14-19 years). Our outcomes strengthen the hypothesis of a progressive and common course of the natural history of endometriosis, which initially may manifest with symptoms, then with signs of pelvic adhesions and finally as adenomyosis, ovarian endometriomas or deep infiltrating endometriosis.

Exposure to Phthalate Esters and the Risk of Endometriosis

Endometriosis is a common gynecologic disease, worldwide, whose true prevalence is uncertain because it is a difficult disease to diagnose. Endometriosis is a common cause of chronic pelvic pain, dysmenorrhea, and infertility, and is also associated with ovarian cancer. Although the risk factors for endometriosis are unclear, there is increasing evidence that exposure to environmental contaminants, especially phthalates, could affect the pathogenesis of endometriosis. Phthalates are industrial chemicals, used to make flexible plastics, and are present in numerous common plastic products, including medical devices and materials. Several in vitro studies have suggested a positive association between exposure to phthalate, or phthalate metabolites, and the risk of endometriosis. Since the 2000s, studies based on human plasma and urinary concentrations of various phthalate metabolites have been published, but there are still limitations to our understanding of the pathophysiology of phthalates and endometriosis. This report aims to review the current state of knowledge about a possible role of phthalates in the pathogenesis of endometriosis based on cell culture, animal models, and human data.

Polymorphisms in the 3′UTR Region of ESR2 and CYP19A1 Genes in Women With Endometriosis

ObjectiveESR2 and CYP19A1 genes play a major role in the hormonal control of women with endometriosis. The aim of the study was to analyze single nucleotide polymorphisms (SNPs) in the 3’UTR region of ESR2 and CYP19A1 genes. The study aimed at localisation of new polymorphisms, the nucleotide variants of which determine the level of susceptibility to endometriosis. Study designThe study included n = 200 patients: 100 with endometriosis and 100 healthy controls. The Sanger’s sequencing method was applied for polymorphism analysis. ResultsStatistically significant correlations were identified between new, not previously described, two SNPs of ESR2 gene and endometriosis: rs4986938 (G>A) and rs928554 (A>G). In the case of rs4986938 polymorphism, the genotype AA was found to decrease the risk of endometriosis (OR = 0.24 95 % PU 0.05-1.22, p = 0.04). Analysis of the rs928554 polymorphism revealed that the occurrence of the AG genotype reduced the risk of endometriosis (OR = 0.38 95 % PU 0.21-0.71, p = 0.002). There were no differences in the distribution of genotypes of the polymorphisms rs10046 (C>T) and rs4646 (C>A) of CYP19A1 gene between patients and control. ConclusionsFurther studies are necessary in groups with higher numbers of patients to explain whether the above-mentioned polymorphisms may be the risk factors for endometriosis.

Факторы риска развития эндометриоза

Факторы риска развития эндометриоза

Association of urinary metabolites of organophosphate and pyrethroid insecticides, and phenoxy herbicides with endometriosis

Endometriosis is a hormone-responsive gynecologic disease, signifying its connotations across a woman’s life span. Previous studies suggested that endocrine disrupting chemicals were risk factors for endometriosis. Nevertheless, little is known on exposure to organophosphate, pyrethroid and phenoxy acid pesticides on endometriosis diagnosis. In this study, we determined the concentrations of 11 pesticides, metabolites of organophosphate and pyrethroid insecticides, and phenoxy herbicides, in urine collected from 619 reproductive-age women in Utah and California, using liquid chromatography-tandem mass spectrometry. The association of urinary concentrations of pesticides with an increase in the odds of endometriosis diagnosis was examined in 594 women who underwent laparoscopy/laparotomy (operative cohort: n = 471) or pelvic magnetic resonance imaging (population cohort: n = 123), during 2007–2009. 2-Isopropyl-4-methyl-6-hydroxypyrimidine (IMPY), malathion dicarboxylic acid (MDA), para-nitrophenol (PNP), 3,5,6-trichloro-2-pyridinol (TCPY), 3-phenoxybenzoic acid (3-PBA), and 2,4-dichlorophenoxyacetic acid (2,4-D) were detected in ≥95% of the urine samples analyzed. Urinary concentrations of IMPY, MDA, PNP, 3-PBA and 2,4-D tended to be higher in younger, non-Hispanic black, nulliparous and less affluent women. IMPY was the most dominant compound in urine followed by PNP and TCPY. When women in the 4th quartile of IMPY and the 2nd quartile of TCPY concentrations (μg/g creatinine) were compared with women in the 1st quartile, the odds ratios (ORs) for diagnosis of endometriosis increased significantly in unadjusted models (IMPY OR = 1.89, 95% confidence interval (Cl) = 1.12–3.20; TCPY OR = 1.65, 95% Cl = 1.02–2.69) for the operative (n = 471) and entire data set (n = 594), respectively. Our results suggest that exposure to elevated concentrations of diazinon (the parent compound of IMPY) and chlorpyrifos and chlorpyrifos-methyl (parent compounds of TCPY) may be associated with endometriosis.

Reproductive and Menstrual Risk Factors for Endometriosis Disease: A Case-Control Study

Objectives: The endometriosis prevalence in the general population is about 7%-10%. In 30% of women, endometriosis is one of the causes of primary and secondary infertility. There are various risk factors for this disease. The present study aimed to determine the reproductive and menstrual risk factors of endometriosis. Materials and Methods: In this case-control study, 185 women of reproductive age with confirmed endometriosis were compared with 370 women of reproductive age who referred to the same center for other problems in terms of reproductive and menstruation risk factors for endometriosis. The two groups were matched for age. Data were collected using a researcher-made questionnaire based on previous studies. Finally, bivariate analysis was done by the chi-square test, and multivariate analysis was performed by the conditional logistic regression for controlling confounder variables. Results: Based on multivariate logistic regression, early menarche age (P=0.004), no history of pregnancy (P<0.001), no child (P=0.002), no lactation history (P<0.001), high age of the first lactation (P=0.029), short duration of breastfeeding (P=0.015), no regular menstruation (P<0.001), short intervals between menstrual bleedings (P=0.016), prolonged menstruation (P<0.001), dysmenorrhea (P<0.001), dyspareunia (P<0.001), and recurrent vaginitis (P<0.001) had a significant relationship with endometriosis. Conclusions: In general, there was a relationship between some reproductive and menstrual characteristics and endometriosis. Therefore, it seems that these characteristics can predict the occurrence of endometriosis disease.

Молекулярные механизмы и факторы риска развития эндометриоза

Молекулярные механизмы и факторы риска развития эндометриоза

Behind the times: revisiting endometriosis and race

Endometriosis is a common gynecologic condition, affecting approximately 10% of reproductive-aged women. It commonly presents with pelvic pain, painful periods, and infertility and can significantly have an impact on one's quality of life. Early exploration into the pathophysiology of this condition identified race as a risk factor for endometriosis, with the condition predominantly identified in white women. It is still unclear whether there is a biological basis for this conviction or whether it can be explained by methodological and social bias that existed in the literature at that time. Although there is more recent literature exploring the association between endometriosis and race/ethnicity, studies have continued to focus on the prevalence of disease and have not taken into account possible variation in disease presentation among women of different ethnicities. Furthermore, information on diverse populations by race/ethnicity, other than white or black, is quite limited. This paper explores the history of how the association between endometriosis and whiteness was established and whether we still ascribe to a certain stereotype of a typical endometriosis patient today. Furthermore, we discuss the potential implications of such a racial bias on patient care and suggest areas of focus to achieve a personalized and patient focused approach in endometriosis care.

CYP17A1 rs743572 polymorphism might contribute to endometriosis susceptibility: evidences from a case-control study.

This case–control study was aimed to evaluate the influence of cytochrome P450 family 17 subfamily A member 1 (CYP17A1) gene rs743572 polymorphism for the susceptibility to endometriosis.Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to genotype rs743572 polymorphism in 143 endometriosis patients and 148 healthy controls. Hardy–Weinberg equilibrium (HWE) test was utilized to detect the representativeness of the study subjects. Association strength was presented by odds ratios (ORs) with corresponding 95% confidence intervals (CIs).Genotype distribution of rs743572 polymorphism was conformed to HWE test both in case and control groups, revealing the good representativeness of our study subjects. Significantly positive association was discovered between rs743572 TT genotype and endometriosis susceptibility (P = .042, OR = 1.952, 95% CI = 1.020–3.736). Rs743572 T allele was more frequently discovered in cases than that in controls, revealing the enhanced susceptibility to endometriosis (P = .041, OR = 1.407, 95% CI = 1.014–1.951). Confounding factors (age and body mass index) were utilized to adjust the results, and then we found that the association strength had no significant changes (TT vs CC, P = .039, OR = 1.961, 95% CI = 1.023–3.742; T vs C, P = .038, OR = 1.413, 95% CI = 1.016–1.957). But we failed to find any obvious association of rs743572 genotypes with endometriosis stages and characteristics.T allele of rs743572 polymorphism might act as a risk factor for endometriosis, although it had no effects on the disease stages and basic features.

ФАКТОРЫ РИСКА НАРУЖНЕГО ГЕНИТАЛЬНОГО ЭНДОМЕТРИОЗА

One of the most common forms of violation of the reproductive system of a woman is endometriosis. It is assumed that the genetic predisposition and environmental factors are closely related to the development of endometriosis. However, despite the high prevalence of endometriosis among women of reproductive age, the risk factors or markers for the development of the disease remain largely unknown. The aim of the study was to identify risk factors for external genital endometriosis. Materials and methods. Study design: retrospective case-control. The study included 154 women. Group I included 77 women with histologically verified external genital endometriosis. Group II consisted of 77 women without endometriosis, who underwent endoscopic surgery due to various diseases of the pelvic organs. Results. The results of the study showed that the most significant risk factors for endometriosis are the early onset of menarche (< 11 years), a shortened menstrual cycle with prolonged menstruation, active and passive smoking, the presence of furnace heating and uterine fibroids, a family history of breast cancer. Typical complaints of patients with endometriosis are pelvic pain, dysmenorrhea and dyspareunia. Conclusions. Further studies are needed to study the significance of these factors in the diagnosis of endometriosis and the understanding of its etiology.

Perfluoroalkyl substances and endometriosis-related infertility in Chinese women

Endometriosis is one of the main causes for female infertility. Previous studies suggested that perfluoroalkyl substances (PFASs), a group of ubiquitous environmental chemicals with properties of endocrine disruption and reproductive toxicity, were risk factors for endometriosis but there lacks direct evidence on the possible role of PFASs in endometriosis-related infertility. To fill this gap, we examined the association between PFASs and endometriosis-related infertility among Chinese reproductive-age women in a case-control study, which comprised 157 surgically confirmed endometriosis cases and 178 controls seeking infertility treatment because of male reproductive dysfunction in 2014 and 2015. Blood specimens were collected at the enrollment and analyzed for ten PFASs. Logistic regression was utilized to estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) for individual PFAS compound. Plasma concentrations of perfluorobutane sulfonic acid (PFBS) were associated with an increased risk of endometriosis-related infertility (second vs. lowest tertile: OR=3.74, 95% CI: 2.04, 6.84; highest vs. lowest tertile: OR=3.04, 95% CI: 1.65, 5.57). This association remained consistent when we restricted to subjects with no previous pregnancy (second vs. lowest tertile: OR=2.91, 95% CI: 1.28, 6.61; highest vs. lowest tertile: OR=3.41, 95% CI: 1.52, 7.65) or to subjects without other gynecologic pathology (second vs. lowest tertile: OR=4.65, 95% CI: 2.21, 9.82; highest vs. lowest tertile: OR=3.36, 95% CI: 1.58, 7.15). Plasma concentrations of perfluoroheptanoic acid (PFHpA), perfluorohexane sulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) were inversely associated with endometriosis-related infertility, but the associations were attenuated in the sensitivity analyses. Our preliminary evidence suggests that exposure to PFBS may increase the risk of female infertility due to endometriosis. Future prospective studies are necessary to confirm these findings.

Combined effect of vascular endothelial growth factor and its receptor polymorphisms in endometriosis: a case-control study

ObjectiveEndometriosis is a multifactorial gynecological disease, whose pathogenesis is crucially dependent on angiogenesis, which is signaled via vascular endothelial growth factor (VEGF) and its receptor (VEGFR2). We hypothesize that single nucleotide polymorphisms (SNPs) in VEGF and VEGFR2 genes may influence the onset and/or the progression of endometriosis. The main aim of this study was to investigate the contribution of VEGF and VEGFR2 SNPs as risk factors for endometriosis, as well as their association with endometriosis symptoms. Study designA case-control study was conducted, involving 293 endometriosis patients and 223 controls, who were submitted to laparoscopic or laparotomy surgery at hospitals from the Brazilian public health system. Genotyping of VEGF (−2578C>A, −460T>C, −1154G>A, +405G>C and +936C>T) and VEGFR2 (−604T>C, 1192C>T) SNPs was performed by TaqMan real-time polymerase chain reaction. The association between SNPs and endometriosis, deep infiltrating endometriosis (DIE) or endometriosis symptoms was estimated by odds ratios (OR) with their 95% confidence intervals (CI), which were calculated using multivariate logistic regression models. ResultsVEGF variant alleles −2578A and −1154A were associated with increased endometriosis risk (OR: 1.39, 95% CI: 1.04–1.87 and OR: 1.63, 95% CI: 1.12–2.37, respectively), whereas VEGF 405C and VEGFR2 1192T were associated with lower risk of endometriosis (OR: 0.66, 95% CI: 0.43–1.00 and OR: 0.58, 95% CI: 0.40–0.84, respectively). The combination of wild-type genotypes of both VEGF −2578C>A and −1154G>A with variant genotypes of both VEGF +405G>C and VEGFR2 1192C>T showed the best protective effect against the development of endometriosis, either considering all cases (OR: 0.33, 95% CI: 0.12–0.89) or only DIE (OR: 0.30, 95% CI: 0.10–0.87). The combination of variant genotypes of VEGF −2578C>A, −1154G>A, +405G>C and VEGFR2 1192C>T was also protective against DIE (OR: 0.67, 95% CI: 0.46–0.96). VEGFR2 1192C>T were associated with reduced cyclical urinary complaints (OR: 0.40, 95% CI: 0.18–0.88). ConclusionsOur results indicate that VEGF SNPs −2578C>A and −1154G>A increase endometriosis risk, whereas VEGF +405G>C and VEGFR2 1192C>T are protective against disease development, with VEGFR2 1192C>T also reducing cyclical urinary symptoms. The combined analysis of VEGF–VEGFR2 genotypes suggests a gene–gene interaction in endometriosis susceptibility.

Endometriomas and deep infiltrating endometriosis in adulthood are strongly associated with anogenital distance, a biomarker for prenatal hormonal environment.

STUDY QUESTIONIs the length of the anogenital distance (AGD), a biomarker of the in-utero prenatal hormonal environment, associated with the presence of endometriomas and deep infiltrating endometriosis (DIE)?SUMMARY ANSWERShorter AGD is associated with presence of endometriomas and DIE.WHAT IS KNOWN ALREADYIt is debated whether hormonal exposure to estrogens in utero may be a risk factor for endometriosis in adulthood. AGD is a biomarker of prenatal hormonal environment and observational studies have shown an association between AGD and reproductive parameters in both sexes.STUDY DESIGN, SIZE, DURATIONThis case–control study of 114 women with endometriosis (endometriomas and/or DIE) and 105 controls was conducted between September 2014 and May 2015.PARTICIPANTS/MATERIALS, SETTING, METHODSCases were attending the Endometriosis Unit of the Hospital. Prevalent as well as incident cases, diagnosed by transvaginal ultrasound (TVUS), were included. Controls were women without endometriosis attending the gynecological outpatient clinic for routine gynecological exams. Participants completed health questionnaires, followed physical and gynecological examinations, including TVUS. Measurements from the anterior clitoral surface to the upper verge of the anus (AGDAC), and from the posterior fourchette to the upper verge of the anus (AGDAF) were obtained in all subjects. Unconditional multiple logistic regression was used to estimate the association between AGD measurements and presence of endometriomas and/or DIE while accounting for important confounders and covariates, including age, body mass index, vaginal delivery or episiotomy.MAIN RESULTS AND THE ROLE OF CHANCEAGDAF was related to presence of endometriomas and/or DIE. For all cases of endometriosis (endometriomas and DIE), women in the lowest tertile of the AGDAF distribution, compared with the upper tertile, were 7.6-times (95% CI 2.8–21.0; P-trend < 0.001) more likely to have endometriosis. With regard to DIE, women with AGDAF below the median, compared with those with AGDAF above the median, were 41.6-times (95% CI 3.9–438; P-value = 0.002) more likely to have endometriosis.LIMITATIONS, REASONS FOR CAUTIONIn case–control studies, information and selection bias has to be ruled out. Physicians conducting the measurement were blind to the status of the patients. Controls came from the same population as the cases. We adjusted for known and suspected confounders and covariates, but the possibility of residual confounding or chance findings should always be considered. As with all observational studies, causal inference is limited.WIDER IMPLICATIONS OF THE FINDINGSThis study suggests that endometriosis, especially the DIE, might have a prenatal origin that may be traced back to the hormonal milieu in which the fetus develops.STUDY FUNDING/COMPETING INTERESTThis work was supported by the Ministry of Economy and Competitiveness, ISCIII (AES), grant no. PI13/01237 and the Seneca Foundation, Murcia Regional Agency of Science and Technology, grant no. 19443/PI/14. The authors have no competing interests to declare.TRIAL REGISTRATION NUMBERNot applicable.

Characteristics of Women Undergoing Hysterectomy for Chronic Pelvic Pain: Prevalence and Risk Factors for Endometriosis

Characteristics of Women Undergoing Hysterectomy for Chronic Pelvic Pain: Prevalence and Risk Factors for Endometriosis

Nickel Allergy Is a Risk Factor for Endometriosis: An 11-Year Population-Based Nested Case-Control Study.

BackgroundA cross-sectional study has reported that nickel allergy is associated with endometriosis. However, causal studies of this association are limited.ObjectiveThe objective of this study was to compare the prevalence of nickel allergy in women with and without endometriosis.MethodsWe used a National Health Insurance Service (NHIS) sample cohort dataset that included approximately 1 million individuals from South Korea; the data were obtained between January 01, 2002, and December 31, 2013. We selected the endometriosis group according to diagnosis code (N80.X), surgery codes, and drug codes during the years 2009~2013. The controls were randomly matched to the endometriosis patients at a ratio of 4:1 by age and socioeconomic status. Patients with nickel allergy were defined in the cohort dataset as those with a simultaneous diagnosis code (L23.0) and patch test code during 2002~2008.ResultsIn total, 4,985 women were selected from the NHIS cohort database and divided into an endometriosis group (997 women) and a control group (3,988 women). The number of patients with nickel allergy in the endometriosis group was eight (0.8%), and that in the control group was thirteen (0.3%). After adjustment for age and socioeconomic status, the rate of nickel allergy in was higher in the endometriosis group than in the control group [odds ratio: 2.474; 95% confidence interval: 1.023~5.988; p = 0.044].ConclusionsWe found that nickel allergy is a risk factor for endometriosis.

KIR2DS5 in the presence of HLA-C C2 protects against endometriosis.

Endometriosis is defined as the presence of functional endometrial tissue outside the uterine cavity. Several hypotheses have attempted to explain the etiology and pathogenesis of endometriosis. Recently, it has been suggested that a defect of the natural killer (NK) activity in the recognition and lysis of endometrial cells is one of the crucial points in the development of this disease. Natural killer cells can express killer immunoglobulin-like receptors (KIR), which recognize class I human leukocyte antigens on target cells. We asked whether polymorphisms in KIR, HLA-C, and HLA-B genes are risk factors for endometriosis. We tested 153 women with endometriosis diagnosed on the basis of laparoscopic and histological examination, and 213 control healthy women, who gave birth to at least one child. The frequency of KIR genes in patients was similar to that in controls except for KIR2DS5, which exerted a protective effect only in HLA-C C2-positive individuals. Moreover, KIR2DS5-positive women with endometriosis had 13 times lower chance that the disease would occupy the peritoneum than KIR2DS5- and KIR2DS4del-negative ones (OR = 0.077, P = 0.0061). Similarly, KIR2DS4del-positive endometriotic persons had 11 times lower chance for peritoneal disease (OR = 0.094, P < 0.001). Negative linkage disequilibrium between KIR2DS5 and KIR2DS4del indicates that these genes are mutually exclusive. Our data suggest that KIR2DS5 may be associated with protection from endometriosis, whereas KIR2DS4del seems to be associated with higher disease stages, possibly by exclusion of protective KIR2DS5.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-015-0828-3) contains supplementary material, which is available to authorized users.

Risk profiles for endometriosis in Japanese women: results from a repeated survey of self-reports.

BackgroundThe prevalence and risk factors for endometriosis may differ according to diagnosis methodologies, such as study populations and diagnostic accuracy. We examined risk profiles in imaging-diagnosed endometriosis with and without surgical confirmation in a large population of Japanese women, as well as the differences in risk profiles of endometriosis based on history of infertility.MethodsQuestionnaires that included items on sites of endometriosis determined by imaging techniques and surgical procedure were mailed to 1025 women who self-reported endometriosis in a baseline survey of the Japan Nurses’ Health Study (n = 15 019).ResultsTwo hundred and ten women had surgically confirmed endometriosis (Group A), 120 had imaging-diagnosed endometriosis without a surgical procedure (Group B), and 264 had adenomyosis (Group C). A short menstrual cycle at 18–22 years of age and cigarette smoking at 30 years of age were associated with significantly increased risk of endometriosis (Group A plus Group B), while older age was associated with risk of adenomyosis (Group C). In women with a history of infertility, a short menstrual cycle was associated with a significantly increased risk of endometriosis in both Group A and Group B, but risk profiles of endometriosis were different between Group A and Group B in women without a history of infertility.ConclusionsWomen with surgically confirmed endometriosis and those with imaging-diagnosed endometriosis without surgery have basically common risk profiles, but these risk profiles are different from those with adenomyosis. The presence of a history of infertility should be taken into consideration for evaluation of risk profiles.

Mutations in the GnRH signaling pathway are risk factors for endometriosis

Some but not all patients with endometriosis have abnormal functioning of their GnRH axis and some but not all endometriosis patients respond to GnRH agonist therapies. The clinical variation observed may be caused by instrinsic genetic variation in these pathways. We tested 177 genes involved in human GnRH signaling for genetic association with endometriosis. Candidate genes involved in human GnRH signaling pathways were obtained using PANTHER database. 1537 Caucasian endometriosis patients were genotyped for 570 exome variants in 179 candidate genes. The frequency of heterozygous affected women was compared with published population data (n>50,000 population controls). Human Exome Beadchips (Illumina, San Diego, CA) were used for genotyping. Single marker association was tested using Fisher’s Exact Test. In silico prediction of protein function was evaluated using the Polyphen 2 database. We tested 570 exome variants representing 177 genes involved in GnRh signaling pathway that showed a causative/deleterious effect. After adjusting for multiple testing (p<8.7E-05), we discovered 5 exome variants representing 5 different genes as shown in Table 1. The top 2 significantly associated variants (CRTC1 and ARHGAP32) are predicted to be damaging to the encoded protein.Table 1CHRPositionVar AlleleEndm FreqPopulation FreqGeneFisher pOR1918876309G0.160990.08759CRTC19.51E-372.0011128839405A0.042070.02420ARHGAP328.09E-091.771877170479A0.003900.00037NFATC12.62E-0810.73112161530A0.001950.000048IGF22.37E-0740.37636075326A0.001300.000029MAPK142.28E-0544.83 Open table in a new tab Gene variants affecting the human GnRH signaling pathway are significant risk factors for predisposition to endometriosis. These gene variants are likely to contribute to the clinical variation observed in women with endometriosis.

Rare mutations in WNT signaling pathways are risk factors for endometriosis

Wnt proto-oncogenes are believed to play a role in endometriosis. Recently, genetic association studies have shown that common variants near Wnt4 are associated with endometriosis across different ethnicities. In order to test the hypothesis that variants in other genes involved in Wnt signaling pathways contribute to the pathogenesis of endometriosis, we tested exome variants found in 230 candidate genes involved in Wnt signaling for genetic association with endometriosis. A list of candidate genes involved in Wnt signaling were obtained using PANTHER database. 1537 Caucasian endometriosis patients were genotyped for 1138 rare exome variants in candidate genes. The number of heterozygous subjects observed was compared with published population data (n>50,000). 1537 patients with surgically confirmed endometriosis were tested using the Infinium HumanExome BeadChip (Illumina, San Diego, CA). Single marker association was tested using Fisher’s exact Test. In silico prediction of protein function was estimated using polyphen 2 database. We tested a total of 1138 variants representing 230 candidate Wnt genes. 88 showed causative/deleterious effect for endometriosis. After adjusting for multiple testing (p< 4.4E-05), we discovered 10 strongly associated variants in 10 distinct genes. None of these associated variants were predicted to be protein altering. The average OR among these associated variants is 10.7. Wnt signaling proteins, particularly the protocadherins, may play a major role in the pathogenesis of endometriosis.Table 1CHRPositionVar AlleleEndm FreqPopulation FreqGeneFisher pOR5140238124A0.06560.0131PCDHA107.54E-705.275140795212A0.00850.0005PCDHGA104.84E-2015.615140230533A0.00920.0020PCDHA91.94E-104.732246929692A0.06440.0399CELSR13.75E-101.651877170479A0.00390.0004NFATC12.62E-0810.735140250471A0.00200.0000PCDHA112.37E-0740.371710212619G0.00330.0004MYH131.83E-068.135140802374A0.00360.0006PCDHGA118.45E-065.911540581543G0.00490.0012PLCB21.74E-053.971668867265G0.00100.0000CDH12.41E-05Inf Open table in a new tab

Tumor Necrosis Factor and Interleukin‐6 Gene Polymorphisms and Endometriosis Risk in Asians: A Systematic Review and Meta‐Analysis

A relationship between endometriosis and tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) gene polymorphisms has been raised for Asians. However, this topic is controversial. This study was a meta-analysis to explore whether TNF-α/IL-6 gene polymorphisms were associated with a risk of endometriosis in Asians. By searching PubMed, HuGENet, and China National Knowledge Infrastructure (CNKI) databases, 17 studies were identified and included (3372 cases and 4008 controls). The odds ratio (OR) with 95% confidence interval (CI) was used to assess the association between TNF-α/IL-6 gene polymorphisms and endometriosis risk. An association of TNF-α gene -1031T/C polymorphism with endometriosis was found (TT + TC vs. CC: OR 0.50, 95% CI 0.30-0.82, I(2) = 37.1%, P = 0.20; TT vs. CC: OR 0.50, 95% CI 0.30-0.82, I(2) = 43.0%, P = 0.173; TC vs. CC: OR 0.49, 95% CI 0.29-0.83, I(2) = 10.6%, P = 0.327). In addition, TNF-α-238A/G and IL-6 -174C/G gene polymorphisms were also likely to be associated with endometriosis in Asians. For the TNF-α-238A/G gene polymorphism, the OR was 1.577 (95% CI: 1.01-2.48). For the IL-6 -174C/G gene polymorphism, the OR was 1.554 (95% CI: 1.04-2.31). No associations were detected between the TNF-α-308A/G and IL-6 -634C/G polymorphisms and susceptibility to endometriosis. Our results indicate that the TNF-α gene -1031T/C polymorphism can reduce the risk of endometriosis, but for Asians, TNF-α-238A/G and IL-6 -174C/G gene polymorphisms may be a risk factor for endometriosis. No association was found for the TNF-α-308A/G and IL-6 -634C/G gene polymorphisms.