Human Reproduction Update Advance Access originally published online on September 19, 2008
Human Reproduction Update 2009 15(1):97-118; doi:10.1093/humupd/dmn040
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Functional genetic polymorphisms and female reproductive disorders: Part II—endometriosis
1 Department of Obstetrics and Gynecology, Medical University, 1090 Vienna, Austria 2 Department of Medicine, Endocrinology and Metabolism, University of Modena and Reggio Emilia, I-41100 Modena, Italy 3 Stratified Medicine Group, Merck Serono International S.A, 1202 Geneva, Switzerland 4 Department of Reproductive Medicine and Gynecology, University Medical Center, 3508 GA Utrecht, The Netherlands
5 Correspondence address. E-mail: clemens.tempfer{at}meduniwien.ac.at
 |
Abstract |
|---|
 TOP Abstract IntroductionGenetic association studies of...Systematic review search...ResultsDiscussionFundingAcknowledgementsReferences |
|---|
BACKGROUND: Endometriosis has a strong genetic component, and numerous genetic studies have been reported.
METHODS: We have systematically reviewed these studies and included 114 in our final selection.
RESULTS: We found no consistent evidence linking endometriosis with specific polymorphisms in genes encoding inflammatory mediators, proteins involved in sex steroid metabolism, vascular function and tissue remodelling. Although a number of polymorphisms have been associated with endometriosis in selected populations, the associations have not been independently confirmed, either because only single studies were carried out on these markers/genes or because other studies reported no association. The most solid evidence linking specific polymorphisms to endometriosis came from studies investigating glutathione-S-transferase, a phase II detoxification enzyme. Carriage of the GSTT1 null deletion variant showed consistent association with endometriosis with a 29% increased risk; however, it cannot be excluded that this result was due to publication bias, and this association should be independently confirmed in large-scale, well-designed case–control studies.
CONCLUSIONS: The evidence of an association between genetic polymorphisms and endometriosis is weak. Carriage of the GSTT1 null deletion may moderately increase the risk of this disease. We suggest that the methodology of association studies should be improved in order to identify and validate associations in endometriosis.
Key words: endometriosis / female reproduction / genetic polymorphisms / detoxification / sex steroids
|
Introduction |
|---|
|
TOPAbstractIntroductionGenetic association studies of...Systematic review search...ResultsDiscussionFundingAcknowledgementsReferences |
|---|
The association between genetic polymorphisms and clinical disease has long been recognized. For example, a relationship between blood group and gastrointestinal cancer was described in the 1950s (Billington, 1956
). More recently, technological advances in molecular biology have fuelled the interest in molecular polymorphisms and their influence on the susceptibility and clinical presentation of diseases (Tempfer et al., 2004).
Many aspects of female reproductive function are strongly influenced by genetic factors, and numerous studies have attempted to identify susceptibility genes for disorders affecting female fertility such as polycystic ovary syndrome, endometriosis, fibroids, cancer (ovarian, vulvar, cervical), premature ovarian failure, recurrent pregnancy loss and pre-eclampsia (Levanat et al., 2004; Modugno, 2004; Escobar-Morreale et al., 2005; Goswami and Conway, 2005; Tempfer et al., 2005; Ferreira et al., 2006; Layman, 2006). For many of these conditions, the search for genetic disease markers is ongoing, and no strong candidate has yet emerged.
Endometriosis is characterized by the presence and growth of endometrial cells outside the uterus, which impair fertility (Wenzl et al., 2003; Halis and Arici, 2004), and the disease has a strong genetic component (Treloar et al., 1999; Bischoff and Simpson, 2004; Vigano et al., 2007). In a study of the genetic influence on endometriosis risk in an Australian twin sample, for example, the risk ratio of affected versus population prevalence was 3.58 for monozygotic twins and 2.32 for dizygotic twins (Treloar et al., 1999). Clarifying the genetic etiology of endometriosis would have implications for diagnosis, identification of individuals at risk and the development of targeted therapeutics.
This disorder has been the focus of a large number of association studies investigating a wide variety of polymorphisms. Previous reviews assessed the possible role of specific polymorphisms or groups of polymorphisms, indicating that the number of robust associations may be low (Falconer et al., 2007). Some have even challenged the evidence for endometriosis having a genetic background (Di and Guo, 2007).
In this review, we assess evidence for the role of genetic polymorphisms in endometriosis. We present a systematic review of the published literature across all polymorphisms investigated in relation to endometriosis. We have evaluated the reliability and strength of the evidence for each of the 114 selected studies and discuss methods for improving association studies. However, to enable proper evalauation of the studies, we first explore the methodology of molecular association.
|
Genetic association studies of polymorphisms |
|---|
|
TOPAbstractIntroductionGenetic association studies of...Systematic review search...ResultsDiscussionFundingAcknowledgementsReferences |
|---|
The genetic basis of disease may be elucidated in different ways. One approach is to scan across the genome to identify markers/genes of interest; a second approach is to investigate specific ‘candidate’ genes. We discuss these approaches below, and provide examples of such studies in endometriosis.
Genome-wide linkage analysis using affected sibling-pairs has been applied to endometriosis by Australian, British and Icelandic groups (Stefansson et al., 1998; Treloar et al., 2000; Kennedy et al., 2001). These studies aim to find chromosomal regions shared by related individuals harbouring disease-predisposing genes. In these linkage studies, which are conceptually different from case–control studies in unrelated individuals, a possible informative locus on chromosome 10q has been reported (Treloar et al., 2000). In addition, in a separate linkage analysis of families with three or more affected members, Zondervan et al. (2007) suggested that there may be one or more high-penetrance susceptibility loci for endometriosis on chromosome 7. A dominant mode of inheritance with reduced penetrance and a recessive mode of inheritance with high penetrance have been suggested for these potential genetic variants. To our knowledge, genome-wide genetic association studies on unrelated individuals have not been carried out.
Genetic case–control studies identify markers/genes that are associated with a trait of interest, such as a given disease. Genetic association studies do not, however, prove an etiological link between the polymorphism and/or the gene in question and the investigated trait. Once identified, the association of a specific genetic marker within a candidate gene with the trait should be investigated further. Specifically, it has to be clarified, whether the allele of interest has a direct biological effect or whether the association is based on biological effects downstream of the allele, which are in linkage disequilibrium. Since linkage disequilibrium may vary in different populations, this is an important source of inconsistency.
A particular problem in interpreting the results from genetic association studies in endometriosis is linked to the fact that this is not a monogenic trait but a complex trait. Therefore, various genetic factors can be expected to have an effect with an additional level of variation regarding the individual effect sizes. Especially small effect sizes may be easily missed in individual studies with small sample sizes. Common methodological problems in genetic association studies include low sample size, chance findings, multiple comparisons and subsequent type I error inflation, different ethnic backgrounds of the study subjects, varying disease definitions and inclusion/exclusion criteria and ascertainment bias. To help overcome these methodological problems, Zondervan et al. (2002) proposed the following criteria for case–control studies to identify an association between genetic polymorphisms and endometriosis: (i) use newly diagnosed, i.e. incident, cases with endometriosis, (ii) collect information predating symptoms and (iii) use at least one population-based female control group matched for unadjustable confounders and ideally also screened for pelvic symptoms. These criteria for high-quality case–control studies, however, have not been fulfilled by the majority of the studies discussed in this review. Therefore, positive associations between genetic polymorphisms and endometriosis have to be interpreted with caution.
Ethnic background is an important source of variation. As illustrated by this review, genetic associations are often inconsistent across ethnic barriers, which may be due to different frequencies of polymorphic alleles as well as gene–gene interactions. In this respect, a genetic association, although valid in a specific ethnic population, may not be relevant for individuals of another ethnicity. This has to be acknowledged when judging the external validity of any genetic association study.
Some of these methodological problems can be overcome—at least in part—by summarizing data from individual studies in the form of a meta-analysis. This tool has been increasingly used to confirm or rule out associations. Applying meta-analysis can be generally expected to confirm only a fraction of associations previously reported in individual small studies. Also, a strong association in individual studies with a P-value <0.001 has been reported to be a good predictor of confirmation in a meta-analysis (Lohmueller et al., 2003).
In this review, we have assessed the quality of evidence for every group of polymorphisms investigated in endometriosis association studies according to the agreement between studies, the presence or absence of meta-analyses and the strength of the association.
|
Systematic review search criteria |
|---|
|
TOPAbstractIntroductionGenetic association studies of...Systematic review search...ResultsDiscussionFundingAcknowledgementsReferences |
|---|
We systematically searched the PubMed and EMBASE databases for gene association studies published up to the end of August 2007 using the term ‘endometriosis’ combined with ‘polymorphism OR polymorphisms’ or ‘mutation OR mutations’. The search was not limited by language of publication. Translations of non-English papers were not obtained. The principle author (C.B.T.) selected relevant studies using the following criteria: all studies investigating polymorphic genetic variants with cases, i.e. women with a clinical and/or surgical diagnosis of endometriosis irrespective of disease stage, and with controls, i.e. women irrespective of definition of controls, listing absolute numbers of the respective genotype distributions. The interpretation of the consistency of an association with endometriosis always refers to a specific polymorphism and not to any investigated polymorphism in a specific gene.
|
Results |
|---|
|
TOPAbstractIntroductionGenetic association studies of...Systematic review search...ResultsDiscussionFundingAcknowledgementsReferences |
|---|
The search for endometriosis susceptibility polymorphisms was focused mainly on genes involved in inflammation, sex steroid regulation, metabolism, biosynthesis, detoxification, vascular function and tissue remodelling.
Genes of inflammatory mediators
It is widely accepted that endometriosis is an inflammatory process, associated with altered immune cell function, immune cell numbers, and elevated levels of inflammatory cytokines (Agic et al., 2006). This observation has led researchers to investigate the effects of polymorphisms in genes encoding cytokines and other molecules involved in inflammation (see Table I).
|
Cytokines
In Taiwanese women, the –509C/T promoter polymorphism in the transforming growth factor (TGF) β1 gene (Hsieh et al., 2005f
), the 881T/C polymorphism in the interleukin (IL)-2 receptor β gene (Hsieh et al., 2005b) and the –627A/C promoter polymorphism in the IL-10 gene (Hsieh et al., 2003) have all been associated to endometriosis susceptibility. Two polymorphisms in the promoter region of the IL-10 gene, –1082G/A and –592C/A [note that this is the same as the –627A/C single-nucleotide polymorphism (SNP) studied by Hsieh et al. (2003)], have been investigated in Japanese women but do not appear to influence endometriosis susceptibility in this population (Kitawaki et al., 2002). However, the same research group found that the genotype for the CA repeat microsatellite in the interferon-
gene may have an effect on endometriosis susceptibility in Japanese women (Kitawaki et al., 2004). Polymorphisms in genes encoding other interleukins (IL-1β, IL-4, IL-6 and IL-18) and their receptors (IL-1 receptor and IL-12 receptor β) have been investigated but failed to show a consistent association with endometriosis susceptibility (Hsieh et al., 2001a, 2002, 2005b; Lee et al., 2002; Wieser et al., 2003a, b; Bhanoori et al., 2005b; Kitawaki et al., 2006; Wen et al., 2006). Wieser et al. (2003a) suggest that the IL-6 promoter polymorphism 174G/C predisposes women to endometriosis with chocolate cysts. In one study, carriage of the IL-1 receptor antagonist A2 allele was associated with endometriosis in a Chinese population (Wen et al., 2006). D’Amora et al. (2006) also reported that the BsrBI C/A, but not the PstI C/T polymorphism of the IL-1 receptor gene, is associated with a reduced risk of endometriosis.
The insulin-like growth factor II (IGF2) ApaI polymorphism was not found to be associated with endometriosis in Taiwanese women (Hsieh et al., 2004c). Also, a polymorphism in the TGF beta 1 gene (509C/T) was not associated with deep infiltrating endometriosis in Dutch women (van Kaam et al., 2007a).
A number of groups have investigated a possible link between polymorphisms in the tumour necrosis factor (TNF) gene and increased endometriosis risk. Polymorphisms in the promoter region of the TNF-
gene do not appear to influence endometriosis risk in Korean, Taiwanese or Caucasian women (Hsieh et al., 2002; Lee et al., 2002; Wieser et al., 2002a). An Australian study investigating 26 polymorphisms in the promoter and coding regions of TNF also found no association with endometriosis (Zhao et al., 2007). However, the –1031T/C TNF promoter polymorphism may affect disease severity in Japanese women (Asghar et al., 2004). In Japanese women, the TNF-U01 haplotype (–1031T, –863C, –857C) has also been linked to endometriosis susceptibility, although it should be noted that this haplotype is in strong linkage disequilibrium with the HLA-B*0702 allele, making it difficult to determine which gene is responsible for the association (Teramoto et al., 2004). A Chinese study found an association between endometriosis and the +252 polymorphism in intron 1 of the TNF beta gene (Luo et al., 2006).
Nitric oxide and adhesion molecules
Elevated levels of the pro-inflammatory molecule nitric oxide (NO) have been reported in women with endometriosis (Wu et al., 2003). Endothelial NO synthase catalyses the production of NO, and the p.E298D polymorphism in the NOS3 gene has been associated with endometriosis susceptibility (Zervou et al., 2003). Intercellular adhesion molecule-1 (ICAM-1) is thought to mediate interactions between endometrial cells and lymphocytes during the pathogenesis of endometriosis (Vigano et al., 2003). In Caucasian women, the p.G241R polymorphism in the ICAM1 gene may influence disease severity (Vigano et al., 2003), but neither this nor the p.K469E polymorphism appear to have a direct influence on endometriosis susceptibility in either Caucasian or Japanese women (Vigano et al., 2003; Yamashita et al., 2005; Kitawaki et al., 2006). The PmII C/T polymorphism of the epithelial cadherin (CDH1) gene was associated with late-stage endometriosis in Taiwanese women (Hsieh et al., 2005c). In a Chinese study, the CDH1 3'-UTR C/T polymorphism, but not the –160C/A or –347G/GA promoter polymorphisms, was associated with endometriosis (Shan et al., 2007).
Human leukocyte antigens
Human leukocyte antigens (HLAs) are key components of the major histocompatibility complex (MHC), which is involved in immune cell signalling processes such as T-cell activation. HLA genes involved in both MHC I (HLA-A and HLA-B) and MHC II (HLA-DPB1, HLA-DQB1 and HLA-DRB1) have been studied in women with endometriosis. A study of Chinese women found that HLA-B genotype, but not HLA-A genotype, influences endometriosis susceptibility (Wang et al., 2001). In Japanese women, both the HLA-DRB1*1403 and HLA-DQB1*0301 alleles have been linked to increased endometriosis risk, whereas HLA-DPB1 alleles do not appear to affect susceptibility (Ishii et al., 2002, 2003). It should be noted that the HLA-DRB1 and HLA-DQB1 genes are in strong linkage disequilibrium (de Bakker et al., 2006), which may explain why they both show an association with endometriosis. Studies of Chinese and Korean women investigating many of the known alleles of the HLA-DRB1 gene found no association between these alleles and endometriosis susceptibility in these populations (Wang et al., 2002; Whang et al., 2006). Two polymorphisms in the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene were found not to be associated with endometriosis (Vigano et al., 2005).
Regulation upon activation normal T-cell expressed and secreted
Regulation upon Activation Normal T cell Expressed and Secreted (RANTES, recently renamed CCL5) is an inflammatory cytokine that has been implicated in the induction of monocyte migration in the peritoneal fluid of women with endometriosis (Pritts et al., 2002). Although the –403G/A and –28C/G polymorphisms in the CCL5 gene and the delta32 and p.V64I polymorphisms in the RANTES receptor genes, CCR5 and CCR2, respectively, do not appear to affect endometriosis susceptibility (Antinolo et al., 2003, 2004), the p.P12A polymorphism in the gene encoding PPAR- (PPARG), which regulates the expression of CCL5, has been linked to an increased risk of endometriosis (Dogan et al., 2004). On the other hand, no association was found in Japanese women between the PPARG p.P12A polymorphism and endometriosis, but an association was found with the exon 6 161C/T polymorphism in that same gene (Kiyomizu et al., 2006).
Summary
No consistent evidence linking endometriosis with specific polymorphisms of genes coding for inflammatory mediators is available. A number of polymorphisms have been found to be associated with endometriosis in selected populations (Table I). However, these associations have not been independently confirmed across ethnic barriers, either because only single studies are available or because other studies investigating these polymorphisms reported no association. Nor have meta-analyses of these studies been published. Therefore, no specific polymorphisms of genes encoding inflammatory mediators have been convincingly shown to play a role in the susceptibility to endometriosis.
Genes involved in sex hormone activity
Investigations of the influence of polymorphisms in genes encoding sex hormones and hormone regulators are set out in Table II.
|
Estrogen receptor
The influence of estrogen receptor gene (ESR1) polymorphisms has been investigated both in European and in Asian women with endometriosis. The XbaI (–351A/G) and the PvuII (–397T/C) restriction fragment-length polymorphisms (RFLPs) were not associated with endometriosis in a Korean population (Kim et al., 2005b
), but appear to affect endometriosis susceptibility in Taiwanese women (Hsieh et al., 2007b). The association between endometriosis and the PvuII RFLP (–397T/C) was also found in Greek and Italian women (Georgiou et al., 1999; Luisi et al., 2006), and has been shown to influence disease severity, but not susceptibility, in German and Egyptian women (El-Gindi et al., 2002; Renner et al., 2006). This polymorphism was not found to affect endometriosis susceptibility in Korean women (Kim et al., 2005b), and studies investigating its importance in Japanese women have reported conflicting results (Kitawaki et al., 2001; Wang et al., 2004). An Austrian group investigated the effect of the ESR1 –397T/C polymorphism, which they named IVS1–401T/C, but found no association with endometriosis susceptibility (Huber et al., 2005). A TA repeat microsatellite upstream of the ESR1 gene has been linked to endometriosis susceptibility in Greek, Taiwanese and Korean women (Georgiou et al., 1999; Kim et al., 2005b; Hsieh et al., 2005d), and has been associated with susceptibility to mild endometriosis in Korean women (Kim et al., 2005b). Studies of Japanese, Korean and Italian women found no link between the XbaI RFLP (–351A/C) in the ESR1 gene and endometriosis susceptibility (Wang et al., 2004; Kim et al., 2005b; Luisi et al., 2006), although a study of German women suggested that it may influence lesion severity (Renner et al., 2006). The AluI RFLP (1730A/G) in the ESR2 gene was linked to an increased risk of stage IV endometriosis in Japanese women (Wang et al., 2004), but was not shown to influence disease susceptibility in groups of Italian and Korean women (Luisi et al., 2006; Lee et al., 2007).
Progesterone receptor
Groups in Austria, Brazil and Italy have demonstrated a link between the PROGINS polymorphism in the PGR gene and endometriosis susceptibility (Wieser et al., 2002b; Lattuada et al., 2004a; De Carvalho et al., 2007). A study of Dutch women with deep infiltrating endometriosis found no association with PROGINS, but did observe an association with the PGR 331G/A polymorphism (van Kaam et al., 2007b). A study from India (Govindan et al., 2007) and an analysis of pooled data from an Australian group who conducted several studies investigating the PROGINS polymorphism and five SNPs in the PGR gene, indicated that there was no association with endometriosis susceptibility for any of these variants (Treloar et al., 2005a).
Androgen receptor
The CAG repeat microsatellite in the AR gene has been linked to an increased risk of uterine fibroids, and the 21 CAG repeat allele showed an association with endometriosis susceptibility in Taiwanese women (Hsieh et al., 2001b). However, an Italian study found no association between CAG repeat length and endometriosis susceptibility (Lattuada et al., 2004c). Receptor interacting protein 140 co-regulates the activities of estrogen and progesterone receptors and is essential for female fertility (Caballero et al., 2005). The p.R448G polymorphism in the gene encoding this protein (NRIP1) has been linked to endometriosis susceptibility in Spanish women (Caballero et al., 2005).
Summary
No consistent evidence linking specific polymorphisms of genes encoding proteins involved in sex hormone activity with endometriosis is available. A number of polymorphisms have been found to be associated with endometriosis in selected populations (Table II). However, these associations have not been independently confirmed across ethnic barriers, either because only single studies are available or because other studies investigating the respective polymorphisms reported no association. A systematic review and meta-analysis of studies investigating sex steroid biosynthesis and sex steroid receptors in women with endometriosis has been published, demonstrating no consistent association of the investigated polymorphisms with endometriosis (Guo, 2006a). Therefore, no specific polymorphisms of genes encoding proteins involved in sex hormone activity have been convincingly shown to play a role in the susceptibility to endometriosis.
17-β hydroxysteroid dehydrogenase type 1
The 17-β hydroxysteroid dehydrogenase type 1 (HSD17B1) gene encodes a key enzyme involved in testosterone biosynthesis and estrogen metabolism. The p.S312G polymorphism in this gene has been linked to an increased risk of endometriosis in Japanese women (Tsuchiya et al., 2005b), and the –27A/C (vIV) polymorphism was associated with an increased risk of endometriosis in a cohort of Austrian women (Huber et al., 2005).
Detoxification enzymes
The CYP1A1 and CYP1B1 genes encode phase I detoxification enzymes involved in estrogen metabolism. Studies in Austrian, Indian, Chinese, Japanese and Taiwanese populations found no association between known polymorphisms in the CYP1A1 gene and susceptibility to endometriosis (Peng et al., 2002; Iizuka et al., 2003; Babu et al., 2005; Huber et al., 2005; Juo et al., 2006). However, studies in Greece and the UK indicated that the MspI RFLP (6235T/C) in the CYP1A1 gene may influence endometriosis susceptibility when associated with the GSTM1 null deletion variant (Arvanitis et al., 2001, 2003; Hadfield et al., 2001). Peng et al. (2003a) reported that the CYP1A1 4889A/G polymorphism is associated with endometriosis in Chinese women. An Austrian group investigated the p.N453S polymorphism in the CYP1B1 gene but this did not appear to influence susceptibility to endometriosis (Huber et al., 2005). In a Korean study, the CYP1B1 p.L432V, Asp(449)C/T and p.A453S polymorphisms were not associated with late stage endometriosis (Cho et al., 2007). Polymorphisms in genes encoding other enzymes involved in estrogen metabolism (COMT) or phase I detoxification (myeloperoxidase) have also been investigated, but failed to show an effect on endometriosis susceptibility (Wieser et al., 2002c; Hsieh et al., 2004a; Huber et al., 2005; Juo et al., 2006).
The CYP17A1 and CYP19A1 genes both code for enzymes involved in estrogen biosynthesis. Whereas studies of Taiwanese women have shown a possible relation between endometriosis susceptibility and the –34T/C polymorphism in the promoter region of the CYP17A1 gene (Hsieh et al., 2004b, 2005d), no strong association with CYP17A1 polymorphisms has been found in UK, Brazilian, Austrian, Taiwanese or Japanese study populations (Kado et al., 2002; Asghar et al., 2005; Huber et al., 2005; Juo et al., 2006; De Carvalho et al., 2007). The TTTA repeat microsatellite in the CYP19A1 gene may increase the risk of endometriosis in Greek women (Arvanitis et al., 2003), and shows a weak association in Japanese women (Kado et al., 2002). Another polymorphism in this gene (p.R264C) was studied in Japanese and Austrian women, but did not appear to influence endometriosis susceptibility (Huber et al., 2005; Tsuchiya et al., 2005b).
The GSTM1, GSTP1, GSTT1, NAT1 and NAT2 genes all encode phase II detoxification enzymes. Null deletions in the glutathione-S-transferase GSTM1 gene have been linked to an increased risk of endometriosis in French, Russian, Indian, Chinese and Taiwanese women (Baranova et al., 1997, 1999; Ivashchenko et al., 2003; Peng et al., 2003b; Hsieh et al., 2004a; Babu et al., 2005). These null deletions were not shown to affect endometriosis susceptibility in Korean, Japanese and Australian study populations (Baxter et al., 2001; Iizuka et al., 2003; Morizane et al., 2004; Hur et al., 2005), although the Australian study indicated that GSTM1 null deletion may predispose endometrial lesions to malignant transformation (Baxter et al., 2001). The p.I105V polymorphism in the GSTP1 gene is associated with an increased risk of endometriosis in Turkish women (Ertunc et al., 2005), but does not seem to have an effect on susceptibility in Korean women (Hur et al., 2005). Studies conducted in Greece, France, India, UK, Japan and Korea showed no correlation between the GSTT1 null deletion variant and endometriosis susceptibility (Baranova et al., 1999; Arvanitis et al., 2003; Morizane et al., 2004; Babu et al., 2005; Hur et al., 2005), whereas a study of Russian women did show such an association (Ivashchenko et al., 2003). Several studies have investigated the association between NAT2 polymorphisms and endometriosis susceptibility, but they reported conflicting results (Baranova et al., 1999; Nakago et al., 2001; Iizuka et al., 2003; Ivashchenko et al., 2003; Babu et al., 2004; Deguchi et al., 2005; Iskhakova, 2006). One study investigated NAT1 polymorphisms and found no association with endometriosis susceptibility (Deguchi et al., 2005).
The arylhydrocarbon receptor (AhR) and the AhR nuclear translocator (ARNT) are transcription factors that promote the expression of a number of genes encoding metabolic enzymes (including CYP1A1 and GST). The action of AhR is suppressed by the AhR repressor (AhRR). In Japanese women, the p.A185P polymorphism in the AHRR gene has been shown to confer endometriosis susceptibility and severity, but polymorphisms in the AHR and ARNT genes did not have an effect (Tsuchiya et al., 2005a). In a Korean study, concomitant carriage of the p.A185P polymorphism in the AHRR gene and the GSTT1 null deletion, but not carriage of AHRR p.A185P, GSTT1 null deletion or GSTM1 null deletion alone, was associated with endometriosis (Kim et al., 2007b). The AHRR p.A185P polymorphism was not associated with endometriosis in Japanese women (Watanabe et al., 2001).
Summary
The most solid evidence so far linking specific polymorphisms to endometriosis comes from studies investigating phase II detoxification enzymes, namely the GSTT1 null deletion variant. A systematic review and meta-analysis of the GSTM1 and GSTT1 variants demonstrated a consistent association between GSTT1 polymorphisms and endometriosis with a moderate effect size. There was a 29% increased risk of endometriosis in GSTT1 null deletion carriers (Guo, 2005). It has to be mentioned, however, that there was evidence of publication bias in this meta-analysis, indicating that the size of the increased risk associated with the GSTT1 deletion variant may actually be smaller or non-existent. In addition, a number of polymorphisms have been found to be associated with endometriosis in selected populations, e.g. HSD17B1 p.S312G and –27A/C (vIV), CYP1A1 MspI RFLP (6235T/C), NAT2*5, CYP17A1 –34T/C, CYP19A1 TTTA repeat microsatellite and AHRR p.A185P (Table III). These associations, however, have not been independently confirmed across ethnic barriers either because only single studies are available or because other studies investigating these polymorphisms reported no association.
|
Genes regulating vascular function and tissue remodelling
Endometriosis shows some of the characteristics typically seen in malignant cells, such as neovascularization and local invasion (Hsieh et al., 2005c). Therefore, polymorphisms in a number of genes involved in vascular and cellular growth and reorganization have been investigated for a possible role in endometriosis.
Vascular endothelial growth factor, epidermal growth factor receptor and endostatin
Vascular endothelial growth factor (VEGF) mediates vascular permeability and angiogenesis, and is known to be a key molecule in the pathogenesis of endometriosis (Bhanoori et al., 2005a; Kim et al., 2005a). Three polymorphisms in the VEGF gene have been evaluated in women with endometriosis. The 405G/C polymorphism has been linked to endometriosis susceptibility in South Indian women, and with susceptibility to advanced-stage endometriosis in Korean women (Bhanoori et al., 2005a; Kim et al., 2005a). In contrast, the –460C/T polymorphism did not appear to affect susceptibility in either of these populations (Bhanoori et al., 2005a; Kim et al., 2005a), but may influence the risk of endometriosis in Taiwanese women (Hsieh et al., 2004d). The VEGF 936C/T polymorphism and the endostatin 4349G/A polymorphism were not associated with endometriosis in Korean women (Kim et al., 2007a) (Table IV). The epidermal growth factor receptor (EGFR) is another molecule involved in angiogenesis, and the EGFR 2073*T allele has been linked to an increased risk of endometriosis in Taiwanese women (Hsieh et al., 2005e) (Table I).
|
Angiotensin-I-converting enzyme
Angiotensin-I-converting enzyme (ACE) catalyzes the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. Three polymorphisms in the gene encoding this enzyme have been investigated in Taiwanese women with endometriosis, and both the 2350A/G and –240A/T variants as well as the insertion/deletion (I/D) polymorphism are associated with endometriosis susceptibility in this population (Hsieh et al., 2005a
, 2007a).
Matrix metalloproteinases
Matrix metalloproteinases (MMPs) are thought to be involved in the tissue invasion that occurs during endometriotic lesion formation (Ferrari et al., 2006). Polymorphisms in MMP1, MMP3, MMP7 and MMP9 genes have been investigated in Chinese women with endometriosis. A single I/D polymorphism 1G/2G (also referred to as –1607ins/delG) in the promoter region of the MMP1 gene and the –181A/G polymorphism in the MMP7 gene were associated with an increased risk of endometriosis (Kang et al., 2005; Shan et al., 2006). In contrast, a single I/D polymorphism –1171ins/delA (5A/6A) in the promoter region of the MMP3 gene did not appear to affect endometriosis susceptibility (Kang et al., 2005; Shan et al., 2005). The MMP1(2G)/MMP3(6A) combination showed an association (Kang et al., 2005; Shan et al., 2005), but this is probably due to the effects of the MMP1 (2G) genotype rather than a combined effect of both genes. The –1562C/T polymorphism in the MMP9 gene was not associated with endometriosis susceptibility (Shan et al., 2006). A group that investigated MMP polymorphisms in a population of Italian women found no association between MMP1 or MMP3 gene polymorphisms and susceptibility to endometriosis (Ferrari et al., 2006).
2-HS glycoprotein, plasminogen activator inhibitor-1
2-HS glycoprotein (AHSG) has been implicated in tissue development, and polymorphisms in the AHSG gene (p.T230M and p.T238S) have been linked to endometriosis susceptibility in Korean women (Kim et al., 2004). The plasminogen activator inhibitor 1 (PAI-1) 4G/5G promoter polymorphism has been investigated in 75 women with laparoscopically confirmed endometriosis and 43 controls (Bedaiwy et al., 2006). In this study, the 4G/4G genotype, known to be associated with hypofibrinolysis, was found to be over-represented among women with endometriosis.
Summary
No consistent evidence linking specific polymorphisms of genes endoding proteins involved in vascular function and tissue remodelling with endometriosis is available. A number of polymorphisms have been found to be associated with endometriosis in selected populations (Table IV). These associations, however, have not been independently confirmed across ethnic barriers either because only single studies are available or because other studies investigating these polymorphisms reported no association. No meta-analysis of respective studies has been published. Therefore, no specific polymorphisms of genes encoding proteins involved in vascular function and tissue remodelling have been convincingly shown to play a role in the susceptibility to endometriosis.
Other genes linked to endometriosis
Genes involved in signal transduction (STAT6, Table IV), malignant transformation (TP53, P21, KRAS, Table IV; BRAF), apoptosis (FAS, Table I; FASLG, Table I) and galactose metabolism (GAL T,Table IV) have been investigated for a role in endometriosis susceptibility, but no consistent association has been found (Tables I–IV) (Cramer et al., 1996; Morland et al., 1998; Hadfield et al., 1999; Hsieh et al., 2001c; Stefansson et al., 2001; Chang et al., 2002; Lattuada et al., 2004b; Omori et al., 2004; Fernandez et al., 2005; He et al., 2006; Hsieh and Lin, 2006; Zhao et al., 2006; Bhanoori et al., 2007; Vietri et al., 2007). Two exceptions are the STAT6 3'-UTR 2964G/A polymorphism (Bhanoori et al., 2007) and the GALT p.N314D polymorphism (Cramer et al., 1996), which are over-represented among South Indian women and US women with endometriosis, respectively. Hsieh and Lin (2006) found that the TP53 codon p.R72P polymorphism was associated with endometriosis in Taiwanese women and also looked for the presence of mutations at codons 11 and 248 in this population, but did not find any (Table I). An Australian study of 22 polymorphisms in the EMX2 gene and 15 polymorphisms in the PTEN gene found no association with endometriosis (Treloar et al., 2007).
Summary
No consistent and independently confirmed evidence linking specific polymorphisms of the STAT6, TP53, P21, FAS, FASLG, EMX2, PTEN, CTLA4 and GALT genes is available.
|
Discussion |
|---|
|
TOPAbstractIntroductionGenetic association studies of...Systematic review search...ResultsDiscussionFundingAcknowledgementsReferences |
|---|
In this review, we have summarized the current evidence linking genetic polymorphisms and endometriosis, showing that the majority of polymorphisms investigated so far are not associated with this disease in a methodologically reliable way. This may be because they have been investigated in only a single study or a limited number of studies, or because conflicting results were obtained.
The most solid evidence to date linking specific polymorphisms to endometriosis comes from studies investigating phase II detoxification enzymes. A systematic review and meta-analysis of studies investigating the glutathione-S-transferases GSTM1 and GSTT1 variants demonstrated a consistent association of a GSTT1 polymorphism and endometriosis, with a 29% increased risk of endometriosis in GSTT1 null deletion carriers.
There is no consistent evidence to link specific polymorphisms of genes encoding inflammatory mediators and proteins involved in sex steroid metabolism, vascular function and tissue remodelling with endometriosis. Although a number of polymorphisms have been found associated with endometriosis in selected populations, these associations have not been independently confirmed across ethnic barriers, either because only single studies are available or because other studies reported no association. The majority of polymorphisms have not been subjected to meta-analysis due to the limited availability of comparable studies. However, a systematic review and meta-analysis of sex steroid biosynthesis and sex steroid receptors demonstrated no consistent association of the investigated polymorphisms with endometriosis.
Clearly, absence of evidence of an association between a specific polymorphism and endometriosis does not rule out that this gene in general or other polymorphisms of this gene in particular may be involved in the etiology of this disease.
To date, most studies are retrospective genetic association studies, whereas others are studies with prospectively identified cases. This is a potential source of inconsistency, since studies including prospectively identified cases, i.e. incident cases, may produce different results compared with studies using retrospectively identified cases, i.e. prevalent cases. Other problems facing researchers in this field are well-illustrated in two recent reviews on the genetics of endometriosis (Guo, 2006a, b). The author ruled out many of the previous positive findings, highlighting issues such as lack of independent confirmation for many studies (Guo, 2006b) and faulty analyses (Guo, 2006a).
In order to further explore the importance of known and new polymorphisms in female reproductive function, it is essential that studies are well-designed and sufficiently powered. Whereas retrospective studies are useful for generating hypotheses, a prospective design must be used to test these hypotheses. Exploratory (hypothesis-generating) studies should aim to screen large numbers of genetic variations. This becomes an option for more researchers as high-throughput genotyping technologies improve and become more widely accessible. The exploratory phase should be followed by validation of a limited number of candidate markers (hypothesis testing), and prospective studies should be conducted whenever an association is confirmed. This approach will allow the identification and validation of polymorphisms, and those with strong links to susceptibility may help in developing new drugs or regimens. In addition, the discovery of genes that influence treatment response may enable individualized treatment to be tailored on the basis of genotype.
|
Funding |
|---|
|
TOPAbstractIntroductionGenetic association studies of...Systematic review search...ResultsDiscussionFundingAcknowledgementsReferences |
|---|
The preparation of this manuscript was sponsored by an unrestricted educational grant from Merck Serono, Geneva, Switzerland.
|
Acknowledgements |
|---|
|
TOPAbstractIntroductionGenetic association studies of...Systematic review search...ResultsDiscussionFundingAcknowledgementsReferences |
|---|
The authors would like to thanks Drs Polly Field, Imogen Horsey and Kay Elder for their assistance in drafting the manuscript.
|
References |
|---|
|
TOPAbstractIntroductionGenetic association studies of...Systematic review search...ResultsDiscussionFundingAcknowledgementsReferences |
|---|
Agic A, Xu H, Finas D, Banz C, Diedrich K, Hornung D. Is endometriosis associated with systemic subclinical inflammation? Gynecol Obstet Invest (2006) 62:139–147.[CrossRef][Web of Science][Medline]
Antinolo G, Fernandez RM, Noval JA, Garcia-Lozano JC, Borrego S, Marcos I, Molini JL. Evaluation of germline sequence variants within the promoter region of RANTES gene in a cohort of women with endometriosis from Spain. Mol Hum Reprod (2003) 9:491–495.
Antinolo G, Fernandez RM, Noval JA, Molini JL, Borrego S. Analysis of the involvement of CCR5-Delta32 and CCR2-V64I variants in the development of endometriosis. Mol Hum Reprod (2004) 10:155–157.
Arvanitis DA, Goumenou AG, Matalliotakis IM, Koumantakis EE, Spandidos DA. Low-penetrance genes are associated with increased susceptibility to endometriosis. Fertil Steril (2001) 76:1202–1206.[CrossRef][Web of Science][Medline]
Arvanitis DA, Koumantakis GE, Goumenou AG, Matalliotakis IM, Koumantakis EE, Spandidos DA. CYP1A1, CYP19, and GSTM1 polymorphisms increase the risk of endometriosis. Fertil Steril (2003) 79(Suppl 1):702–709.[CrossRef][Web of Science][Medline]
Asghar T, Yoshida S, Kennedy S, Negoro K, Zhuo W, Hamana S, Motoyama S, Nakago S, Barlow D, Maruo T. The tumor necrosis factor-alpha promoter—1031C polymorphism is associated with decreased risk of endometriosis in a Japanese population. Hum Reprod (2004) 19:2509–2514.
Asghar T, Yoshida S, Nakago S, Morizane M, Ohara N, Motoyama S, Kennedy S, Barlow D, Maruo T. Lack of association between endometriosis and the CYP17 MspA1 polymorphism in UK and Japanese populations. Gynecol Endocrinol (2005) 20:59–63.[Web of Science][Medline]
Babu KA, Rao KL, Reddy NG, Kanakavalli MK, Zondervan KT, Deenadayal M, Singh A, Shivaji S, Kennedy S. N-acetyl transferase 2 polymorphism and advanced stages of endometriosis in South Indian women. Reprod Biomed Online (2004) 9:533–540.[Web of Science][Medline]
Babu KA, Reddy NG, Deendayal M, Kennedy S, Shivaji S. GSTM1, GSTT1 and CYP1A1 detoxification gene polymorphisms and their relationship with advanced stages of endometriosis in South Indian women. Pharmacogenet Genomics (2005) 15:167–172.[Web of Science][Medline]
Baranova H, Bothorishvilli R, Canis M, Albuisson E, Perriot S, Glowaczower E, Bruhat MA, Baranov V, Malet P. Glutathione S-transferase M1 gene polymorphism and susceptibility to endometriosis in a French population. Mol Hum Reprod (1997) 3:775–780.
Baranova H, Canis M, Ivaschenko T, Albuisson E, Bothorishvilli R, Baranov V, Malet P, Bruhat MA. Possible involvement of arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1 genes in the development of endometriosis. Mol Hum Reprod (1999) 5:636–641.
Baxter SW, Thomas EJ, Campbell IG. GSTM1 null polymorphism and susceptibility to endometriosis and ovarian cancer. Carcinogenesis (2001) 22:63–65.
Bedaiwy MA, Falcone T, Mascha EJ, Casper RF. Genetic polymorphism in the fibrinolytic system and endometriosis. Obstet Gynecol (2006) 108:162–168.[CrossRef][Web of Science][Medline]
Bhanoori M, Arvind BK, Pavankumar Reddy NG, Lakshmi RK, Zondervan K, Deenadayal M, Kennedy S, Shivaji S. The vascular endothelial growth factor (VEGF) +405G>C 5'-untranslated region polymorphism and increased risk of endometriosis in South Indian women: a case control study. Hum Reprod (2005) a 20:1844–1849.
Bhanoori M, Babu KA, Deenadayal M, Kennedy S, Shivaji S. The interleukin-6 -174G/C promoter polymorphism is not associated with endometriosis in South Indian women. J Soc Gynecol Investig (2005) b 12:365–369.[Web of Science][Medline]
Bhanoori M, Deenadayal M, Kennedy S, Shivaji S. The G2964A 3'-untranslated region polymorphism of the signal transducer and activator of transcription 6 gene is associated with endometriosis in South Indian women. Hum Reprod (2007) 22:1026–1030.
Billington BP. Gastric cancer; relationships between ABO blood-groups, site, and epidemiology. Lancet (1956) 271:859–862.[Medline]
Bischoff F, Simpson JL. Genetic basis of endometriosis. Ann NY Acad Sci (2004) 1034:284–299.[CrossRef][Web of Science][Medline]
Caballero V, Ruiz R, Sainz JA, Cruz M, Lopez-Nevot MA, Galan JJ, Real LM, de CF, Lopez-Villaverde V, Ruiz A. Preliminary molecular genetic analysis of the Receptor Interacting Protein 140 (RIP140) in women affected by endometriosis. J Exp Clin Assist Reprod (2005) 2:11.[CrossRef][Medline]
Chang CC, Hsieh YY, Tsai FJ, Tsai CH, Tsai HD, Lin CC. The proline form of p53 codon 72 polymorphism is associated with endometriosis. Fertil Steril (2002) 77:43–45.[CrossRef][Web of Science][Medline]
Cho YJ, Hur SE, Lee JY, Song IO, Moon HS, Koong MK, Chung HW. Single nucleotide polymorphisms and haplotypes of the genes encoding the CYP1B1 in Korean women: no association with advanced endometriosis. J Assist Reprod Genet (2007) 24:271–277.[CrossRef][Web of Science][Medline]
Cramer DW, Hornstein MD, Ng WG, Barbieri RL. Endometriosis associated with the N314D mutation of galactose-1-phosphate uridyl transferase (GALT). Mol Hum Reprod (1996) 2:149–152.
D’Amora P, Sato H, Girao MJ, Silva ID, Schor E. Polymorphisms in exons 1B and 1C of the type I interleukin-1 receptor gene in patients with endometriosis. Am J Reprod Immunol (2006) 56:178–184.[Medline]
de Bakker PI, McVean G, Sabeti PC, Miretti MM, Green T, Marchini J, Ke X, Monsuur AJ, Whittaker P, Delgado M, et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet (2006) 38:1166–1172.[CrossRef][Web of Science][Medline]
De Carvalho CV, Nogueira-De-Souza NC, Costa AM, Baracat EC, Girao MJ, D’Amora P, Schor E, da S I. Genetic polymorphisms of cytochrome P450cl7alpha (CYP17) and progesterone receptor genes (PROGINS) in the assessment of endometriosis risk. Gynecol Endocrinol (2007) 23:29–33.[CrossRef][Web of Science][Medline]
Deguchi M, Yoshida S, Kennedy S, Ohara N, Motoyama S, Maruo T. Lack of association between endometriosis and N-acetyl transferase 1 (NAT1) and 2 (NAT2) polymorphisms in a Japanese population. J Soc Gynecol Investig (2005) 12:208–213.[CrossRef][Web of Science][Medline]
Di W, Guo SW. The search for genetic variants predisposing women to endometriosis. Curr Opin Obstet Gynecol (2007) 19:395–401.[CrossRef][Web of Science][Medline]
Dogan S, Machicao F, Wallwiener D, Haering HU, Diedrich K, Hornung D. Association of peroxisome proliferator-activated receptor gamma 2 Pro-12-Ala polymorphism with endometriosis. Fertil Steril (2004) 81:1411–1413.[CrossRef][Web of Science][Medline]
El-Gindi E, El-Adawy AR, Faris M, El-Moghazy D, El-Hamshary M. Genetic polymorphism in endometriosis among infertile Egyptian women. Middle East Fert Soc J (2002) 7:44–47.
Ertunc D, Aban M, Tok EC, Tamer L, Arslan M, Dilek S. Glutathione-S-transferase P1 gene polymorphism and susceptibility to endometriosis. Hum Reprod (2005) 20:2157–2161.
Escobar-Morreale HF, Luque-Ramirez M, San Millan JL. The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome. Endocr Rev (2005) 26:251–282.
Falconer H, D’Hooge T, Fried G. Endometriosis and genetic polymorphisms. Obstet Gynecol Surv (2007) 62:616–628.[CrossRef][Web of Science][Medline]
Fernandez RM, Noval JA, Garcia-Lozano JC, Borrego S, Molini JL, Antinolo G. Polymorphisms in the promoter regions of FAS and FASL genes as candidate genetic factors conferring susceptibility to endometriosis. Int J Mol Med (2005) 15:865–869.[Web of Science][Medline]
Ferrari MM, Biondi ML, Rossi G, Grijuela B, Gaita S, Perugino G, Vigano P. Analysis of two polymorphisms in the promoter region of matrix metalloproteinase 1 and 3 genes in women with endometriosis. Acta Obstet Gynecol Scand (2006) 85:212–217.[Medline]
Ferreira PM, Catarino R, Pereira D, Matos A, Pinto D, Coelho A, Lopes C, Medeiros R. Cervical cancer and CYP2E1 polymorphisms: implications for molecular epidemiology. Eur J Clin Pharmacol (2006) 62:15–21.[CrossRef][Web of Science][Medline]
Georgiou I, Syrrou M, Bouba I, Dalkalitsis N, Paschopoulos M, Navrozoglou I, Lolis D. Association of estrogen receptor gene polymorphisms with endometriosis. Fertil Steril (1999) 72:164–166.[CrossRef][Web of Science][Medline]
Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update (2005) 11:391–410.
Govindan S, Ahmad SN, Vedicherla B, Kodati V, Jahan P, Rao KP, Ahuja YR, Hasan Q. Association of progesterone receptor gene polymorphism (PROGINS) with endometriosis, uterine fibroids and breast cancer. Cancer Biomark (2007) 3:73–78.[Medline]
Guo S-W. Glutathione S-transferases M1/T1 gene polymorphisms and endometriosis: A meta-analysis of genetic association studies. Mol Hum Reprod (2005) 11:729–743.
Guo S-W. Association of endometriosis risk and genetic polymorphisms involving sex steroid biosynthesis and their receptors: a meta-analysis. Gynecol Obstet Invest (2006) a 61:90–105.[CrossRef][Web of Science][Medline]
Guo S-W. The association of endometriosis risk and genetic polymorphisms involving dioxin detoxification enzymes: a systematic review. Eur J Obstet Gynecol Repro Biol (2006) b 124:134–143.[CrossRef][Web of Science][Medline]
Hadfield RM, Manek S, Nakago S, Mukherjee S, Weeks DE, Mardon HJ, Barlow DH, Kennedy SH. Absence of a relationship between endometriosis and the N314D polymorphism of galactose-1-phosphate uridyl transferase in a UK population. Mol Hum Reprod (1999) 5:990–993.
Hadfield RM, Manek S, Weeks DE, Mardon HJ, Barlow DH, Kennedy SH. Linkage and association studies of the relationship between endometriosis and genes encoding the detoxification enzymes GSTM1, GSTT1 and CYP1A1. Mol Hum Reprod (2001) 7:1073–1078.
Halis G, Arici A. Endometriosis and inflammation in infertility. Ann N Y Acad Sci (2004) 1034:300–315.[CrossRef][Web of Science][Medline]
He C, Song Y, He X, Zhang W, Liao L. No association of endometriosis with galactose-1-phosphate uridyl transferase mutations in a Chinese population. Environ Mol Mutagen (2006) 47:307–309.[CrossRef][Web of Science][Medline]
Hsieh YY, Chang CC, Tsai FJ, Wu JY, Shi YR, Tsai HD, Tsai CH. Polymorphisms for interleukin-1 beta (IL-1 beta)-511 promoter, IL-1 beta exon 5, and IL-1 receptor antagonist: nonassociation with endometriosis. J Assist Reprod Genet (2001) a 18:506–511.[CrossRef][Web of Science][Medline]
Hsieh YY, Chang CC, Tsai FJ, Wu JY, Tsai CH, Tsai HD. Androgen receptor trinucleotide polymorphism in endometriosis. Fertil Steril (2001) b 76:412–413.[CrossRef][Web of Science][Medline]
Hsieh YY, Tsai FJ, Chang CC, Chen WC, Tsai CH, Tsai HD, Lin CC. p21 gene codon 31 arginine/serine polymorphism: non-association with endometriosis. J Clin Lab Anal (2001) c 15:184–187.[CrossRef][Web of Science][Medline]
Hsieh YY, Chang CC, Tsai FJ, Hsu Y, Tsai HD, Tsai CH. Polymorphisms for interleukin-4 (IL-4) -590 promoter, IL-4 intron3, and tumor necrosis factor alpha -308 promoter: non-association with endometriosis. J Clin Lab Anal (2002) 16:121–126.[CrossRef][Web of Science][Medline]
Hsieh YY, Chang CC, Tsai FJ, Lin CC, Tai CT, Ho M. Association of an A allele for interleukin-10 -627 gene promoter polymorphism with higher susceptibility to endometriosis. J Reprod Med (2003) 48:735–738.[Web of Science][Medline]
Hsieh YY, Chang CC, Tsai FJ, Lin CC, Chen JM, Tsai CH. Glutathione S-transferase M1*null genotype but not myeloperoxidase promoter G-463A polymorphism is associated with higher susceptibility to endometriosis. Mol Hum Reprod (2004) a 10:713–717.
Hsieh YY, Chang CC, Tsai FJ, Lin CC, Tsai CH. Cytochrome P450c17alpha 5'-untranslated region *T/C polymorphism in endometriosis. J Genet (2004) b 83:189–192.[CrossRef][Web of Science][Medline]
Hsieh YY, Chang CC, Tsai FJ, Peng CT, Yeh LS, Lin CC. Insulin-like growth factor II gene Apa I polymorphism is not associated with endometriosis susceptibility. Genet Mol Biol (2004) c 27:165–166.
Hsieh YY, Chang CC, Tsai FJ, Yeh LS, Lin CC, Peng CT. T allele for VEGF gene-460 polymorphism at the 5'-untranslated region: association with a higher susceptibility to endometriosis. J Reprod Med (2004) d 49:468–472.[Web of Science][Medline]
Hsieh YY, Chang CC, Tsai FJ, Hsu CM, Lin CC, Tsai CH. Angiotensin I-converting enzyme ACE 2350*G and ACE-240*T-related genotypes and alleles are associated with higher susceptibility to endometriosis. Mol Hum Reprod (2005) a 11:11–14.
Hsieh YY, Chang CC, Tsai FJ, Hsu CM, Lin CC, Tsai CH. Interleukin-2 receptor beta (IL-2R beta)-627*C homozygote but not IL-12R beta 1 codon 378 or IL-18 105 polymorphism is associated with higher susceptibility to endometriosis. Fertil Steril (2005) b 84:510–512.[CrossRef][Web of Science][Medline]
Hsieh YY, Chang CC, Tsai FJ, Hsu CM, Lin CC, Tsai CH. The cuttable C-related genotype and allele for the E-cadherin 3'-UTR Pm/l polymorphism are associated with higher susceptibility to endometriosis. Genet Mol Biol (2005) c 28:661–664.
Hsieh YY, Chang CC, Tsai FJ, Lin CC, Tsai CH. Estrogen receptor alpha dinucleotide repeat and cytochrome P450c17alpha gene polymorphisms are associated with susceptibility to endometriosis. Fertil Steril (2005) d 83:567–572.[CrossRef][Web of Science][Medline]
Hsieh YY, Chang CC, Tsai FJ, Lin CC, Tsai CH. T homozygote and allele of epidermal growth factor receptor 2073 gene polymorphism are associated with higher susceptibility to endometriosis and leiomyomas. Fertil Steril (2005) e 83:796–799.[CrossRef][Web of Science][Medline]
Hsieh YY, Chang CC, Tsai FJ, Peng CT, Yeh LS, Lin CC. Polymorphism for transforming growth factor beta 1-509 (TGF-B1-509): association with endometriosis. Biochem Genet (2005) f 43:203–210.[CrossRef][Web of Science][Medline]
Hsieh YY, Lin CS. P53 codon 11, 72, and 248 gene polymorphisms in endometriosis. Int J Biol Sci (2006) 2:188–193.[Medline]
Hsieh YY, Lee CC, Chang CC, Wang YK, Yeh LS, Lin CS. Angiotensin I-converting enzyme insertion-related genotypes and allele are associated with higher susceptibility of endometriosis and leiomyoma. Mol Reprod Dev (2007) a 74:808–814.[CrossRef][Web of Science][Medline]
Hsieh YY, Wang YK, Chang CC, Lin CS. Estrogen receptor alpha-351 XbaI*G and -397 PvuII*C-related genotypes and alleles are associated with higher susceptibilities of endometriosis and leiomyoma. Mol Hum Reprod (2007) b 13:117–122.
Huber A, Keck CC, Hefler LA, Schneeberger C, Huber JC, Bentz EK, Tempfer CB. Ten estrogen-related polymorphisms and endometriosis: a study of multiple gene-gene interactions. Obstet Gynecol (2005) 106:1025–1031.[Web of Science][Medline]
Hur SE, Lee JY, Moon HS, Chung HW. Polymorphisms of the genes encoding the GSTM1, GSTT1 and GSTP1 in Korean women: no association with endometriosis. Mol Hum Reprod (2005) 11:15–19.
Iizuka S, Kosugi Y, Isaka K, Takayama M. Could polymorphisms of N-acetyltransferase 2 (NAT2), glutathione S-transferase M1 (GSTM1), and cytochrome P450 (CYP1A1) be responsible for genetic predisposition to endometriosis among Japanese? J Tokyo Med Univ (2003) 61:59–66.
Ishii K, Takakuwa K, Mitsui T, Tanaka K. Studies on the human leukocyte antigen-DR in patients with endometriosis: genotyping of HLA-DRB1 alleles. Hum Reprod (2002) 17:560–563.
Ishii K, Takakuwa K, Kashima K, Tamura M, Tanaka K. Associations between patients with endometriosis and HLA class II; the analysis of HLA-DQB1 and HLA-DPB1 genotypes. Hum Reprod (2003) 18:985–989.
Iskhakova GMA. Polymorphism of the arylamine-N-acetyltransferase gene in endometriosis patients in the Republic of Bashkortostan. Balkan J Med Genet (2006) 9:55–60.
Ivashchenko TE, Shved NI, Kramareva NA, Ailamazian EK, Baranov VS. Analysis of the polymorphic alleles of genes encoding phase 1 and phase 2 detoxication enzymes in patients with endometriosis. Genetika (2003) 39:525–529.[Medline]
Juo SH, Wang TN, Lee JN, Wu MT, Long CY, Tsai EM. CYP17, CYP1A1 and COMT polymorphisms and the risk of adenomyosis and endometriosis in Taiwanese women. Hum Reprod (2006) 21:1498–1502.
Kado N, Kitawaki J, Obayashi H, Ishihara H, Koshiba H, Kusuki I, Tsukamoto K, Hasegawa G, Nakamura N, Yoshikawa T, et al. Association of the CYP17 gene and CYP19 gene polymorphisms with risk of endometriosis in Japanese women. Hum Reprod (2002) 17:897–902.
Kang S, Wang Y, Zhang JH, Jin X, Fang SM, Li Y. Single nucleotide polymorphism in the matrix metalloproteinases promoter is associated with susceptibility to endometriosis and adenomyosis. Zhonghua Fu Chan Ke Za Zhi (2005) 40:601–604.[Medline]
Kennedy S, Bennett S, Weeks DE. Affected sib-pair analysis in endometriosis. Hum Reprod Update (2001) 7:411–418.
Kim JG, Kim H, Ku SY, Kim SH, Choi YM, Moon SY. Association between human alpha 2-Heremans Schmidt glycoprotein (AHSG) polymorphism and endometriosis in Korean women. Fertil Steril (2004) 82:1497–1500.[CrossRef][Web of Science][Medline]
Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod (2005) a 20:2904–2908.
Kim SH, Choi YM, Jun JK, Kim SH, Kim JG, Moon SY. Estrogen receptor dinucleotide repeat polymorphism is associated with minimal or mild endometriosis. Fertil Steril (2005) b 84:774–777.[CrossRef][Web of Science][Medline]
Kim JG, Kim JY, Jee BC, Suh CS, Kim SH, Choi YM. Association between endometriosis and polymorphisms in endostatin and vascular endothelial growth factor and their serum levels in Korean women. Fertil Steril (2007) a 89:243–245.[CrossRef][Web of Science][Medline]
Kim SH, Choi YM, Lee GH, Hong MA, Lee KS, Lee BS, Kim JG, Moon SY. Association between susceptibility to advanced stage endometriosis and the genetic polymorphisms of aryl hydrocarbon receptor repressor and glutathione-S-transferase T1 genes. Hum Reprod (2007) b 22:1866–1870.
Kitawaki J, Obayashi H, Ishihara H, Koshiba H, Kusuki I, Kado N, Tsukamoto K, Hasegawa G, Nakamura N, Honjo H. Oestrogen receptor-alpha gene polymorphism is associated with endometriosis, adenomyosis and leiomyomata. Hum Reprod (2001) 16:51–55.
Kitawaki J, Obayashi H, Ohta M, Kado N, Ishihara H, Koshiba H, Kusuki I, Tsukamoto K, Hasegawa G, Nakamura N, et al. Genetic contribution of the interleukin-10 promoter polymorphism in endometriosis susceptibility. Am J Reprod Immunol (2002) 47:12–18.[Medline]
Kitawaki J, Koshiba H, Kitaoka Y, Teramoto M, Hasegawa G, Nakamura N, Yoshikawa T, Ohta M, Obayashi H, Honjo H. Interferon-gamma gene dinucleotide (CA) repeat and interleukin-4 promoter region (-590C/T) polymorphisms in Japanese patients with endometriosis. Hum Reprod (2004) 19:1765–1769.
Kitawaki J, Kiyomizu M, Obayashi H, Ohta M, Ishihara H, Hasegawa G, Nakamura N, Yoshikawa T, Honjo H. Synergistic effect of interleukin-6 promoter (IL6 -634C/G) and intercellular adhesion molecule-1 (ICAM-1 469K/E) gene polymorphisms on the risk of endometriosis in Japanese women. Am J Reprod Immunol (2006) 56:267–274.[Medline]
Kiyomizu M, Kitawaki J, Obayashi H, Ohta M, Koshiba H, Ishihara H, Honjo H. Association of two polymorphisms in the peroxisome proliferator-activated receptor-gamma gene with adenomyosis, endometriosis, and leiomyomata in Japanese women. J Soc Gynecol Investig (2006) 13:372–377.[CrossRef][Web of Science][Medline]
Lattuada D, Somigliana E, Vigano P, Candiani M, Pardi G, Di Blasio AM. Genetics of endometriosis: a role for the progesterone receptor gene polymorphism PROGINS? Clin Endocrinol (Oxf) (2004) a 61:190–194.[CrossRef][Medline]
Lattuada D, Vigano P, Somigliana E, Abbiati A, Candiani M, Di Blasio AM. Analysis of the codon 72 polymorphism of the TP53 gene in patients with endometriosis. Mol Hum Reprod (2004) b 10:651–654.
Lattuada D, Vigano P, Somigliana E, Odorizzi MP, Vignali M, Di Blasio AM. Androgen receptor gene cytosine, adenine, and guanine trinucleotide repeats in patients with endometriosis. J Soc Gynecol Investig (2004) c 11:237–240.[CrossRef][Web of Science][Medline]
Layman LC. Editorial: BMP15—the first true ovarian determinant gene on the X-chromosome? J Clin Endocrinol Metab (2006) 91:1673–1676.
Lee MK, Park AJ, Kim DH. Tumor necrosis factor-alpha and interleukin-6 promoter gene polymorphisms are not associated with an increased risk of endometriosis. Fertil Steril (2002) 77:1304–1305.[CrossRef][Web of Science][Medline]
Lee GH, Kim SH, Choi YM, Suh CS, Kim JG, Moon SY. Estrogen receptor beta gene +1730 G/A polymorphism in women with endometriosis. Fertil Steril (2007) 88:785–788.[CrossRef][Web of Science][Medline]
Levanat S, Musani V, Komar A, Oreskovic S. Role of the hedgehog/patched signaling pathway in oncogenesis: a new polymorphism in the PTCH gene in ovarian fibroma. Ann N Y Acad Sci (2004) 1030:134–143.[CrossRef][Web of Science][Medline]
Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet (2003) 33:177–182.[CrossRef][Web of Science][Medline]
Luisi S, Galleri L, Marini F, Ambrosini G, Brandi ML, Petraglia F. Estrogen receptor gene polymorphisms are associated with recurrence of endometriosis. Fertil Steril (2006) 85:764–766.[CrossRef][Web of Science][Medline]
Luo M, He YL, Zhang HB, Shen DX, Zong LL, Guan T. Association of tumor necrosis factors-beta gene polymorphism with endometriosis in women in Guangdong Province. Nan Fang Yi Ke Da Xue Xue Bao (2006) 26:1163–1165.[Medline]
Modugno F. Ovarian cancer and polymorphisms in the androgen and progesterone receptor genes: a HuGE review. Am J Epidemiol (2004) 159:319–335.
Morizane M, Yoshida S, Nakago S, Hamana S, Maruo T, Kennedy S. No association of endometriosis with glutathione S-transferase M1 and T1 null mutations in a Japanese population. J Soc Gynecol Investig (2004) 11:118–121.[CrossRef][Web of Science][Medline]
Morland SJ, Jiang X, Hitchcock A, Thomas EJ, Campbell IG. Mutation of galactose-1-phosphate uridyl transferase and its association with ovarian cancer and endometriosis. Int J Cancer (1998) 77:825–827.[CrossRef][Web of Science][Medline]
Nakago S, Hadfield RM, Zondervan KT, Mardon H, Manek S, Weeks DE, Barlow D, Kennedy S. Association between endometriosis and N-acetyl transferase 2 polymorphisms in a UK population. Mol Hum Reprod (2001) 7:1079–1083.
Omori S, Yoshida S, Kennedy SH, Negoro K, Hamana S, Barlow DH, Maruo T. Polymorphism at codon 72 of the p53 gene is not associated with endometriosis in a Japanese population. J Soc Gynecol Investig (2004) 11:232–236.[CrossRef][Web of Science][Medline]
Peng DX, He YL, Qiu LW, Yang F, Lin JM. Susceptibility to endometriosis in women of Han Nationality in Guangdong Province associated with Msp I polymorphisms of cytochrome P450 1A1 gene. Di Yi Jun Yi Da Xue Xue Bao (2002) 22:814–816.[Medline]
Peng DX, He YL, Qiu LW, Yang F, Lin JM. Association between gene mutation of cytochrome P450 1A1 in exon 7 A4889G locus and susceptibility to endometriosis. Chin J Med Genet (2003) a 20:284–286.
Peng DX, He YL, Qiu LW, Yang F, Lin JM. Association between glutathione S-transferase M1 gene deletion and genetic susceptibility to endometriosis. Di Yi Jun Yi Da Xue Xue Bao (2003) b 23:458–459. 462.[Medline]
Pritts EA, Zhao D, Ricke E, Waite L, Taylor RN. PPAR-gamma decreases endometrial stromal cell transcription and translation of RANTES in vitro. J Clin Endocrinol Metab (2002) 87:1841–1844.
Renner SP, Strick R, Oppelt P, Fasching PA, Engel S, Baumann R, Beckmann MW, Strissel PL. Evaluation of clinical parameters and estrogen receptor alpha gene polymorphisms for patients with endometriosis. Reproduction (2006) 131:153–161.
Shan K, Ying W, Jian-Hui Z, Wei G, Na W, Yan L. The function of the SNP in the MMP1 and MMP3 promoter in susceptibility to endometriosis in China. Mol Hum Reprod (2005) 11:423–427.
Shan K, Lian-Fu Z, Hui D, Wei G, Na W, Xia J, Yan L. Polymorphisms in the promoter regions of the matrix metalloproteinases-7, -9 and the risk of endometriosis and adenomyosis in China. Mol Hum Reprod (2006) 12:35–39.
Shan K, Xiao-Wei M, Na W, Xiu-Feng Z, ng-Gui W, Wei G, Zheng-Mao Z, Yan L. Association of three single nucleotide polymorphisms of the E-cadherin gene with endometriosis in a Chinese population. Reproduction (2007) 134:373–378.
Stefansson H, Geirsson RT, Guanason GA. A genome-wide search for endometriosis in Icelandic patients. Am J Hum Genet (1998) 63:A310.
Stefansson H, Einarsdottir A, Geirsson RT, Jonsdottir K, Sverrisdottir G, Gudnadottir VG, Gunnarsdottir S, Manolescu A, Gulcher J, Stefansson K. Endometriosis is not associated with or linked to the GALT gene. Fertil Steril (2001) 76:1019–1022.[CrossRef][Web of Science][Medline]
Tempfer CB, Schneeberger C, Huber JC. Applications of polymorphisms and pharmacogenomics in obstetrics and gynecology. Pharmacogenomics (2004) 5:57–65.[CrossRef][Web of Science][Medline]
Tempfer CB, Riener EK, Keck C, Grimm C, Heinze G, Huber JC, Gitsch G, Hefler LA. Polymorphisms associated with thrombophilia and vascular homeostasis and the timing of menarche and menopause in 728 white women. Menopause (2005) 12:325–330.[CrossRef][Web of Science][Medline]
Teramoto M, Kitawaki J, Koshiba H, Kitaoka Y, Obayashi H, Hasegawa G, Nakamura N, Yoshikawa T, Matsushita M, Maruya E, et al. Genetic contribution of tumor necrosis factor (TNF)-alpha gene promoter (-1031, -863 and -857) and TNF receptor 2 gene polymorphisms in endometriosis susceptibility. Am J Reprod Immunol (2004) 51:352–357.[Medline]
Treloar SA, O’Connor DT, O’Connor VM, Martin NG. Genetic influences on endometriosis in an Australian twin sample. Fertil Steril (1999) 71:701–710.[CrossRef][Web of Science][Medline]
Treloar SA, Bahlo M, Ewen K. Suggestive linkage for endometriosis found in genome-wide scan. Am J Hum Genet (2000) 67:727–736.[CrossRef][Web of Science][Medline]
Treloar SA, Zhao ZZ, Armitage T, Duffy DL, Wicks J, O’Connor DT, Martin NG, Montgomery GW. Association between polymorphisms in the progesterone receptor gene and endometriosis. Mol Hum Reprod (2005) a 11:641–647.
Treloar SA, Wicks J, Nyholt DR, Montgomery GW, Bahlo M, Smith V, et al. Genomwide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26. Am J Hum Genet (2005) b 77:365–376.[CrossRef][Web of Science][Medline]
Treloar SA, Zhao ZZ, Le L, Zondervan KT, Martin NG, Kennedy S, Nyholt DR, Montgomery GW. Variants in EMX2 and PTEN do not contribute to risk of endometriosis. Mol Hum Reprod (2007) 13:587–594.
Tsuchiya M, Katoh T, Motoyama H, Sasaki H, Tsugane S, Ikenoue T. Analysis of the AhR, ARNT, and AhRR gene polymorphisms: genetic contribution to endometriosis susceptibility and severity. Fertil Steril (2005) a 84:454–458.[CrossRef][Web of Science][Medline]
Tsuchiya M, Nakao H, Katoh T, Sasaki H, Hiroshima M, Tanaka T, Matsunaga T, Hanaoka T, Tsugane S, Ikenoue T. Association between endometriosis and genetic polymorphisms of the estradiol-synthesizing enzyme genes HSD17B1 and CYP19. Hum Reprod (2005) b 20:974–978.
van Kaam KJ, Romano A, Dunselman GA, Groothuis PG. Transforming growth factor beta1 gene polymorphism 509C/T in deep infiltrating endometriosis. Reprod Sci (2007) a 14:367–373.
van Kaam KJ, Romano A, Schouten JP, Dunselman GA, Groothuis PG. Progesterone receptor polymorphism +331G/A is associated with a decreased risk of deep infiltrating endometriosis. Hum Reprod (2007) b 22:129–135.
Vietri MT, Molinari AM, Iannella I, Cioffi M, Bontempo P, Ardovino M, Scaffa C, Colacurci N, Cobellis L. Arg72Pro p53 polymorphism in Italian women: no association with endometriosis. Fertil Steril (2007) 88:1468–1469.[CrossRef][Web of Science][Medline]
Vigano P, Infantino M, Lattuada D, Lauletta R, Ponti E, Somigliana E, Vignali M, DiBlasio AM. Intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms in endometriosis. Mol Hum Reprod (2003) 9:47–52.
Vigano P, Lattuada D, Somigliana E, Abbiati A, Candiani M, Di Blasio AM. Variants of the CTLA4 gene that segregate with autoimmune diseases are not associated with endometriosis. Mol Hum Reprod (2005) 11:745–749.
Vigano P, Somigliana E, Vignali M, Busacca M, Blasio AM. Genetics of endometriosis: current status and prospects. Front Biosci (2007) 12:3247–3255.[CrossRef][Web of Science][Medline]
Wang X, Lin Q, Guo S. Study on polymorphism of human leukocyte antigen I in patients with endometriosis. Zhonghua Fu Chan Ke Za Zhi (2001) 36:150–152.[Medline]
Wang X, Liu C, Lin Q, Fang X, Lin L, Mei Q. Study on polymorphism of human leukocyte antigen-DRB1 allele in patients with endometriosis. Zhonghua Fu Chan Ke Za Zhi (2002) 37:346–348.[Medline]
Wang Z, Yoshida S, Negoro K, Kennedy S, Barlow D, Maruo T. Polymorphisms in the estrogen receptor beta gene but not estrogen receptor alpha gene affect the risk of developing endometriosis in a Japanese population. Fertil Steril (2004) 81:1650–1656.[CrossRef][Web of Science][Medline]
Watanabe T, Imoto I, Kosugi Y, Fukuda Y, Mimura J, Fujii Y, Isaka K, Takayama M, Sato A, Inazawa J. Human arylhydrocarbon receptor repressor (AHRR) gene: genomic structure and analysis of polymorphism in endometriosis. J Hum Genet (2001) 46:342–346.[CrossRef][Web of Science][Medline]
Wen J, Deng L, Zhang XM. Research on relationship between gene polymorphisms of interleukin-1 family and endometriosis. Zhejiang Da Xue Xue Bao Yi Xue Ban (2006) 35:653–657.[Medline]
Wenzl R, Kiesel L, Huber JC, Wieser F. Endometriosis: a genetic disease. Drugs Today (Barc) (2003) 39:961–972.[CrossRef][Medline]
Whang DH, Kim SH, Choi YM, Park MH, Noh JH, Kim YB. No association between HLA-DRB1 alleles and susceptibility to advanced stage endometriosis in a Korean population. Hum Reprod (2006) 21:129–133.
Wieser F, Fabjani G, Tempfer C, Schneeberger C, Zeillinger R, Huber JC, Wenzl R. Tumor necrosis factor-alpha promotor polymorphisms and endometriosis. J Soc Gynecol Investig (2002) a 9:313–318.[Web of Science][Medline]
Wieser F, Schneeberger C, Tong D, Tempfer C, Huber JC, Wenzl R. PROGINS receptor gene polymorphism is associated with endometriosis. Fertil Steril (2002) b 77:309–312.[CrossRef][Web of Science][Medline]
Wieser F, Wenzl R, Tempfer C, Worda C, Huber J, Schneeberger C. Catechol-O-methyltransferase polymorphism and endometriosis. J Assist Reprod Genet (2002) c 19:343–348.[CrossRef][Web of Science][Medline]
Wieser F, Fabjani G, Tempfer C, Schneeberger C, Sator M, Huber J, Wenzl R. Analysis of an interleukin-6 gene promoter polymorphism in women with endometriosis by pyrosequencing. J Soc Gynecol Investig (2003) a 10:32–36.[CrossRef][Web of Science][Medline]
Wieser F, Hefler L, Tempfer C, Vlach U, Schneeberger C, Huber J, Wenzl R. Polymorphism of the interleukin-1beta gene and endometriosis. J Soc Gynecol Investig (2003) b 10:172–175.[Web of Science][Medline]
Wu MY, Chao KH, Yang JH, Lee TH, Yang YS, Ho HN. Nitric oxide synthesis is increased in the endometrial tissue of women with endometriosis. Hum Reprod (2003) 18:2668–2671.
Yamashita M, Yoshida S, Kennedy S, Ohara N, Motoyama S, Maruo T. Association study of endometriosis and intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms in a Japanese population. J Soc Gynecol Investig (2005) 12:267–271.[CrossRef][Web of Science][Medline]
Zervou S, Karteris E, Goumenou AG, Vatish M, Koumantakis EE, Hillhouse EW. The Glu298–>Asp polymorphism of the endothelial nitric oxide synthase gene is associated with endometriosis. Fertil Steril (2003) 80:1524–1525.[CrossRef][Web of Science][Medline]
Zhao ZZ, Nyholt DR, Le L, Martin NG, James MR, Treloar SA, Montgomery GW. KRAS variation and risk of endometriosis. Mol Hum Reprod (2006) 12:671–676.
Zhao ZZ, Nyholt DR, Le L, Thomas S, Engwerda C, Randall L, Treloar SA, Montgomery GW. Genetic variation in tumour necrosis factor and lymphotoxin is not associated with endometriosis in an Australian sample. Hum Reprod (2007) 22:2389–2397.
Zondervan KT, Cardon LR, Kennedy SH. What makes a good case-control study? Design issues for complex traits such as endometriosis. Hum Reprod (2002) 17:1415–1423.
Zondervan KT, Treloar SA, Lin J, Weeks DE, Nyholt DR, Mangion J, et al. Significant evidence of one or more susceptibility loci for endometriosis with near-Mendelian inheritance on chromosome 7p13-15. Hum Reprod (2007) 22:717–728.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. O.A. Omwandho, L. Konrad, G. Halis, F. Oehmke, and H.-R. Tinneberg Role of TGF-{beta}s in normal human endometrium and endometriosis Hum. Reprod., November 5, 2009; (2009) dep382v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. D'Amora, T. T. Maciel, R. Tambellini, M. A. Mori, J. B. Pesquero, H. Sato, M. J. B. C. Girao, I. D. C. Guerreiro da Silva, and E. Schor Disrupted Cell Cycle Control in Cultured Endometrial Cells from Patients with Endometriosis Harboring the Progesterone Receptor Polymorphism PROGINS Am. J. Pathol., July 1, 2009; 175(1): 215 - 224. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||