ETM Experimental and Therapeutic Medicine 1792-0981 1792-1015 D.A. Spandidos 10.3892/etm.2016.3110 ETM-0-0-3110 Articles Association between glutathione S-transferase M1/T1 gene polymorphisms and susceptibility to endometriosis: A systematic review and meta-analysis XINXIAOYAN 1 * JINZHISHAN 1 * GUHUAJIAN 2 LIYUANYUE 1 WUTINGTING 1 HUATENG 1 WANGHONGBO 1 Department of Gynecology and Obstetrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China Department of General Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550001, P.R. China Correspondence to: Professor Hongbo Wang, Department of Gynecology and Obstetrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, P.R. China, E-mail: hb_wang1969@sina.com

Contributed equally

 05 2016 26 02 2016 11 5 1633 1646 29122014 11022016 Copyright: © Xin et al. 2016 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Endometriosis is a polygenic/multifactorial disease caused by interactions between multiple genes and the environment. Findings from studies evaluating the association between the glutathione S-transferase (GST) M1/T1 null genotype and susceptibility to endometriosis are inconsistent. This meta-analysis updated and reevaluated the possible associations between GSTM1, GSTT1 and combined GSTM1/GSTT1 (null genotype versus wild-type) gene polymorphisms and susceptibility to endometriosis. The PubMed, Embase and Chinese BioMedical Literature databases and Google Scholar were searched for case-control genetic association studies on GSTM1/GSTT1 (null genotype versus wild-type) gene polymorphisms and endometriosis in comparison with non-endometriosis or healthy controls. Fixed-effect and random-effect meta-analytical techniques were conducted for the outcome measure and subgroup analyses. The meta-analysis demonstrated significant associations between the GSTM1 [odds ratio (OR)=1.56; 95% confidence interval (CI): 1.25–1.95; P<0.0001), GSTT1 (OR=1.31; 95% CI: 1.02–1.68; P=0.037) and GSTM1/GSTT1 (OR=1.68; 95% CI: 1.29–2.17; P<0.0001) null genotypes and increased risk for endometriosis. The results suggest that the GSTM1, GSTT1, and combined GSTM1/GSTT1 null genotypes increase susceptibility to endometriosis. Additional well-designed studies and precise analyses are warranted to confirm these findings.

 gene polymorphisms glutathione S-transferase M1 glutathione S-transferase T1 endometriosis meta-analysis Introduction

Endometriosis manifests as ectopic endometrial cells outside the uterus. It is an intractable disease that causes infertility, dysmenorrhea and pelvic pain. Endometriosis occurs in 10% of women of childbearing age. Notably, the incidence of endometriosis has been rising in recent years (1). The pathogenesis of endometriosis remains to be elucidated.

Published reports indicate that endometriosis is a polygenic/multifactorial disease caused by interactions between multiple genes and the environment (2,3). In particular, a correlation has been identified between endometriosis and exposure to environmental toxins such as dioxin (4); dioxin and dioxin-like compounds have been implicated in the development of endometriosis (5,6).

The phase II conjugation enzymes usually function to inactivate environmental toxins. Among these, glutathione S-transferase (GST) may be critical for the detoxification of dioxins. Human GSTs are classified into two distinct categories: Soluble or cytosolic and membrane-bound microsomal. The soluble or cytosolic GSTs are subdivided into seven families named α, µ, ω, π, σ, θ and ζ (7). Genes in several of these families are polymorphic, including: GSTA2 in the α family, GSTM1 and GSTM3 in the µ family, GSTP1 in the π family, GSTO, GSTT1, and GSTT2 in the θ family, and GSTZ1 in the ζ family. Heritable allelic differences in GSTM1, GSTM3, GSTT1 and GSTP1 may have marked relevance for individual susceptibility to disease.

GSTM1 and GSTT1 are two candidate genes that may play an important role in the development of endometriosis. GSTM1 and GSTT1 are located on chromosomes 1p13.3 and 22q11.23, respectively. They are critical in the detoxification of the products of oxidative stress produced during the repair of the ovarian epithelium. GSTM1 and GSTT1 null alleles have reduced enzyme activity, a state that may contribute to inefficient detoxification of intermediates produced during stress. This may increase damage to various host genes and contribute to the pathogenesis of endometriosis (8,9).

A meta-analysis summarizing the literature up to the year 2005 suggested that the GSTT1 null genotype, but not the GSTM1 null genotype, was associated with an increased risk for endometriosis (7). In the years since 2005, additional reports investigating this topic have been published. The objective of the present study was to update the existing meta-analysis and reevaluate the possible associations between GSTM1, GSTT1 and combined GSTM1/GSTT1 (null genotype vs. wild-type) gene polymorphisms and susceptibility to endometriosis.

 Materials and methods <sec> <title>Searches

For this systematic review and meta-analysis, PubMed (from January 1996 to January 2014), Embase (from January 1996 to January 2014), Chinese BioMedical Literature database (from January 1996 to January 2014) and Google Scholar (from January 1996 to January 2014) were searched. The following keywords were used: ‘endometriosis’, ‘polymorphisms’, ‘glutathione S-transferases’, ‘GSTM1’ and ‘GSTT1’ or their combinations.

Reference lists from articles identified by the electronic search were searched by hand. This process was performed iteratively until no additional articles could be identified.

 Inclusion and exclusion criteria

Articles published in English or Chinese were included if they reported quantitative outcomes from case-control genetic association studies on GSTM1, GSTT1 or combined GSTM1/GSTT1 (null genotype vs. wild-type) gene polymorphisms and endometriosis versus non-endometriosis or healthy controls.

Studies were excluded if they were case reports, case-only studies, letters, reviews or meta-analyses; included subjects who were related; included cases of adenomyosis, which has unknown etiology (10); reported insufficient data; or were duplicate studies.

 Selection of studies

Two reviewers (XYX and ZSJ) independently examined titles and abstracts to select eligible studies. Records were removed that were ongoing or unpublished studies, or were published as abstracts or conference proceedings. Where data sets were overlapping or duplicated, only the most recent information was included. The full text of potentially relevant studies was retrieved. Two reviewers (XYX and HJG) independently examined the full text records to determine which studies met the inclusion criteria. Disagreement about the selection of studies was resolved by discussion and consensus.

 Data extraction and management

Two reviewers (XYX and ZSJ) independently extracted data from eligible studies including the first author's last name, publication year, study location, ethnicity, matching variability, diagnostic criteria, stages of disease, source of controls, numbers of cases and controls, and numbers and/or percentages of null genotypes. Disagreement about data extraction was resolved by discussion and consensus.

 Assessment of quality of evidence in included studies

Two reviewers (YYL and HJG) independently assessed quality of evidence in the included studies using the 9-star Newcastle-Ottawa Scale, which considers selection, comparability and outcome evaluation criteria.

 Assessment of heterogeneity

Heterogeneity was assessed using the χ2 test and I2 test. The I2 statistic was interpreted as follows: I2=0–40%, heterogeneity may not be important; I2= 30–60%, heterogeneity may be moderate; I2=50–90%, heterogeneity may be substantial; and I2=75–100%, considerable heterogeneity (11). If heterogeneity was present, meta-regression was used to find the source.

 Assessment of reporting biases

A funnel plot of effect estimates against their standard errors (SEs) was created to assess possible reporting bias between studies. Funnel plot asymmetry was assessed using Egger's linear regression test and Begg's rank correlation test; P<0.05 suggested publication bias.

 GSTM1/GSTT1 and risk for endometriosis

Two reviewers (XYX and HJG) independently combined data from trials using a fixed-effect model (DerSimonian and Laird method) when there was no significant heterogeneity in populations (I2<50%) and a random-effect model (Mantel-Haenszel method) when there was considerable heterogeneity. Variables were synthesized using odds ratios (ORs). A P-value of 0.05 was used as the cut-off value to determine statistical significance, and data are presented as the estimated OR with 95% confidence intervals (CIs). All statistical analyses were performed using STATA software, version 12.0 (StataCorp, College Station, TX, USA). Inconsistencies in data analysis were resolved through consensus and discussion with a third reviewer (ZSJ).

 Sensitivity and subgroup analyses

Sensitivity analyses were performed to explore the impact of excluding outlying results. Subgroup analyses were performed by stratifying patients according to ethnicity (Caucasian, Asian or mixed), characteristics of controls (hospital patients or healthy individuals), and quality of evidence (high-quality or low-quality).

 Results <sec> <title>Screening and selection

The searches identified 120 articles. Titles and abstracts were screened, and 36 studies were identified as potentially eligible for inclusion. The full text articles for these studies were retrieved. Following analysis of the full text articles, four studies were excluded and 32 studies were found to be eligible for inclusion according to the criteria used for considering studies in this review (Fig. 1).

 Included studies

The characteristics of the included studies are shown in Table I. There were 32 case-control genetic association studies involving 3,990 cases of endometriosis and 4,625 controls. One publication addressed two groups of subjects with different ethnicities and was considered as two case-control genetic association studies (12); thus, the total number of studies was considered to be 33. Studies included data relevant to the GSTM1 genotype, GSTT1 genotype or the combined GSTM1/GSTT1 genotype. Of the 32 eligible studies, 20 were conducted in Asia (12–31), eight in Europe (32–39), two in North America (40,41), and two in South America (42,43). The evidence reported in 23 studies was identified as high-quality, and that in 10 studies was identified as low-quality.

 Excluded studies

Of the 36 studies that were relevant to the GSTM1/GSTT1 genotype and endometriosis, four were excluded. Of these, three were duplicates (13,14,32), and one included subjects who were related (44).

 GSTM1/GSTT1 and risk for endometriosis GSTM1genotype

Data reporting on the GSTM1 gene polymorphism are described in 33 case-control studies (3,990 cases of endometriosis and 4,625 controls). The meta-analysis demonstrated that there was a significant association between the GSTM1 null genotype and an increased risk for endometriosis (OR=1.56; 95% CI: 1.25–1.95; P<0.0001; Fig. 2A).

Subgroup analyses stratified by ethnicity (Caucasian: OR=1.599; 95% CI: 1.205–2.122; P=0.001; Asian: OR=1.772; 95% CI: 1.242–2.528, P=0.002), source of controls (hospital patients: OR=1.561; 95% CI: 1.151–2.117; P=0.004; healthy individuals: OR=1.569; 95% CI: 1.131–2.176; P=0.007), and quality of evidence (high-quality: OR=1.563; 95% CI: 1.253–1.949; P<0.0001) confirmed this finding.

Subgroup analysis stratified for mixed ethnicity (two case control studies involving 111 cases of endometriosis and 78 controls) demonstrated a significant association between the GSTM1 null genotype and a decreased risk for endometriosis (OR=0.404; 95% CI: 0.219–0.745; P=0.004; Table II). Compared with individual Caucasian and Asian populations, the difference was statistically significant (P<0.001; data shown in Table III).

 GSTT1 genotype

Data reporting on the GSTT1 gene polymorphism are described in 18 case-control studies (2,371 cases of endometriosis and 2,490 controls). The meta-analysis demonstrated a significant association between the GSTT1 null genotype and an increased risk for endometriosis (OR=1.31; 95% CI: 1.02–1.68; P=0.037; Fig. 2B).

Subgroup analysis stratified by ethnicity demonstrated a significant association between the GSTT1 null genotype and an increased risk for endometriosis among Asians (OR=1.573; 95% CI: 1.186–2.085; P=0.002), but not among Caucasians (OR=1.124; 95% CI: 0.745–1.697; P=0.577).

Subgroup analyses stratified by the source of controls found no significant association between the GSTT1 null genotype and an increased risk for endometriosis among hospital-based studies (OR=1.284; 95% CI: 0.963–1.712; P=0.089) or among healthy individuals (OR=1.315; 95% CI: 0.767–2.254; P=0.320).

Subgroup analyses stratified by quality of evidence demonstrated a significant association between the GSTT1 null genotype and an increased risk for endometriosis among studies considered high-quality evidence (OR=1.376; 95% CI: 1.020–1.858; P=0.037), but not among studies considered low-quality evidence (OR=1.121, 95% CI: 0.646–1.944; P=0.684; Table II).

 Combined GSTM1/GSTT1 genotype

Data reporting on the combined GSTM1/GSTT1 gene polymorphism are described in eight case-control studies (1,083 cases of endometriosis and 1,222 controls). The meta-analysis demonstrated a significant association between the combined GSTM1/GSTT1 null genotype and an increased risk for endometriosis (OR=1.68, 95% CI: 1.29–2.17; P<0.0001; Fig. 2C).

This association was unchanged by subgroup analyses stratified by source of controls (hospital-based studies: OR=1.797; 95% CI: 1.081–2.989; P=0.024; healthy individuals: OR=1.657; 95% CI: 1.085–2.532; P=0.001) or quality of evidence (high-quality evidence: OR=1.753; 95% CI: 1.265–2.430; P=0.001; low-quality evidence: OR=1.542; 95% CI: 1.009–2.356, P=0.045; Table II).

Subgroup analysis stratified by ethnicity demonstrated a significant association between the combined GSTM1/GSTT1 null genotype and an increased risk for endometriosis among Asian populations (OR=1.898; 95% CI: 1.404–2.565; P<0.001), but not among Caucasian populations (OR=1.185; 95% CI: 0.717–1.961; P=0.508).

 Publication bias

Visual inspection of a Funnel plot, Egger's test and Begg's rank correlation test revealed no significant publication bias for the GSTM1, GSTT1 and combined GSTM1/GSTT1 studies (Fig. 3; Table IV).

 Heterogeneity analysis

There was evidence of significant heterogeneity (I2>50%) between studies of GSTM1 and GSTT1, and those used in subgroup analyses, although not among studies of GSTM1/GSTT1 combined (Table IV). Therefore, the random-effect model was used in all analyses with the exception of the analysis of combined GSTM1/GSTT1 gene polymorphisms. For the GSTM1 and GSTT1 gene polymorphisms, a meta-regression was conducted in which publication year, ethnicity, source of controls, sample size, and quality of evidence were covariates. All the covariates were entered into the meta-regression model simultaneously, and the covariates that had the highest P-values were omitted one at a time in order to identify any sources of heterogeneity among them. However, the meta-regression analysis did not identify any of these covariates as a significant source of heterogeneity (Figs. 4 and 5).

 Sensitivity analysis

To explore the effects of individual studies on the pooled OR estimates, a sensitivity analysis was performed, with the omission of one study at a time. The OR estimates for the GSTM1 polymorphism were not notably altered (Fig. 6A). The OR estimates for the GSTT1 and combined GSTM1/GSTT1 polymorphisms were altered when studies were excluded (Fig. 6B and C).

 Discussion

In the present study, a meta-analysis of data from 33 studies was conducted to examine the associations between the GSTM1, GSTT1 and combined GSTM1/GSTT1 null genotypes and susceptibility to endometriosis. The risk for endometriosis was significantly increased in the presence of the GSTM1, GSTT1 and combined GSTM1/GSTT1 null genotypes compared with the wild-type. Subgroup analyses stratified by ethnicity, source of controls and quality of evidence confirmed this finding among several subgroups, but particularly among studies considered high-quality evidence. Notably, among patients of mixed ethnicity, the GSTM1 null genotype was significantly associated with a decreased risk for endometriosis compared with the wild-type.

A similar meta-analysis of 23 studies performed in 2005 demonstrated an increased risk for endometriosis in women with the GSTT1 null genotype (8). However, the authors requested that their findings be interpreted with caution as asymmetry in the funnel plot was evident, which was likely due to publication bias (8). This previous study did not include subgroup analyses or an evaluation of the combined GSTM1/GSTT1 null genotype-endometriosis association.

Previous meta-analyses have found that the GSTM1/GSTT1 gene polymorphism is associated with cervical cancer (45), breast cancer (46), bladder cancer (47), gastric cancer (48,49) and acute leukemia (50). In accordance with the observations of the present study, several studies have shown that the GSTM1 (OR=32.6, 95% CI: 15.07–70.32, P<0.0001) (18) and GSTT1 (OR>3; P<0.0001) null genotypes (12,16) are associated with an increased risk for endometriosis. However, other reports suggest the GSTM1 (OR=0.21, 95% CI: 0.09–0.52, P<0.0001; OR=0.35, 95% CI: 0.15–0.83, P<0.0001) (40,43), GSTT1 (OR≥5; P<0.0001) (16) and combined GSTM1/GSTT1 (OR=0.38; P<0.001) (17) null genotypes are associated with a decreased risk for endometriosis. These divergent results may be explained by differences in GSTM1/GSTT1 null genotype frequencies and study locations. The frequency of the GSTM1/GSTT1 null genotype may vary from 10 to 65% depending on the region and population studied (51). Different study locations may introduce confounding variables associated with variations in lifestyles and exposures to toxic substances of the study populations.

The results of the present study must be interpreted with caution due to the presence of substantial heterogeneity. Among analyses of the studies of GSTM1 and GSTT1, the cause of heterogeneity remains unclear, despite meta-regression analyses being conducted. Among the analyses of combined GSTM1/GSTT1 studies, subgroup and sensitivity analyses suggested that studies that included patients with advanced stage endometriosis caused most of the variability. Publication bias was unlikely to have influenced the findings.

In addition to the heterogeneity, there were several limitations to this study. Firstly, the composition of the endometriosis patient and control populations varied between studies. For instance, some studies included only patients with advanced endometriosis (17–20,22,27,35), while control populations consisted of a mixture of infertile (29), postmenopausal (43) and premenopausal (18,35) women, and newborn babies that had not been exposed to the environment (17). Furthermore, patients and controls were not always accurately matched by age or environmental exposures. Secondly, gene-gene or gene-environment interactions may jointly increase the risk for endometriosis; therefore, different lifestyle and environmental factors may contribute to differential genotypic frequencies in cases and controls. Attempts were made to mitigate inaccuracies associated with this limitation through a subgroup analysis stratified according to ethnicity. Thirdly, this study was based on published articles. As a positive result is more likely to be published, publication bias is an inherent limitation of all meta-analyses irrespective of the outcomes of the Egger's linear regression test and Begg's rank correlation test.

In conclusion, the present meta-analysis shows the GSTM1, GSTT1 and combined GSTM1/GSTT1 null genotypes are likely associated with increased susceptibility to endometriosis. These data are in contrast to those reported previously. Therefore, further studies reporting higher quality evidence are necessary to verify these conclusions.

 Acknowledgements

The study was supported by Hubei Provincial Natural Science Foundation of China (Grant No.2013060602010236).

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meta-analysis of epidemiologic studiesDig Dis Sci5518311838201010.1007/s10620-009-1000-419960261 WangHZhouYZhuangWYinYQLiuGJWuTXYaoXDuLWeiMLWuXTGlutathione S-transferase M1 null genotype associated with gastric cancer among AsiansDig Dis Sci5518241830201010.1007/s10620-009-0971-519763824 DasPShaikAPBammidiVKMeta-analysis study of glutathione-S-transferases (GSTM1, GSTP1, and GSTT1) gene polymorphisms and risk of acute myeloid leukemiaLeuk Lymphoma5013451351200910.1080/1042819090300323619811334 NelsonHHWienckeJKChristianiDCChengTJZuoZFSchwartzBSLeeBKSpitzMRWangMXuXEthnic differences in the prevalence of the homozygous deleted genotype of glutathione S-transferase thetaCarcinogenesis16l2431245199510.1093/carcin/16.5.1243

PRISMA 2009 flow diagram showing the article screening and selection process. Using the search strategy, 120 articles were identified by the initial search, and 36 required further assessment. Finally, 32 articles were included in this review, one of which was considered as two studies. GSTM1, glutathione S-transferase µ1; GSTT1, glutathione S-transferase θ1.

Association between GSTM1, GSTT1 and the combined GSTM1/GSTT1 null genotypes and susceptibility to endometriosis. (A) A total of 33 studies described the association between the GSTM1 null genotype and susceptibility to endometriosis [odds ratio (OR)=1.56; 95% confidence interval (CI): 1.25–1.95; P<0.0001]; and (B) 18 studies described the association between the GSTT1 null genotype and susceptibility to endometriosis (OR=1.31; 95% CI: 1.02–1.68; P=0.037). GSTM1, glutathione S-transferase μ1;. GSTT1, glutathione S-transferase θ1.

Continued. (C) Eight studies described the association between the combined GSTM1/GSTT1 null genotypes and susceptibility to endometriosis [odds ratio (OR)=1.68; 95% confidence interval (CI): 1.29–2.17; P<0.0001]. GSTM1, glutathione S-transferase µ1;. GSTT1, glutathione S-transferase θ1.

Assessment of publication bias for studies on (A) GSTM1, (B) GSTT1 and (C) combined GSTM1/GSTT1 genotypes. GSTM1, glutathione S-transferase µ1;. GSTT1, glutathione S-transferase θ1.

Meta-regression for GSTM1 studies, with publication year, ethnicity, source of controls, sample size, and quality of evidence as covariates. All covariates were entered into the meta-regression model simultaneously, and the covariates with the highest P-values were omitted one at a time to identify sources of heterogeneity. The meta-regression did not identify any of these covariates as a significant source of heterogeneity. Variables were omitted in the following order: Size (A→B), source (B→C), publication year (C→D), ethnicity (D→E). GSTM1, glutathione S-transferase µ1.

Meta-regression for GSTT1 studies, with publication year, ethnicity, source of controls, sample size, and quality of evidence as covariates. All covariates were entered into the meta-regression model simultaneously, and covariates with the highest P-values were omitted one at a time to identify sources of heterogeneity. Meta-regression identified publication year as a significant source of heterogeneity (P=0.048), but after omitting this covariate heterogeneity remained substantial (I2=67.21%) Variables were omitted in the order: Source (A→B), quality (B→C), ethnicity (C→D), size (D→E). GSTT1, glutathione S-transferase θ1

Sensitivity analyses investigating the association between the (A) GSTM1, (B) GSTT1 and (C) combined GSTM1/GSTT1 null genotypes and susceptibility to endometriosis; one study was omitted at a time. GSTM1, glutathione S-transferase µ1;. GSTT1, glutathione S-transferase θ1.

Characteristics of included studies on the GSTM1, GSTT1 and combined GSTM1/GSTT1 gene polymorphisms.

GSTM1 (n) GSTT1 (n) GSTM1+GSTT1 (n)
First author, year Ethnicity Countries Source of controls Quality Cases/null Controls/null Cases/null Controls/null Cases/null Controls/null Refs.
Baranov, 1996 Caucasian Russia Healthy individuals Low 42/34 67/26 (33)
Baranova, 1999 Caucasian Russia, France Hospital patients High 65/50 72/33 65/13 72/7 (32)
Baranov, 1999 Caucasian Russia Healthy individuals Low 150/88 99/42 (34)
Hadfield, 2001 Caucasian UK Hospital patients High 132/59 52/27 116/29 50/14 (35)
Baxter, 2001 Caucasian England Healthy individuals High 84/40 219/107 (36)
Bischoff, 2002 Caucasian USA Hospital patients Low 62/13 36/20 (40)
Ivaschenko, 2003 Caucasian Russia Hospital patients High 74/42 40/17 74/27 40/6 74/16 40/2 (37)
Arvanitis, 2003 Caucasian Greece Healthy individuals High 275/161 346/181 275/24 346/31 275/11 346/16 (38)
Peng, 2003 Asian China Hospital patients High 76/50 80/37 (15)
Lin, 2003 Asian China Hospital patients High 68/49 28/12 68/53 28/9 (16)
Morizane, 2004 Asian Japan Healthy individuals Low 108/57 173/89 108/52 173/71 108/30 173/43 (17)
Hsieh, 2004 Asian China Hospital patients High 150/95 159/8 (18)
De Carvalho, 2004 Mixed Brazil Hospital patients Low 61/21 32/17 (42)
Ding, 2004 Asian China Healthy individuals High 80/46 105/55 80/59 105/47 80/34 105/24 (12)
Ding, 2004 Asian China Healthy individuals High 41/21 107/57 41/15 107/32 41/10 107/14 (12)
Babu, 2005 Caucasian India Hospital patients High 310/121 215/64 310/42 215/34 310/14 215/11 (19)
Hur, 2005 Asian Korea Hospital patients Low 194/112 259/145 194/104 259/125 (20)
Aban, 2007 Caucasian Turkey Hospital patients High 150/88 150/65 150/59 150/44 (21)
Chang, 2007 Asian China Hospital patients High 74/48 65/30 74/46 65/32 74/27 65/13 (30)
Kim, 2007 Asian Korea Hospital patients High 316/183 256/146 316/178 256/124 (22)
Rozati, 2009 Caucasian India Hospital patients High 97/26 102/15 (13)
Yang, 2009 Asian China Hospital patients Low 216/134 216/100 (14)
Cao, 2009 Asian China Hospital patients High 51/33 102/61 51/22 102/39 (23)
Wu, 2009 Asian China Hospital patients High 96/63 85/40 (24)
Huang, 2010 Asian China Hospital patients High 28/12 29/10 (25)
Trabert, 2011 Caucasian USA Healthy individuals High 254/137 567/268 (41)
Hosseinzadeh, 2011 Caucasian Iran Healthy individuals High 120/87 200/80 (26)
Wu, 2012 Asian China Healthy individuals Low 121/57 171/52 121/40 171/33 121/23 171/15 (27)
Seifati, 2012 Caucasian Iran Hospital patients High 101/51 142/74 (28)
Vichi, 2012 Caucasian Italy Hospital patients High 181/104 162/85 181/20 162/32 (39)
Matsuzaka, 2012 Asian Japan Hospital patients High 97/43 143/67 97/38 143/56 (29)
Frare, 2013 Mixed Brazil Healthy individuals Low 50/25 46/34 50/16 46/27 (43)
Sachan, 2013 Caucasian Iran Healthy people Low 66/27 100/16 (31)

Null genotype vs. wild type gene polymorphisms and susceptibility to endometriosis. GSTM1, glutathione S-transferase µ1; GSTT1, glutathione S-transferase θ1.

Meta-analysis of the association between GSTM1, GSTT1 and combined GSTM1/GSTT1 (null genotype vs. wild-type) gene polymorphisms and susceptibility to endometriosis.

Group No. of studies No. of subjects (cases/controls) OR [95%CI] P-value
Total studies
  GSTM1 genotype 33 3,990/4,625 1.563 [1.253–1.949] <0.001
  GSTT1 genotype 18 2,371/2,490 1.345 [1.044–1.733] 0.022
  GSTM1+GSTT1 genotype   8 1,083/1,222 1.672 [1.291–2.166] 0.005
Caucasian
  GSTM1 genotype 16 2,163/2,569 1.599 [1.205–2.122] 0.001
  GSTT1 genotype   7 1,171/1,035 1.124 [0.745–1.697] 0.577
  GSTM1+GSTT1 genotype   3 659/601 1.185 [0.717–1.961] 0.508
Asian
  GSTM1 genotype 15 1,716/1,978 1.772 [1.242–2.528] 0.002
  GSTT1 genotype 10 1,150/1,409 1.573 [1.186–2.085] 0.002
  GSTM1+GSTT1 genotype   5 424/621 1.898 [1.404–2.565] <0.001
Mixed
  GSTM1 genotype   2 111/78 0.404 [0.219–0.745] 0.004
  GSTT1 genotype   1 50/46
  GSTM1+GSTT1 genotype   0
Controls from hospital patients
  GSTM1 genotype 21 2,599/2,425 1.561 [1.151–2.117] 0.004
  GSTT1 genotype 12 1,696/1,542 1.284 [0.963–1.712] 0.089
  GSTM1+GSTT1 genotype   3 458/320 1.797 [1.081–2.989] 0.024
Controls from healthy individuals
  GSTM1 genotype 12 1,391/2,200 1.569 [1.131–2.176] 0.007
  GSTT1 genotype   6 675/948 1.315 [0.767–2.254] 0.320
  GSTM1+GSTT1 genotype   5 625/902 1.657 [1.085–2.532] 0.001
High quality
  GSTM1 genotype 23 2,920/3,426 1.563 [1.253–1.949] <0.001
  GSTT1 genotype 14 1,898/1,841 1.376 [1.020–1.858] 0.037
  GSTM1+GSTT1 genotype   6 854/878 1.753 [1.265–2.430] 0.001
Low quality
  GSTM1 genotype 10 1,070/1,199 1.259 [0.785–2.020] 0.340
  GSTT1 genotype   4 473/649 1.121 [0.646–1.944] 0.684
  GSTM1+GSTT1 genotype   2 229/344 1.542 [1.009–2.356] 0.045

OR, odds ratio; CI, confidence interval; GSTM1, glutathione S-transferase µ1; GSTT1, glutathione S-transferase θ1.

Comparisons of subgroup analyses for GSTM1, GSTT1 and combined GSTM1/GSTT1 studies.

A, Analysis of the GSTM1 gene
GSTM1 (n)
Subgroup Subjects Null Normal χ2 P-value
Ethnicity 3.245 0.72a
  Caucasian Cases 1,128 1,035
  Controls 1,120 1,449
  Asian Cases 1,003 713
  Controls 909 1,069
  Mixed Cases 46 65 18.737 <0.001b
Controls 51 27 23.467 <0.001c
Source of controls 0.130 0.718
  Hospital patients Cases 1,397 1,202
Controls 1,073 1,352
  Healthy individuals Cases 780 611
Controls 1,007 1,193
Quality 0.825 0.364
  High quality Cases 1,609 1,311
Controls 1,539 1,887
  Low quality Cases 568 502
Controls 541 658
B, Analysis of the GSTT1 gene
GSTT1 (n)
Subgroup Subjects Null Normal χ2 P-value
Ethnicity 6.766 0.009
  Caucasian Cases 214 957
Controls 168 867
  Asian Cases 607 543
Controls 568 841
Source of controls 0.638 0.425
  Hospital patients Cases 631 1,065
Controls 522 1,020
  Healthy individuals Cases 206 469
Controls 241 707
Quality 0.062 0.803
  High quality Cases 625 1,273
  Controls 507 1,334
  Low quality Cases 212 261
Controls 256 393
C, Analysis of GSTM1+GSTT1 genes
GSTM1+GSTT1 (n)
Subgroup Subjects Null Normal χ2 P-value
Ethnicity 7.642 0.006
  Caucasian Cases 41 618
Controls 29 572
  Asian Cases 124 300
Controls 109 152
Source of controls 0.091 0.763
  Hospital patients Cases 57 401
Controls 26 294
  Healthy individuals Cases 108 517
Controls 112 790
Quality 0.022 0.882
  High quality Cases 112 542
Controls 80 598
  Low quality Cases 53 176
Controls 58 286

Caucasians vs..Asians

Caucasians vs. mixed

Asians vs. mixed.

Heterogeneity and publication bias of GSTM1, GSTT1 and combined GSTM1/GSTT1 studies.

Heterogeneity Publication bias (P-value)
Group I2 value (%) P-value Egger's test Begg's funnel plot
Total studies
  GSTM1 genotype 81.8 <0.001 0.313 0.412
  GSTT1 genotype 69.9 <0.001 0.557 0.705
  GSTM1+GSTT1 genotype 44.7 0.081 0.170 1.000
Caucasian
  GSTM1 genotype 79.2 <0.001 0.454 0.322
  GSTT1 genotype 64.7 0.009 0.339 0.764
  GSTM1+GSTT1 genotype 58.5 0.090 0.021 0.296
Asian
  GSTM1 genotype 83.8 <0.001 0.098 0.083
  GSTT1 genotype 62.4 0.004 0.160 0.210
  GSTM1+GSTT1 genotype 13.6 0.081 0.340 0.806
Mixed
  GSTM1 genotype 0.0 0.664 <0.001 0.317
Controls from hospital patients
  GSTM1 genotype 83.6 <0.001 0.390 0.506
  GSTT1 genotype 65.9 0.001 0.335 0.451
  GSTM1+GSTT1 genotype 62.2 0.071 0.585 1.000
Controls from healthy individuals
  GSTM1 genotype 79.4 <0.001 0.598 0.784
  GSTT1 genotype 78.4 <0.001 0.431 0.707
  GSTM1+GSTT1 genotype 45.9 0.116 0.531 1.000
High quality
  GSTM1 genotype 80.9 <0.001 0.042 0.068
  GSTT1 genotype 69.9 <0.001 0.530 0.189
  GSTM1+GSTT1 genotype 49.0 0.081 0.641 1.000
Low quality
  GSTM1 genotype 85.1 <0.001 0.788 0.516
  GSTT1 genotype 77.2 0.004 0.347 1.000
  GSTM1+GSTT1 genotype 62.9 0.101

GSTM1, glutathione S-transferase µ1;. GSTT1, glutathione S-transferase θ1.