Hum. Reprod. Advance Access originally published online on January 9, 2007
Human Reproduction 2007 22(4):1026-1030; doi:10.1093/humrep/del486
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The G2964A 3'-untranslated region polymorphism of the signal transducer and activator of transcription 6 gene is associated with endometriosis in South Indian women
1 Centre for Cellular and Molecular Biology, Hyderabad, Andhra Pradesh, India 2 Infertility Institute and Research Centre, Hyderabad, India 3 Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, UK
4 To whom correspondence should be addressed at: Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, Andhra Pradesh, India. Tel: +00 91 40-27192504; Fax: +00 91 40-27160591; E-mail: shivas{at}ccmb.res.in or shivajisisinthy{at}yahoo.com
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Abstract |
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BACKGROUND: The aim of the study was to test whether the signal transducer and activator of transcription 6 (STAT6) gene influences the risk of developing endometriosis.
METHODS: The single-nucleotide polymorphism, G2964A, in the 3'-untranslated region (UTR) of the STAT6 gene was tested for association in a case–control study of 232 affected women and 210 women with no evidence of disease. All the women were infertile, ascertained from the same infertility clinic and of South Indian origin. The genotype frequencies of this polymorphism were compared using PCR and sequencing analysis.
RESULTS: There were statistically significant differences in the genotype distributions (P = 0.002) and allele frequencies (P = 0.0002) between the cases and controls, according to codominant, dominant and recessive genotype models.
CONCLUSIONS: We report for the first time an association between the STAT6 G2964A 3'-UTR polymorphism and endometriosis in South Indian women. This finding suggests that STAT6 may contribute to disease susceptibility in endometriosis, which carries an extra interest as the gene lies in a region which has been implicated, albeit weakly, in a previous genomewide scan.
Key words: endometriosis/STAT6 gene/polymorphism
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An intricate interplay of cytokines mediates the immunoregulatory responses leading to the development and maintenance of endometriosis, a common gynaecological disease, defined as the presence of endometrial-like tissue in ectopic sites (Lebovic et al., 2001
; Seli and Arici, 2003). For example, an imbalance between Th1 and Th2 cells towards the Th2 arm has been demonstrated in the peritoneal fluid of women with endometriosis. Increased levels of Th2-specific cytokines such as interleukin (IL)-4, IL-10 and IL-5 in turn impair T-cell cytotoxicity, facilitating the implantation of endometrial cells at ectopic sites (Ho et al., 1997; Hsu et al., 1997; Gallinelli et al., 2004). Signal transducer and activator of transcription 6 (STAT6) is a transcription factor implicated in the initiation of signals from activated Th2 cells, specifically through IL-4 and IL-13 receptors (Kelly-Welch et al., 2003). STAT6 is also implicated in the pathogenesis of several tumours (Ostrand-Rosenberg et al., 2000) because of its critical role in the negative regulation of immunosurveillance (Terabe et al., 2000).
A common G2964A single-nucleotide polymorphism (SNP) in the STAT6 gene 3'-untranslated region (UTR) has shown to be associated with asthma and mild atopy (Gao et al., 2000), nut allergy (Amoli et al., 2000; Amoli et al., 2002) and Crohn's disease (Klein et al., 2005). In the present study, we investigated the STAT6 gene G2964A 3'-UTR polymorphism in South Indian women with and without endometriosis.
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Subjects
All the women were of South Indian origin and non-smokers. About 232 unrelated, infertile women with moderate–severe (III–IV) endometriosis staged using the revised American Fertility Society (rAFS) classification system (1997) were recruited at the Infertility Institute and Research Centre, Hyderabad, India. At screening, all women had a trans-vaginal ultrasound scan (TVS) followed, if an endometrioma was seen, by a laparoscopy to confirm the diagnosis histologically (rAFS III = 76, IV = 156). Women with other ovarian cysts, ultrasound evidence of adenomyosis, ovarian cancer and fibroids were excluded. Their mean age ± SD was 27.5 ± 4.4 (range 20–40) years. They all complained of dysmenorrhoea: mild (no pain-killers needed) = 43%; moderate (pain-killers sometimes needed) = 32%; severe (pain-killers always needed and/or confined to bed) = 25%; 70% had dyspareunia and 70% had primary infertility.
About 210 infertile women were recruited from the same clinic population and had an equal opportunity to be identified as cases, thereby meeting the criteria for appropriate controls set by Zondervan et al. (2002). These controls consisted of 141 (67%) women with no evidence of endometriosis on TVS and laparoscopy and 69 (33%) women with no evidence of an ovarian endometrioma on TVS and no clinical symptoms of endometriosis, who therefore did not subsequently have a laparoscopy because it was not indicated clinically. Their mean age ± SD was 26.7 ± 3.9 (range 22–39) years. Among the controls, 29% complained of mild dysmenorrhoea and 20% had dyspareunia; 78% had primary infertility. Written, informed consent was obtained from all participants. The Institutional Review Board of the Centre for Cellular and Molecular Biology, Hyderabad, approved the study.
Determination of the STAT6 genotype
Genomic DNA was extracted from 1 ml of EDTA anti-coagulated whole blood by the salting-out method (Miller et al., 1988). Genotyping of the G2964A SNP in the 3'-UTR region of the STAT6 gene (NCBI SNP CLUSTER ID: rs324015) was determined by PCR and sequencing analysis. The primers used were 5'-AGCTCTTCTACTACCCCCACA-3' (forward) and 5'-ACATGTCCAGACCCCTCCTA-3' (reverse). PCR amplification was performed in a programmable thermal-cycler gradient PCR system (Eppendorf AG, Hamburg, Germany). The PCR amplification was carried out for 35 cycles (denaturation at 94°C for 1 min, annealing at 54°C for 1 min, extension at 72°C for 1 min and final extension for 10 min at 72°C). The PCR product of 510 bp was sequenced with a Taq-Dye deoxy-terminator cycle sequencing kit using an automated ABI 3770 sequencer (Applied BioSystems, Foster City, USA). Genotype calling was done by analysing sequence chromatograms by Chromas V. 2.23 (Technelysium, Pty. Ltd).
Statistical analysis
Statistical analysis was performed using the Statistical Package for the Social Sciences (V 11.0). The genotypic distribution among subjects was tested for Hardy–Weinberg equilibrium using the Arlequin program (Version 2; Genetics and Biometry Laboratory, University of Geneva, Switzerland) (Schneider et al., 2000). The allele ratios and genotype distributions in the cases and controls were analysed with Pearson 
2-test. All P-values were two-tailed and 95% confidence intervals (CIs) are given and odds ratio with 95% CI determined.
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The genotypic distributions of the individual SNPs, as well as the STAT6 allele system, were in Hardy–Weinberg equilibrium in both the cases and controls. Sequence analyses of the 510 bp product of the STAT6 3'-UTR region SNP are shown in Figure 1. GG and AA homozygotes manifest as a single peak, whereas the heterozygote AG is seen as a double peak. Allele and genotype frequencies for the SNP are summarized in Table I. There were statistically significant differences in the genotype (P < 0.05) distributions and allele frequencies (P = 0.0002) of the STAT6 G2964A SNP between the cases and controls, according to codominant, dominant and recessive genotype models (Table I).
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Discussion |
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Endometriosis is a polygenically inherited disease with multifactorial pathogenesis. Several case–control studies have been performed to assess whether the association exists between endometriosis and SNPs in genes encoding cytokines such as IL-1, IL-4, IL-6 and tumour necrosis factor-
(Lee et al., 2002; Wieser et al., 2003; Kitawaki et al., 2004; Bhanoori et al., 2005), which have a critical role in the pathophysiology of the disease. However, few studies have been conducted on the down-stream signalling molecules like members of Janus kinase (JAK)–STAT family. Endometriosis development is accompanied by the activation of a T-helper type 2 immune response at the systemic and local levels. Both mRNA expression and intracellular synthesis of IL-4 and IL-10 are sharply increased in peripheral lymphocytes. The same changes were observed for IL-4 in the ectopic endometrium of women with endometriosis (Antsiferova et al., 2005), which may be responsible for the defective immunosurveillance against overgrowth of endometriotic tissues (Szyllo et al., 2003). STAT6 is required for mediating responses to IL-4 and for development of Th2 cells (Kaplan et al., 1996), and it plays a critical role in the regulation of GATA-3 and c-maf transcription factor expression, which are crucial for Th2 function (Zhou and Ouyang, 2003). This transcription factor also initiates a significant chromatin remodelling at the IL-4 gene locus, suggesting a role in the regulation of IL-4 expression (Agarwal and Rao, 1998). The potential role of STAT6 in the regulation of immunoglobulin E (IgE) expression is also well demonstrated (Nelms et al., 1999). In the present study, we show that a G2964A 3'-UTR polymorphism in the STAT6 gene may increase susceptibility to endometriosis in South Indian women.
Interestingly, a recently published genomewide linkage study identified one major susceptibility region linked to endometriosis on chromosome 10q26 and minor peaks with a maximum logarithm of odds score > 1.0 on chromosomes 2, 6, 7, 8, 12, 14, 15 and 17 (Treloar et al., 2005). The marker on chromosome 12, D12S368, defines a region 12p13.2–q24.1, which is a susceptibility locus for inflammatory bowel disease (Satsangi et al., 1996). It also harbours the STAT6 gene (12q 13.3–q14.1) (Patel et al., 1998), suggesting a possible functional significance for this Th2-specific transcription factor in the pathophysiology of endometriosis.
Previous case–control studies have revealed an association between 2964G allele homozygosity and an increased risk of allergy, asthma and Crohn's disease in UK, Japanese and German populations (Amoli et al., 2002; Tamura et al., 2003; Klein et al., 2005). In the present study also, the frequency of the 2964G allele was found to be significantly higher in endometriosis patients when compared with controls without the disease (P = 0.0002). This SNP has been reported to show a significant ethnic variation. For example, the ‘G’ allele frequency was observed to be high (0.7) in Caucasian populations of UK, Sweden, Dutch and Germany (Amoli et al., 2000; Duetsch et al., 2002; Xia et al., 2003; Klein et al., 2005), whereas this is not observed in the frequencies of the two alleles ‘A’ and ‘G’ in Chinese population (Zhu et al., 2006). But, our study shows that the 2964G allele is the less frequent (0.2) allele in the South Indian population, a finding that is consistent with the Japanese data (Gao et al., 2000). Although studies indicate that genetic variants within STAT6 contribute significantly to IgE regulation (Weidinger et al., 2004), the functional significance of this polymorphism is not well understood. It is evident from the literature that the 3'-UTR region plays an essential role in the appropriate expression of many genes by affecting translation and mRNA stability (Conne et al., 2000), suggesting an important role for 3'-UTR polymorphisms in gene expression. Some studies have indicated that STAT6 3'-UTR polymorphisms significantly contribute to elevated total serum IgE levels (Duetsch et al., 2002; Schedel et al., 2004). Moreover, the G2964A polymorphism was in significant linkage disequilibrium with the dinucleotide repeat polymorphism (13-GT repeat allele) of STAT6 exon 1 (Tamura et al., 2003), which is known to modulate the STAT6 promoter activity and serum IgE levels (Gao et al., 2004). Interestingly, an enhanced expression of IgE-dependent histamine releasing factor (Oikawa et al., 2003) and eosinophil activation (Eidukaite and Tamosiunas, 2004) have been reported in endometriosis patients. Women with the disease are also more likely to have a self-reported history of asthma and atopy diseases, consistent with the finding that the affected women are more likely to have asthma and atopy diseases (Sinaii et al., 2002). Unfortunately, however, we did not ask about a history of these conditions when the study was designed and we could not question the patients again.
JAK–STAT proteins are expressed in the endometrium and this pathway has functional significance in the endometrial receptivity (Catalano et al., 2005) and immune regulation in the reproductive tract (Kawana et al., 2005). This pathway also plays a crucial role in the estrogen biosynthesis by regulating expression of the aromatase gene (Zhao et al., 1995). IL-4–STAT6 pathway is active in a variety of cancer cell types including those of breast and colon cancers. STAT6 induces the expression of 3
-hydroxysteroid dehydrogenase type I, an isoenzyme that catalyses an essential step in the active steroid hormone formation (Gingras et al., 2001). Given that endometriosis is an estrogen dependent disease (Gurates and Bulun, 2003), JAK–STAT appears to have a role in disease development and progression. Recent studies by Matsuzaki et al. (2004), using complementary DNA microarray and laser capture microdissection, revealed an up-regulation in JAK1 expression in epithelial and stromal cells from deep endometriosis compared with their matched eutopic endometrium. This finding, when considered with the fact that JAK1 is an upstream kinase for STAT6, lends further support to the importance of STAT6 in endometriosis. In conclusion, the present study shows a significant association between the STAT6 gene G2964A 3'-UTR polymorphism and endometriosis in South Indian women.
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The authors would also like to thank K. Arvind Babu and N. G. Pavankumar Reddy, CCMB for their help in DNA isolation. Manjula Bhanoori would like to thank the DST, Government of India for the financial grant, WOS-A (SR/WOS-A/LS-304/2003), to carry out this work. The authors would like to thank the Wellcome Trust for the financial support.
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Submitted on October 5, 2006; resubmitted on November 6, 2006; accepted on November 16, 2006.
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