GSTT1 Null Mutations Research Articles

Susceptibility of Glutathione-S-Transferase Polymorphism to CVD Develo- pment in Type 2 Diabetes Mellitus - A Review.

Metabolic disorder affects normal homeostasis and can lead to the development of diseases. Diabetes mellitus is the most common metabolic disorder, and a cluster of metabolic conditions can lead to cardiovascular disease (CVD) development. Diabetes mellitus and CVD are closely related, with oxidative stress, playing a major role in the pathophysiology. Glutathione-S-Transferases (GST) potentially play an important role by reducing oxidative stress and is found to be the underlying pathophysiology in the development of diabetes, cardiovascular diseases (CVD), etc Background: In this review, the role of GST genetic variant in the development of diabetes mellitus, CVD and diabetic vascular complications has been focused. Objectives: Based on the literature, it is evident that the GST can act as an important biochemical tool providing significant evidence regarding oxidative stress predominant in the development of diseases. Analysis of GST gene status, particularly detection of GSTM1 and GSTT1 null mutations and GSTP1 polymorphism, have clinical importance. Results: The analysis of GST polymorphism may help identify the people at risk and provide proper medical management. Genotyping of GST gene would be a helpful biomarker for early diagnosis of CVD development in DM and also in CVD cases. More studies focusing on the association of GST polymorphism with CVD development in diabetic patients will help us determine the pathophysiology better.

Association Between Polycystic Ovary Syndrome and the Polymorphisms of Aryl Hydrocarbon Receptor Repressor, Glutathione-S-transferase T1, and Glutathione-S-transferase M1 Genes

Objective To investigate the association between the aryl hydrocarbon receptor repressor (AhRR) C/G polymorphisms and glutathione-S-transferase M1 (GSTM1) and GSTT1 null mutation and the risk of polycystic ovary syndrome (PCOS) in Korean women. Methods This was a case–control study of 478 women with PCOS and 376 aged-matched healthy controls. Genotyping of the AhRR C/G polymorphism and GSTM1 and GSTT1 were performed using real-time PCR analysis and multiplex PCR, respectively. Results The genotype distribution of the AhRR C/G polymorphisms and GSTM1/GSTT1 null mutations did not differ between women with PCOS and controls. Using the wild-type combined AhRR CC and GSTT1 present genotype as a reference, the odds that a woman had PCOS were 1.54 (95% CIs 1.04–2.29) times higher if she had a combined AhRR CG or GG and GSTT1 null genotype. The odds that a woman had PCOS was 1.48 (95% CIs 1.08–2.04) times higher if she had a combined GSTM1/GSTT1 null genotype compared with the wild-type combined GSTM1/GSTT1 present genotype. However, there were no significant associations between the risk of PCOS and any combined AhRR and GSTM1. Conclusions Our data suggest that a combined AhRR CG or GG and GSTT1 null genotype or a combined GSTT1/GSTM1 null genotype might be associated with an increased risk of PCOS.

Clinical and Molecular Risk Factors of Anti-tubercular Therapy Induced Hepatitis

This is a case-control study aimed at evaluating clinical as well as molecular risk factors for occurrence of ATT induced hepatitis in Northern Indian population. 100 patients of tuberculosis were recruited from both Outdoor patient department and wards of Lok Nayak Hospital, New Delhi. 40 out of 100 patients who developed ATT induced hepatitis were taken as test group and 60 out of 100 patients who didn't develop liver dysfunction on ATT were taken as controls and studied and compared for clinical factors such as age, gender, nutritional status, HBsAg carrier, chronic hepatitis C and HIV infection. Molecular factors i.e. NAT2 acetylator status, GSTT1 and M1 null mutations were also determined in all of the patients in each group and compared. Mean body weight and serum albumin were significantly lower in the ATT induced hepatitis patients as compared to the control group. No preferential association was observed between age and gender with ATT induced hepatitis. HBsAg carrier (OR-6.5; P=0.03), HIV infection (OR-5.1; P=0.01), slow acetylator phenotype (OR-3.85; P=0.02), GSTM1 null mutation (OR-2.72; P=0.02) and GSTT1 null mutation (OR-3.12; P=0.02) were found to be positively co-related to ATT induced hepatitis according to the univariate analysis. HBsAg carrier (OR-23.18; P=0.01), HIV infection (OR-16.92; P=0.02), Slow acetylator phenotype (OR-70.90; P=0.001), GSTM1 null mutation (OR-37.03; P=0.002) and GSTT1 null mutation (OR-8.19; P=0.014) were also found to be independently increasing the risk of ATT induced hepatitis using multivariate analysis. The present study established a positive co-relation between malnutrition, HBsAg carrier, HIV infection, NAT2 slow acetylators, GSTM1 null mutation, GSTT1 null mutation and ATT induced hepatitis.

Molecular Approach for Assessing the Risk Factors for Anti-tubercular Therapy-Induced Hepatotoxicity

Introduction: The present study was designed to study the role of genetic risk factors like N-acetyl transferase2 (NAT2) polymorphism and glutathione S-transferase (GST T1 and M1) mutations for increasing the susceptibility of anti tubercular therapy (ATT)-induced hepatotoxicity. Methods: Forty pulmonary tuberculosis patients who developed hepatotoxicity while on treatment with antituberculosis drug (ATD) were included. Sixty pulmonary tuberculosis patients without clinical symptoms and biochemical evidence of liver dysfunction, who were on antitubercular treatment, were included as controls. NAT2 genotyping was performed by generation of 895 bp intronless NAT2 PCR fragment. NAT2 genotyping was carried out by PCR-RFLP at 3 major polymorphic sites of gene coding for T481C (rs1799929, NAT2*5), G509A (rs1799930, NAT2*6), and G587A (rs1799931, NAT2*7). Genotyping of GST M1 and GST T1 genes was carried out by multiplex polymerase chain reaction protocol. Results: Out of the 40 patients of ATT-induced hepatitis, 67.50% were slow acetylators as compared to 35% in the control group. The risk of anti-TB DIH occurrence was significantly higher in slow acetylators than in rapid/intermediate acetylator (56.25% vs. 25%, p value 0.05). Slow acetylator phenotype was found to be a risk factor for anti-TB drug-induced hepatitis having an odds ratio of 3.85 (95% confidence interval [CI] 1.68-8.84; p value 0.02). The GSTM1 null mutation was found in 19 out of 40 cases (47.5%) compared to 15 out of 60 controls (25.0%). Subjects with GSTM1 null genotype were found to be at a 2.72 times risk of developing ATT induced hepatitis than those who had GSTM1 gene (p value 0.02). Similarly, the frequency of GSTT1 null mutation was found to be 32.50% in the ATT-induced hepatitis group as compared to 13.33% in the control group and GSTT1 null genotype, was also found to be an independent risk factor with an odds ratio of 3.12 (95% CI 1.18-8.22; p value- 0.02). It was also observed that presence of GSTM1 and GSTT1 null genotype together increased the likelihood of developing ATT induced hepatitis to up to 17 times (p value 0.002). Conclusion: This study could establish a positive co-relation between NAT2 slow acetylators, GSTM1 null mutation, GSTT1 null mutation, and ATT induced hepatitis. Thus, it will be prudent on the part of the clinicians to look for the above risk factors while treating Koch’s patients with anti-tubercular therapy.

Glutathione-S-transferase polymorphism and acute lymphoblastic leukemia (ALL) in north Indian children: a case-control study and meta-analysis.

Various studies on association of glutathione S-transferase (GST) polymorphisms and childhood acute lymphoblastic leukemia (ALL) have yielded conflicting results. We examined this association among north Indian children and conducted an updated meta-analysis to overcome sample size-related limitations. GSTM1, GSTP1 and GSTT1 genotypes in 100 children with ALL and 300 healthy controls were compared. GSTT1 null mutation (odds ratio (OR) 2.54, 95% confidence interval (CI) 1.50-4.32) and GSTP1 homozygous mutation (OR 3.13, 95%CI 1.48-6.59) were found to increase the risk of childhood ALL, while GSTM1 did not alter the risk. Meta-analysis included 22, 10 and 20 studies examining the association of childhood ALL with GSTM1, GSTP1 and GSTT1 genotypes, respectively. Only GSTM1 genotype (OR 1.29, 95%CI 1.10-1.62) was associated with increased risk in the overall analysis. However, both GSTM1 (OR 1.54, 95%CI 1.12-2.10) and GSTT1 (OR 1.63, 95%CI 1.32-1.99) null genotypes were associated with increased risk in Asian subjects. The risk of developing childhood ALL was not associated with GSTP1 genotype.

Association between susceptibility to advanced pelvic organ prolapse and glutathione S-transferase P1 Ile105Val polymorphism

ObjectiveOxidative stress is associated with the pathogenesis of pelvic organ prolapse (POP). Because glutathione S-transferases (GSTs) are the major detoxification enzymes which protect cells against oxidative stress, genetic variations in the GST gene may modulate the risk of POP. This study aimed to determine the association between advanced POP and the polymorphisms of GSTM1, GSTT1 and GSTP1 (rs1695). Study designThis is a hospital-based case-control study. The POP group consisted of 189 women diagnosed with POP stage III or IV, and the control group consisted of 156 postmenopausal women with POP stage 0 or I. The GSTM1 and GSTT1 null mutations were detected by multiplex PCR, and the GSTP1 Ile105Val polymorphism was genotyped by real-time PCR analysis using a TaqMan assay. ResultsThere was no significant association between the GSTM1 and GSTT1 null mutations and advanced POP (p>0.05). The distribution of the GSTP1 Ile105Val genotypes, however, was significantly different between the POP and control groups (AA/AG/GG rates=74.1%/25.9%/0% vs. 64.1%/32.1%/3.8%, p=0.008), and the G allele frequency was significantly lower in the POP group than in the control group (13.0% vs. 19.9%, p=0.014). Women with the non-AA genotype had a 0.63-fold lower risk of developing advanced POP than women with the AA genotype (95% CI, 0.39–0.99), and women with the G allele had a 0.60-fold lower risk of advanced POP than women with the A allele (95% CI, 0.40–0.90). ConclusionsThe GSTP1 Ile105Val polymorphism is a protective factor against advanced POP.

Associations between null mutations in GSTT1 and GSTM1, the GSTP1 Ile105Val polymorphism, and mortality in breast cancer survivors

PurposeHere we assessed associations between null mutations in glutathione-S-transferase (GST)T1 and GSTM1 genes, and the rs1695 polymorphism in GSTP1 (Ile105Val), and risk of breast cancer-specific (n=45) and all-cause (n=99) mortality in a multiethnic, prospective cohort of 533 women diagnosed with stage I-IIIA breast cancer in 1995–1999, enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study.MethodsWe measured the presence of the null mutation in GSTT1 and GSTM1, and the rs1695 polymorphism in GSTP1 by polymerase chain reaction. We assessed associations between breast-cancer specific and all-cause mortality using Cox proportional hazards models.ResultsParticipants with ER-negative tumors were more likely to be GSTT1 null (χ2=4.52; P=0.03), and African American women were more likely to be GSTM1 null (χ2=34.36; P<0.0001). Neither GSTM1 nor GSTT1 null mutations were associated with breast cancer-specific or all-cause mortality. In a model adjusted for body mass index, race/ethnicity, tumor stage and treatment received at diagnosis, the variant Val allele of rs1695 was associated with increased risk of all-cause (HR=1.81, 95% CI 1.16-2.82, P=0.008), but not breast cancer-specific mortality. The GSTT1 null mutation was associated with significantly higher levels of C-reactive protein.ConclusionsGSTM1 and GSTT1 null genotypes had no effect on outcome; however the variant allele of rs1695 appears to confer increased risk for all-cause mortality in breast-cancer survivors.Given the limited sample size of most studies examining associations between GST polymorphisms with breast cancer survival, and the lack of women undergoing more contemporary treatment protocols (treated prior to 1999), it may be helpful to re-examine this issue among larger samples of women diagnosed after the late 1990s, who all received some form of chemotherapy or radiotherapy.

In Vitro Investigation of the Glutathione Transferase M1 and T1 Null Genotypes as Risk Factors for Troglitazone-Induced Liver Injury

The double null mutation of glutathione transferase, GSTM1 and GSTT1, is reported to influence troglitazone-associated abnormal increases of alanine aminotransferase and aspartate aminotransferase. However, no nonclinical data with a bearing on the clinical outcomes and underlying mechanisms have hitherto been reported. To investigate whether deficiency in GSTM1 and/or GSTT1 is related to troglitazone hepatotoxicity in vitro, the covalent binding level (CBL) (an index of reactive metabolite formation) and cytotoxicity of troglitazone and rosiglitazone, another thiazolidinedione but with low hepatotoxicity, were examined using human liver samples phenotyped for cytochrome P450s and genotyped for GSTM1 and GSTT1. Despite addition of GSH, CBLs of troglitazone and rosiglitazone in human liver microsomes were correlated with CYP3A (or CYP2C8) and CYP2C8 activities, respectively. With addition of recombinant GSTM1, the microsomal CBLs of troglitazone and rosiglitazone decreased. However, the CBLs of troglitazone in GSTM1/GSTT1 wild-type hepatocytes were unexpectedly higher than those in null hepatocytes. Although this discrepancy has not been fully explained, the GSTM1 and GSTT1 null mutations increased the cytotoxicity of troglitazone, independent of CYP3A or CYP2C8 activities. Furthermore, a GSH adduct of troglitazone, M2, limited to GSTM1 wild-type hepatocytes was detected. Of clear interest, GSTM1 and/or GSTT1 null mutation-dependent cytotoxicity and higher exposure to the reactive metabolite trapped as M2 as for troglitazone were not observed for rosiglitazone. This result might at least partly explain the findings related to clinical hepatotoxicity, suggesting that measurement of GSH adducts or cytotoxicity using GSTM1- and GSTT1-genotyped hepatocytes might offer an important in vitro system to assist in better prediction of idiosyncratic hepatotoxicity.

GSTT1 and GSTM1 null mutations and adverse reactions induced by antituberculosis drugs in Koreans

Adverse reactions induced by antituberculosis drugs (ATD) often result in serious morbidities, impeding scheduled treatment and cure. In the development of ATD-induced adverse reactions, glutathione S-transferase has been suggested to play a protective role as an intracellular scavenger by conjugating toxic reactive metabolites of ATD. This study examined the association of null mutations in GST enzyme genes (GSTT1 and GSTM1) with the development of ATD-induced hepatitis and cutaneous reactions. We compared the frequencies of GSTT1 and GSTM1 null mutations in 57 patients with hepatitis, 94 patients with cutaneous adverse reactions, and 190 ATD-tolerant controls. The frequency of null mutations in GSTT1 and GSTM1 in patients with ATD-induced hepatitis was not significantly different from that of controls (59.6% vs. 54.2% and 45.6% vs. 54.7%, respectively). Additionally, no significant difference was observed in the frequency of either null mutation in patients with ATD-induced cutaneous reactions, including maculopapular eruption, compared with controls (58.5% vs. 54.1% for GSTT1 and 59.6% vs. 54.6% for GSTM1). These findings indicate that GSTT1 and GSTM1 null mutations are not associated with the development of ATD-induced hepatitis or cutaneous reactions in this Korean population, and suggest that glutathione S-transferase enzymes do not play important roles in the pathogenesis of these conditions.

Lung cancer in never smokers in Florida: 1981-2003

Oxidative stress is associated with the pathogenesis of pelvic organ prolapse (POP). Because glutathione S-transferases (GSTs) are the major detoxification enzymes which protect cells against oxidative stress, genetic variations in the GST gene may modulate the risk of POP. This study aimed to determine the association between advanced POP and the polymorphisms of GSTM1, GSTT1 and GSTP1 (rs1695).This is a hospital-based case-control study. The POP group consisted of 189 women diagnosed with POP stage III or IV, and the control group consisted of 156 postmenopausal women with POP stage 0 or I. The GSTM1 and GSTT1 null mutations were detected by multiplex PCR, and the GSTP1 Ile105Val polymorphism was genotyped by real-time PCR analysis using a TaqMan assay.There was no significant association between the GSTM1 and GSTT1 null mutations and advanced POP (p > 0.05). The distribution of the GSTP1 Ile105Val genotypes, however, was significantly different between the POP and control groups (AA/AG/GG rates = 74.1%/25.9%/0% vs. 64.1%/32.1%/3.8%, p = 0.008), and the G allele frequency was significantly lower in the POP group than in the control group (13.0% vs. 19.9%, p = 0.014). Women with the non-AA genotype had a 0.63-fold lower risk of developing advanced POP than women with the AA genotype (95% CI, 0.39–0.99), and women with the G allele had a 0.60-fold lower risk of advanced POP than women with the A allele (95% CI, 0.40–0.90).The GSTP1 Ile105Val polymorphism is a protective factor against advanced POP.

Preliminary analysis of polybrominated diphenyl ether exposure, semen quality and genetic polymorphisms

Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental contaminants and are increasing exponentially in human serum samples. Since they share certain properties with polychlorinated biphenyls, including adversely affecting neurodevelopment and thyroid function, we wished to determine their effects on human sperm parameters and to evaluate potential modifying effects of polymorphisms in genes involved in contaminant and sex steroid metabolism. Participants were recruited as part of a couple presenting for fertility work-up at two infertility clinics in Michigan participating in a cross-sectional study on environmental contaminants and male infertility. Participants provided questionnaire data, semen and blood samples. Semen was analyzed according to World Health Organization criteria. Polymorphisms were identified in GSTP1, GSTM1, GSTT1 and CYP1A1 genes from leucocyte DNA samples using polymerase chain reaction amplification. Serum PBDE concentrations were determined by GC-CG. All protocols were approved by the Internal Review Boards of each institution. Of the 198 men tested, 61 had detectable levels of PBDEs, with congeners #47, 153, 99 and 100 being most frequently detected. Mean lipid-adjusted concentration of PBDE 153 was significantly higher in men with the GSTT1 null mutation (P=0.002), and the sum of lipid-adjusted PBDEs was also higher (P=0.069). Heterozygotes for GSTP1 (Ile/Val) had the highest levels of all PBDE congeners, and the sum of PBDEs was also significantly higher in these individualsl (P=0.045). Levels of total lipid-adjusted PBDEs were lower in men with low sperm concentration (<20 million/mil) (P=0.048). When tested for association with low sperm concentration in a logistic regression model, men with detectable PBDEs had significantly lower odds of low concentration (odds ratio (OR)) = 0.34; 95% confidence interval = 0.14, 0.82). Neither GSTT1 nor GSTP1 were significant in the model and did not affect the OR for detectable PBDEs. No other variables (BMI, race, smoking status) were significant. Our results suggest that levels of PBDEs may be modified by certain genetic polymorphisms and that PBDEs may have a protective effect on semen quality.

Relationship of glutathione S‐transferase genotypes with side‐effects of pulsed cyclophosphamide therapy in patients with systemic lupus erythematosus

Cyclophosphamide (CTX) is an established treatment of severe systemic lupus erythematosus (SLE). Cytotoxic CTX metabolites are mainly detoxified by multiple glutathione S-transferases (GSTs). However, data are lacking on the relationship between the short-term side-effects of CTX therapy and GST genotypes. In the present study, the effects of common GSTM1, GSTT1, and GSTP1 genetic mutations on the severity of myelosuppression, gastrointestinal (GI) toxicity, and infection incidences induced by pulsed CTX therapy were evaluated in patients SLE. DNA was extracted from peripheral leucocytes in patients with confirmed SLE diagnosis (n = 102). GSTM1 and GSTT1 null mutations were analyzed by a polymerase chain reaction (PCR)-multiplex procedure, whereas the GSTP1 codon 105 polymorphism (Ile-->Val) was analyzed by a PCR-restriction fragment length polymorphism (RFLP) assay. Our study demonstrated that SLE patients carrying the genotypes with GSTP1 codon 105 mutation [GSTP1*-105I/V (heterozygote) and GSTP1*-105 V/V (homozygote)] had an increased risk of myelotoxicity when treated with pulsed high-dose CTX therapy (Odds ratio (OR) 5.00, 95% confidence interval (CI) 1.96, 12.76); especially in patients younger than 30 years (OR 7.50, 95% CI 2.14, 26.24), or in patients treated with a total CTX dose greater than 1.0 g (OR 12.88, 95% CI 3.16, 52.57). Similarly, patients with these genotypes (GSTP1*I/V and GSTP1*V/V) also had an increased risk of GI toxicity when treated with an initial pulsed high-dose CTX regimen (OR 3.33, 95% CI 1.03, 10.79). However, GSTM1 and GSTT1 null mutations did not significantly alter the risks of these short-term side-effects of pulsed high-dose CTX therapy in SLE patients. The GSTP1 codon 105 polymorphism, but not GSTM1 or GSTT1 null mutations, significantly increased the risks of short-term side-effects of pulsed high-dose CTX therapy in SLE patients. Because of the lack of selective substrates for a GST enzyme phenotyping study, timely detection of this mutation on codon 105 may assist in optimizing pulsed high-dose CTX therapy in SLE patients.

GSTM1, GSTT1 and CYP1A1 detoxification gene polymorphisms and their relationship with advanced stages of endometriosis in South Indian women

Studies on association between endometriosis and various phase I and phase II detoxification genes such as glutathione S-transferase M1 and theta 1 (GSTM1 and GSTT1) and cytochrome P450 (CYP1A1) have produced inconsistent results possibly because of ethnic differences. The present study was undertaken to investigate the frequency of the CYP1A1 (6235T>C) polymorphism and GSTM1, GSTT1 null mutations in a South Indian women's population with and without endometriosis. The frequencies of variants were studied in 310 women with laparoscopically proven endometriosis (rAFS III=101; IV=209) and 215 women without endometriosis using the polymerase chain reaction-restriction fragment length polymorphism method. The GSTM1 null deletion showed significant association (P=0.028) with endometriosis. No significant difference was found in the frequencies of the GSTT1 null deletion in cases and controls. The frequencies of the variant CYP1A1 homozygous and heterozygous alleles in the cases were 9% and 44.2% against 14.4% and 42.3% in the controls. Further, we observed a considerable difference in the GSTM1 null deletion frequency in this population when compared with other populations of the world. We observed an association between endometriosis and the GSTM1 null deletion, but not with GSTT1 null deletions or the CYP1A1 MspI polymorphism in South Indian women.

Polymorphisms of the genes encoding the GSTM1, GSTT1 and GSTP1 in Korean women: no association with endometriosis

Endometriosis, one of the most common gynaecologic disorders, shows significantly elevated prevalence in industrial areas and there is also a possible genetic predisposition. Glutathione-S-transferases (GSTs) are enzymes involved in the metabolism of many disease-causing carcinogens and mutagens that are present in human environments. An association between the incidence of endometriosis and the GST genotypes of patients has been suggested. The objective of the present study was to investigate whether the polymorphisms of GSTM1, GSTT1 and GSTP1 are related to endometriosis. Blood samples were available from 259 controls and 194 patients with advanced endometriosis diagnosed by both pathology and laparoscopic findings. The proportion of the GSTM1, GSTT1 and GSTP1 genotypes of the control group were comparable to other populations. There was no significant evidence that the distribution of the GSTM1 and GSTT1 genotype differed between the patients and the controls, with an allelic odds ratio (OR)=1.074 [95% confidence interval (CI)=0.737-1.564] and 1.239 (95% CI = 0.853-1.799), respectively. Also, there was no significant difference in the proportion of GSTP1 genotypes between the women with endometriosis and the control group with the OR = 0.823 (95% CI = 0.536-1.264). The higher risk alleles were contended as GSTM1, GSTT1 null mutation and GSTP1 Ile105Ile polymorphism. There was no significant increase in the risk of endometriosis as the number of higher risk alleles of the GST family increased. In conclusion, our findings suggest that the GSTM1, GSTT1 and GSTP1 genetic polymorphisms are not associated with the development of endometriosis in Korean women.

No association of endometriosis with glutathione S-transferase M1 and T1 null mutations in a Japanese population.

Endometriosis is inherited as a complex trait, which means that multiple susceptibility genes interact with each other and with environmental factors to produce the phenotype. We investigated the frequency of glutathione S-transferase M1 and T1 (GSTM1 and GSTT1) null mutations in women with endometriosis in a Japanese population. One hundred fourteen unrelated women with endometriosis were enrolled. Samples of umbilical cord blood obtained from 179 female newborn infants were used as population controls. Genomic DNA isolated from endometriosis patients and controls were subjected to multiple polymerase chain reactions to determine the GSTM1 and GSTT1 genotypes. There were no significant differences in the frequencies of the GSTM1 (P = .83, odds ratio 0.95) and GSTT1 (P = .24, odds ratio 0.75) null mutations between endometriosis patients and controls. The endometriosis group was divided into a subgroup of stage IV disease only, but no statistically significant differences were observed in the frequency of the GSTM1 null mutation (P = .88, odds ratio 0.96, 95% confidence interval 0.57-1.63) and the GSTT1 null mutation (P = .33, odds ratio 0.77, 95% confidence interval 0.45-1.30) between any of these groups and the controls. These findings suggest that the GSTM1 and GSTT1 null mutations are not likely to be associated with an increased risk of endometriosis in a Japanese population.

Linkage and association studies of the relationship between endometriosis and genes encoding the detoxification enzymes GSTM1, GSTT1 and CYP1A1

An association between endometriosis and the glutathione S-transferase (GST) M1 null mutation has been reported in French and Slavic populations. We aimed to replicate this association of endometriosis in a UK population, and to test for association with the GSTT1 null mutation or the cytochrome P450 (CYP) 1A1 MspI polymorphism. We genotyped 148 women each with endometriosis (sporadic cases, n = 91; familial cases, n = 57), a population control of 95 male blood donors, and a control group of 53 women with a normal pelvis at hysterectomy. No significant differences were found between cases and controls in the frequencies of the GSTM1 and GSTT1 null mutations, or the CYP1A1 MspI polymorphism. However, the combination of the GSTM1 null genotype and the CYP1A1 MspI polymorphism was associated with a small increased risk of endometriosis, and this warrants further investigation. We also tested for linkage to the chromosome 1p13 region, to which GSTM1 has been mapped, in 52 sister-pairs with stage III-IV disease using three highly polymorphic microsatellite markers. However, there was no evidence of linkage, suggesting that this region may not be implicated in disease susceptibility.