GSTM1 Null Allele Research Articles

Frequency distribution of GSTM1 and GSTT1 null allele in Pakistani population and risk of disease incidence

Glutathione-S-transferases, GSTM1 and GSTT1 play a significant role in detoxification and bioactivation of a broad range of xenobiotic compounds known to be mutagenic and/or carcinogenic. Deletion polymorphisms of these glutathione transferases ( GSTM1 and GSTT1) predispose individuals to environmental carcinogenic compounds. Although a number of studies have shown the relationship between GSTM1 and/or GSTT1 deletion polymorphism and different cancers, these findings cannot be extrapolated to other populations due to intra- and inter-ethnic variability. In order to assess the impact of differential ethnicity on the occurrence of different cancers in local population due to GSTM1, or GSTT1 deletion polymorphism, 111 healthy male and female individuals of different age groups from Southern Punjab, Pakistan were genotyped using a multiplex polymerase chain reaction. From the results it is obvious that null alleles of GSTM1 and GSTT1 genes were found in 45% and 23% individuals, respectively. In 5% of individuals’ simultaneous deletion of both GSTM1 and GSTT1 genes were observed. Frequency of GSTM1 null allele is in concordance with those documented for Chinese, Caucasians, Mongolian, and Japanese populations. However, a significantly higher frequency for GSTT1 null was reported in Chinese and Japanese population as compared to Pakistani population. It is the first ever report on frequency of GSTM1 and GSTT1 null allele in Pakistani population which demonstrate the impact of ethnicity and provide basis for future epidemiological and clinical studies.

Drug-Induced Liver Injury: Past, Present and Future

Drug-induced liver injury (DILI) is a rare but potentially serious idiosyncratic reaction. By using candidate gene and genome-wide association studies, replicated associations for DILI susceptibility with HLA genes and genes relevant to drug metabolism have been detected, mainly since 2000. The HLA associations include a strong association between flucloxacillin-induced injury and the class I allele B*5701 and weaker associations for co-amoxiclav and ximelagatran DILI with the class II genotype. These associations suggest an injury mechanism involving an immune response, possibly to a complex of drug or metabolite and protein. For genes relevant to drug metabolism, the best replicated association is between isoniazid DILI and NAT2 slow acetylation. Homozygosity for GSTM1 null and/or GSTT1 null alleles also seems to be a risk factor for DILI, with associations described independently for several drugs. Other not-yet-replicated associations have been described for genes relevant to drug metabolism and oxidative stress and cytokine genes.

GSTM1, GSTT1, GSTP1, GSTA1 and colorectal cancer risk: A comprehensive meta-analysis

Glutathione S-transferases (GSTs) catalyse reactions between glutathione and lipophilic compounds with electrophilic centres, leading to neutralisation of toxic compounds, xenobiotics and products of oxidative stress. Controversy exists about whether GST polymorphisms (GSTM1 null/present genotype, GSTT1 null/present genotype, GSTP1 Ile105Val and GSTA1∗A/∗B) represent risk factors for colorectal cancer. This meta-analysis aims to examine the associations between the above-mentioned polymorphisms and colorectal cancer risk. Forty-four studies were eligible for GSTM1 (11,998 colorectal cancer cases, 17,552 controls), 34 studies for GSTT1 (8596 cases, 13,589 controls), 19 studies for GSTP1 (5421 cases, 7671 controls) and four studies for GSTA1 polymorphism (1648 cases, 2039 controls). Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random-effects models. Separate analyses were conducted on Caucasian and Chinese populations. Where appropriate, sensitivity analysis concerning the deviation of genotype frequencies in controls from the Hardy–Weinberg equilibrium was performed. GSTM1 null allele carriers exhibited increased colorectal cancer risk in Caucasian populations (pooled OR = 1.150, 95% confidence interval (CI): 1.060–1.248, random effects); no significant association was detected for Chinese subjects (pooled OR = 1.025, 95% CI: 0.903–1.163, fixed effects). Similarly, GSTT1 null allele carriers exhibited increased colorectal cancer risk in Caucasian populations (pooled OR = 1.312, 95% CI: 1.119–1.538, random effects); the association in Chinese subjects was not significant (pooled OR = 1.068, 95% CI: 0.788–1.449, random effects). Concerning GSTP1 Ile105Val no significant associations were demonstrated in either race. GSTA1∗A/∗B polymorphism was not associated with colorectal cancer risk. GSTM1 and GSTT1 null genotypes confer additional risk for colorectal cancer in Caucasian populations.

Influence of class M1 glutathione S-transferase (GST Mu) polymorphism on GST M1 gene expression level and tumor size in oral squamous cell carcinoma

Glutathione S-transferases (GST) are antioxidant enzymes and oxidative stress markers in oral carcinogenesis. They present a system of polymorphic proteins. Some variants are associated with increased sensitivity to toxic compounds, as it is known for the GSTM1-null variant allele. However, the influence of the GSTM1 allele variant genotype on GSTM1-mRNA quantity in oral squamous cell carcinoma (OSCC) and normal mucosa as well as the impact on prognosis remains unclear. The genotype for GSTM1 (mutation vs. wild type) was determined by polymerase chain reaction (PCR) using genomic DNA extracted from peripheral blood from 28 OSCC patients. From the same patients, 28 pairs of OSCC cells and normal oral mucosal cells were obtained by brush biopsy. mRNA was extracted from these paired samples and the expression levels of GSTM1 were examined by real-time reverse transcriptase qPCR (RT-qPCR). The mRNA expression of the OSCC samples was normalized against an external standard, as well as to the corresponding normal mucosa. The coincidence of GSTM1 genotype and GSTM1-mRNA-expression level was examined. In 15 patients (54%), the null genotype GSTM1 was present. In the GSTM1-null allele group, the GSTM1 gene expression level was determined at 1.63 (mean: 3.08; SD 3.4) folds vs. 3.6 (mean: 10.5; SD 14.2) folds in the group with the positive genotype (p=0.06), if calibrated vs. individual normal mucosa. More T3 and T4 OSCCs (+38%), higher UICC stadia (+38%) and more lymphatic metastasis (+28%) were seen in the group with the negative allele. Furthermore, positive GSTM1 genotype and enhanced GSTM1 gene expression was accompanied with increased tumor size, lymphatic metastasis status and UICC stadium. A coincidence of null type GSTM1 and lowered GSTM1 gene expression was observed. The larger tumors and more frequent lymph node metastases in this group could be explained by the insufficient cell protection by GST.

Glutathione-S-transferase genes and asthma phenotypes: a Human Genome Epidemiology (HuGE) systematic review and meta-analysis including unpublished data.

Background Oxidative stress is thought to be involved in the pathogenesis of asthma. Glutathione-S-transferase (GST) enzymes, which play an important role in antioxidant defences, may therefore influence asthma risk. Two common deletion polymorphisms of GSTM1 and GSTT1 genes and the GSTP1 Ile105Val polymorphism have been associated with asthma in children and adults, but results are inconsistent across studies.Methods Systematic review and meta-analysis of the effects of GST genes on asthma, wheezing and bronchial hyper-responsiveness (BHR), with inclusion of unpublished data from three studies, including the large Avon Longitudinal Study of Parents and Children (ALSPAC). Random effect or fixed effect models were used as appropriate, and sensitivity analyses were performed to assess the impact of study characteristics and quality on pooled results.Results The meta-analyses of GSTM1 (n = 22 studies) and GSTT1 (n = 19) showed increased asthma risk associated with the null genotype, but there was extreme between-study heterogeneity and publication bias and the association disappeared when meta-analysis was restricted to the largest studies. Meta-analysis of GSTP1 Ile105Val (n = 17) and asthma suggested a possible protective effect of the Val allele, but heterogeneity was extreme. Few studies evaluated wheezing and BHR and most reported no associations, although weak evidence was found for positive associations of GSTM1 null and GSTP1 Val allele with wheezing and a negative association of GSTP1 Val allele with BHR.Conclusions Our findings do not support a substantial role of GST genes alone in the development of asthma. Future studies of large size should focus on interactions of GST genes with environmental oxidative exposures and with other genes involved in antioxidant pathways. Quality of study conduct and reporting needs to be improved to increase credibility of the evidence accumulating over time.

Influence of Genetic Variability of GSTM1 and GSTT1 Null Alleles Between Donor and Recipient in the Development of Acute Graft Versus Host Disease.

Abstract 1154Poster Board I-176 INTRODUCTIONGlutathione-S-transferase (GST) M1 and T1 are multifunctional enzymes involved in the metabolism of environmental carcinogens and chemotherapeutic drugs. The immunogenic activity of these enzymes and their association with graft rejection has been widely proved in solid organ transplantation. In this study we examined whether genetic variability (absence versus presence of the gene in donor/recipient pairs) could be related to acute graft versus host disease (aGvHD) in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation (alloHSCT) from related donor (RD). PATIENTS AND METHODSWe evaluated 64 patients with acute leukemia (34 AML and 30 ALL) undergoing alloSCT and receiving myeloablative conditioning (MAC), with a minimum follow-up of 100 days. Donors were HLA-identical siblings in all cases, except in 2 presenting only a single HLA disparity. As source of HSCs, bone marrow progenitors were used in 25 patients (40%) and peripheral blood progenitors in 39 (60%). Total body irradiation (TBI) was used for conditioning treatment in 18 cases (28%). GvHD prophylaxis consisted of a short-term combination of Cyclosporine and Methotrexate. Presence in homozygous or heterozygous (positivity) or absence (negativity) of GSTM1/T1 genes were determined by real-time PCR. A Chi-square test was used to evaluate qualitative variables and non-parametric tests for quantitative variables. The Cox proportional-hazard model was applied to multivariate analysis. RESULTSGSTT1 and GSTM1 positivity was observed in 73 and 47% of patients, respectively, and in 72 and 46% of donors, respectively. Nineteen of 64 patients (30%) presented grade II-IV aGvHD. The incidence of grade II-IV aGVHD in GSTM1-positive patients was 79% versus 21% in GSTM1-negative patients. In univariate analysis, only GSTM1 positive patients developed grade II-IV aGvHD (p=0.001). In multivariate analysis, GSTM1 positivity was the only variable significantly associated with the appearance of grade II-IV aGvHD (p=0.002). No significant association was detected between GSTT1 genetic variability and the incidence of aGvHD. We found no significant difference in patients overall survival in relation to GSTM1 and GSTT1 genetic variability. CONCLUSIONSGSTM1-positive recipients develop more likely grade II-IV aGvHD, independently of other known risk factors. GSTM1 gene determination (homozygous or heterozygous) could be used to assess the aGvHD risk in allogeneic hematopoietic stem cell transplantation. DisclosuresNo relevant conflicts of interest to declare.

CYP1A2* 1C, CYP2E1* 5B, and GSTM1 polymorphisms are predictors of risk and poor outcome in head and neck squamous cell carcinoma patients

Head and neck squamous cell carcinoma (HNSCC) is associated with environmental factors, especially tobacco and alcohol consumption. Most of the carcinogens present in tobacco smoke are converted into DNA-reactive metabolites by cytochrome P450 (CYPs) enzymes and detoxification of these substances is performed by glutathione S-transferases (GSTs). It has been suggested that genetic alterations, such as polymorphisms, play an important role in tumorigenesis and HNSCC progression. The aim of this study was to investigate CYP1A1, CYP1A2, CYP2E1, GSTM1, and GSTT1 polymorphisms as risk factors in HNSCC and their association with clinicopathologic data. The patients comprised 153 individuals with HNSCC (cases) and 145 with no current or previous diagnosis of cancer (controls). Genotyping of the single nucleotide polymorphisms (SNPs) of the CYP1A1, CYP1A2, and CYP2E1 genes was performed by PCR-RFLP and the GSTM1 and GSTT1 copy number polymorphisms (CNPs) were analyzed by PCR-multiplex. As expected, a significant difference was detected for tobacco and alcohol consumption between cases and controls (P<0.001). It was observed that the CYP1A2*1D (OR=16.24) variant and GSTM1 null alleles (OR=0.02) confer increased risk of HNSCC development (P<0.001). In addition, head and neck cancer alcohol consumers were more frequently associated with the CYP2E1*5B variant allele than control alcohol users (P<0.0001, OR=190.6). The CYP1A2*1C polymorphism was associated with tumor recurrence (log-rank test, P=0.0161). The CYP2E1*5B and GSTM1 null alleles were significantly associated with advanced clinical stages (T3+T4; P=0.022 and P=0.028, respectively). Overall, the findings suggested that the genetic polymorphisms studied are predictors of risk and are also associated with tumor recurrence, since they are important for determining the parameters associated with tumor progression and poor outcomes in HNSCC.

Polymorphisms in transporter and phase II metabolism genes as potential modifiers of the predisposition to and treatment outcome of de novo acute myeloid leukemia in Israeli ethnic groups

Drug metabolism/disposition and transporter genes may influence predisposition or prognosis of AML (acute myeloid leukemia) patients. We analyzed polymorphisms in 3 transporters and 4 drug metabolism genes in 293 Israeli individuals (112 AML patients and 181 controls). We analyzed: ABCC3 (MRP3) C-211T; ABCG2 ( BCRP) C421A; CNT1 ( SLC28A1) G565A and NAT1, NAT2, and GSTT1 and GSTM1 null alleles for influence on predisposition, as well as treatment response and survival. We found that the ABCC3 C-211T polymorphism and GSTM1 null genotype have adverse prognostic significance in AML. None of the other polymorphisms studied were found to influence either predisposition or prognosis in Israeli AML patients.

Relevance of glutathione S-transferase M1 and cytochrome P450 1A1 genetic polymorphisms to the development of head and neck cancers

Cytochrome P450 (CYP) and glutathione S-transferase (GST) gene variants have been intensively investigated for their implication in the development of different neoplasms. In the present study, we analyzed genetic polymorphisms of CYP1A1, GSTM1, GSTP1, and GSTT1 in 127 head and neck cancer patients and 151 hospital controls. No significant increase in risk in patients with the GSTM1 null genotype (OR=1.52, 95% CI: 0.93-2.49) or CYP1A1 462Val alleles (OR=1.60, 95% CI: 0.73-3.52) or GSTP1 105Val alleles (OR=0.97, 95% CI: 0.59-1.58) was observed. The GSTT1 null genotype was found in 30.5% of the controls and 21.3% of the head and neck cancer patients (p=0.15). The estimated head and neck cancer risk for the combination of either CYP1A1 Ile462Val or CYP1A1 Val462Val genotype with either GSTP1 Ile105Val or Val105Val genotype (OR=2.89, 95% CI: 0.71-11.71) and for the combination of either CYP1A1 Ile462Val or CYP1A1 Val462Val genotype with GSTT1 null genotype (OR=2.62, 95% CI: 0.64-10.85) suggested the absence of the modifying effect of combined variant alleles on head and neck cancer susceptibility. The joint effect of either CYP1A1 Ile462Val or CYP1A1 Val462Val genotype with GSTM1 null genotype significantly increased the risk of head and neck cancer (OR=7.15, 95% CI: 1.49-34.32). Our findings corroborate metabolic genes interactions, especially for CYP1A1 462Val alleles and GSTM1 homozygous deletion, in the development of head and neck cancer in the investigated population groups in Poland.

Genetic polymorphisms of glutathione s-transferase mu1 and theta1 in patients with acquired aplastic anemia: a Brazilian experience

The causes of acquired aplastic anemia (AAA) include immunologic mechanisms and oxidative DNA damage. Glutathione S-transferase (GST) plays an important role in detoxification. In humans, GST genes encode four main clones: alpha (A), mu (M), pi (P) and theta (T). Among GST genes, GST M1 and T1 have null genotypes that result in a lack of activity. The aim of this study was to investigate polymorphisms of the GSTM1 and GSTT1 enzyme in Brazilian patients with AAA. The null allele of GSTM1 was observed in 3 (16.6%) patients and the GSTT1 null genotype was observed in only one (5.5%) patient. This study did not find any association between genetic polymorphisms of the GSTM1/GSTT1 detoxifying enzymes and the pathogenesis of AAA.

Glutathione-S-transferase M1 and T1 and cytochrome P1A1 genetic polymorphisms and susceptibility to cervical intraepithelial neoplasia in Greek women

The aim of the study was to determine the importance of genetic polymorphisms of glutathione-S-transferase T1 and M1 and cytochrome P1A1 genes in the development of cervical intraepithelial neoplasia in Greek women. This was a prospective, case-control study conducted by the Cervical Pathology and Colposcopy Unit of a University Ob/Gyn Department from 1999 to 2003. Cervical smears from 114 controls without any cytological and/or colposcopical evidence of cervical pathology and from 166 women with history of cervical intraepithelial neoplasia (56 CIN I, 54 CIN II and 56 CIN III) were examined with polymerase chain reaction for the above-mentioned genetic polymorphisms, taking also in mind their smoking attitudes. Statistical analysis was performed to detect any association between the null genotype of GSTM1 and GSTT1 genes and the CYP1A1 m1 polymorphism and the severity of cervical intraepithelial neoplasia. The distributions of the GSTT1 and GSTM1 wild-type genotypes were 57.48 and 39.75%, respectively. No woman with homozygous GSTT1 and GSTM1 null/null genotype was identified. CYP1A1 m1 polymorphism frequency was 24.49%. No woman with homozygous CYP1A1 m1/m1 genotype was detected as well. No significant difference in the frequencies of the GSTM1 and GSTT1 null alleles, and the CYP1A1 m1 polymorphism, was found between cases and controls. After application of Mantel-Haenszel chi procedure, there was no linear severity of the lesion and the frequency of these polymorphisms. According to our results, glutathione-S-transferase T1 and M1 and cytochrome P1A1 genetic polymporphisms do not appear to be a risk factor for cervical disease irrespective of smoking habits.

GENOTYPE AND ALLELE FREQUENCIES OF N‐ACETYLTRANSFERASE 2 AND GLUTATHIONE S‐TRANSFERASE IN THE IRANIAN POPULATION

1. Xenobiotic-metabolizing enzymes constitute an important line of defence against a variety of carcinogens. Many are polymorphic, constituting the basis for the wide interindividual variation in metabolic capacity and possibly a source of variation in the susceptibility to chemical-induced carcinogenesis. The aim of the present study was to determine the frequencies of important allelic variants in the N-acetyltransferase 2 (NAT2) and glutathione S-transferase (GST) genes in the Iranian population and compare them with frequencies in other ethnic populations. 2. Genotyping was performed in a total of 229 unrelated healthy subjects (119 men, 110 women) for NAT2 and 170 unrelated healthy subjects (89 men, 81 women) for GST from the general Tehran population. A combination of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) was applied for typing of NAT2 polymorphisms. Detection of GSTM1 and GSTT1 null alleles was performed simultaneously using a multiplex PCR assay. 3. The frequencies of specific NAT2 alleles were 0.299, 0.314, 0.380, 0.007 and 0.000 for 4 (wild-type), 5 (C481T, M1), 6 (G590A, M2), 7 (G857A, M3) and 14 (G191A, M4), respectively. The most prevalent genotypes were NAT2 5/6 (29.70%) and 4/6 (21.40%). The GSTM1- and GSTT1-null alleles were detected in 44.7 and 21.2% of subjects, respectively. 4. We found that Iranians resemble Indians with regard to allelic frequencies of the tested variants of NAT2. The predominance of slow (49.36%) and intermediate (41.47%) acetylation status compared with wild-type rapid acetylation status (9.17%) in the study group suggests the significant prevalence of the slow acetylator (SA) phenotypes in the Iranian population. Our data confirmed that Iranians are similar to other Caucasian populations in the frequency of both GSTM1- and GSTT1-null alleles.

Ferritin H, CYP1A1, and CYP1B1 Altered Expression in Mexican Tobacco Smokers

ISEE-635 Objective: Tobacco smoke is a chemical mixture where many constituents are human carcinogens and regulate the genes expression. The aim of this study was to detect the CYP 1A1, 1B1, and Ferritin mRNA levels and CYP 1A1, 1B1, and GSTM polymorphisms, as possible biomarkers of exposure and susceptibility, respectively in smokers. Materials and Methods: A cross-sectional study was carried out in 102 male unrelated smokers aged 18 to 53 years. Participants were directly interviewed by trained personnel and clinical, occupational, and sociodemographic characteristics. Tobacco exposure was estimated by interview, urinary cotinine, and 1-OHP levels. CYP 1A1, 1B1, and Ferritin H mRNA were evaluated in peripheral lymphocytes by quantitative real-time PCR. GSTM polymorphism was analyzed using a duplex PCR assay and CYP1A1 (Ile462Val) and CYP1B1 (1Leu432Val) polymorphisms were determined by real-time PCR-TaqMan System. All subjects gave written consent after being fully informed about the purpose and nature of the study that was approved by the Ethical Committee of CINVESTAV-IPN. Results: The frequencies of CYP1A1 alleles in our population were 35.2 native, 50.5 heterozygote, and 14.3% mutant, and the frequencies of CYP1B1 were 52.7 native, 37.6% heterozygote, and 9.7% mutated. The polymorphism GSTM1 showed 38% of population were type GSTM1 null allele (GSTM1−/−). In addition the cotinine urinary medium was 4101.43 ng/mL (1210–5789) and the mean value of 1-OHP was 5279.5 nmol/L (0–91756.6). A high correlation between the concentrations of 1-OHP and cotinine was found. A wide variation in gene expression among the samples was observed; however, CYP1B1 gene was related with the cotinine levels (β = 71.31, P = 0.011), and the CYP1B1 polymorphism did not modified this relationship. Conclusions: Our preliminary results suggest specific changes in gene expression of genes in lymphocytes of smokers; and its implications for the metabolic activation of procarcinogens to ultimate carcinogens of tobacco smoke were studied.

Polymorphisms in drug metabolism genes, smoking, and p53 mutations in breast cancer

Polymorphisms in phase I and phase II enzymes may enhance the occurrence of mutations at critical tumor suppressor genes, such as p53, and increase breast cancer risk by either increasing the activation or detoxification of carcinogens and/or endogenous estrogens. We analyzed polymorphisms in CYP1B1, GSTM1, GSTT1, and GSTP1 and p53 mutations in 323 breast tumor samples. Approximately 11% of patients exhibited mutations in p53. Women with mutations had a significantly younger age of diagnosis (P = 0.01) and a greater incidence of tumors classified as stage II or higher (P = 0.002). More women with mutations had a history of smoking (55%) compared to women without mutations (39%). Although none of the genotypes alone were associated with p53 mutations, positive smoking history was associated with p53 mutations in women with the GSTM1 null allele [OR = 3.54; 95% CI = 0.97-12.90 P = 0.06] compared to women with the wild-type genotype and smoking history [OR = 0.62, 95% CI = 0.19-2.07], although this association did not reach statistical significance. To test for gene-gene interactions, our exploratory analysis in the Caucasian cases suggested that individuals with the combined GSTP1 105 VV, CYP1B1 432 LV/VV, and GSTM1 positive genotype were more likely to harbor mutations in p53 [OR = 4.94; 95% CI = 1.11-22.06]. Our results suggest that gene-smoking and gene-gene interactions may impact the prevalence of p53 mutations in breast tumors. Elucidating the etiology of breast cancer as a consequence of common genetic polymorphisms and the genotoxic effects of smoking will enable us to improve the design of prevention strategies, such as lifestyle modifications, in genetically susceptible subpopulations.

Null allele polymorphisms in the GSTT1 and GSTM1 genes in 705 women from a mammographic breast cancer screening program (NMPOA) in southern Brazil

21091 Background: Several genetic polymorphisms in genes related with metabolism have been associated with breast cancer (BC) risk. Among these, the gluthatione-S-transferase M1 and T1 null genotypes have been associated with slightly increased BC risk in some populations. In Brazil, BC is a significant public health problem, due to its high incidence and mortality rates. In Porto Alegre, Brazil`s southernmost capital, a multidisciplinary BC Prevention Project - the Nucleo Mama Porto Alegre Cohort (NMPOA)- was started in 2004 and includes a mammographic screening program for women ages 40–69 years. Goal:Determine the allelic and genotypic frequencies of GSTM1 and GSTT1 null alleles in women undergoing annual mammographic screening and correlate its presence with mammography results and presence of additional BC risk factors at baseline and after 10 years. Methods: A sample of 705 women from the NMPOA BC screening program was consecutively enrolled from November/2005 until March/2006. Mammography results (BIRADS categories) and BC risk information (5-yr and vital estimates using the Gail model, family history of BC, body mass index) were obtained by chart review. Genotyping was performed by multiplex polymerase chain reaction (PCR). Results: Of the 705 patients studied, 145 (20.6%) and 314 (44.5%) had the GSTT1 and GSTM1 null alleles, respectively. Genotypically, 67 (9,5%) were null homozygous for both genes (GSTM1- and GSTT1- ); 78 (11,1%) were GSTT1- and non-null for GSTM1 (GSTT1- and GSTM1+); 247 (35%) were GSTT1+ and GSTM1- and 313(44,4%) were GSTM+ and GSTT+. There was a statistically significant association of the GSTT1+ allele with low-risk mammographic findings (category BIRADS 1; p&lt;0,05). Conclusions: The genotypic and allelic frequencies of the GSTT1 and GSTM1 null alleles were not significantly different from those reported previously for other populations. The non-null GSTT1 allele was associated with lower category mammographic findings. Prospective clinical evaluation of the women followed in this program and correlation of genotype with clinical findings may elucidate additional risks associated with the presence of these polymorphisms. No significant financial relationships to disclose.

Effects of metabolic genotypes on intermediary biomarkers in subjects exposed to PAHS: Results from the EXPAH study

Data from the EXPAH project on PAH exposure and intermediary biomarkers were analyzed with respect to individual genotypes at seven metabolic gene loci. The GSTM1 null allele was associated with significantly higher levels of two biomarkers, malondialdehyde-2′-deoxyguanosine and benzo[ a]pyrene DNA adducts in the total population from three Central and Eastern European countries. The CYP1B1 Leu/Val variant demonstrated effects on both markers of oxidative DNA damage in opposite directions, producing a higher level of M 1dG with a trend from wild type (Leu/Leu) to heterozygotes to homozygous (Val/Val) variants, whereas the effects of these variants were reversed for 8-oxodG. Cluster Analysis was used to group composite genotypes in order to determine if combined genotypes of multiple loci could explain some of the variation seen with the biomarkers, expressed per unit of exposure, referred to as a sensitivity index. This analysis revealed two closely related genotypes each involving four of the loci (GSTM1*0/*0, CYP1A1*1*1, CYP1B1*1/*2, GSTP1*1/*1 and GSTT1*0/*0, CYP1A1*1*1, CYP1B1*1/*2, GSTP1*1/*1.) that conferred significant resistance to the DNA damaging effects of benzo[ a]pyrene, measured as the level of a benzo[ a]pyrene-like adduct per unit of benzo[ a]pyrene exposed.

Genotype Frequencies of Polymorphic GSTM1, GSTT1, and Cytochrome P450 CYP1A1 in Mexicans

The genotype frequencies of three metabolic polymorphisms were determined in a sample of a typical community in central Mexico. CYP1A1*3, GSTM1, and GSTT1 polymorphisms were studied in 150 donors born in Mexico and with Mexican ascendants; with respect to ethnicity the subjects can be considered Mestizos. PCR reactions were used to amplify specific fragments of the selected genes from genomic DNA. An unexpected 56.7% frequency of the CYP1A1*3 allele (which depends on the presence of a Val residue in the 462 position of the enzyme, instead of Ile) was found, the highest described for open populations of different ethnic origins (i.e., Caucasian, Asian, African, or African American). The GSTM1 null genotype was found with a frequency of 42.6%, which is not different from other ethnicities, whereas the GSTT1 null genotype had a frequency of 9.3%, one of the lowest described for any ethnic group but comparable to the frequency found in India (9.7%). The frequency of the combined genotype CYP1A1*3/*3 and the GSTM1 null allele is one of the highest observed to date (or perhaps the highest): 13.7% among all the ethnicities studied, including Caucasians and Asians, whereas the combination of CYP1A1*3/*3 with the GSTT1 null allele reached only 2.8%. The GSTM1 null allele combined with the GSTT1 null allele, on the other hand, has one of the lowest frequencies described, 4.24%, comparable to the frequencies found in African Americans and Indians. Finally, the combined CYP1A1*3/*3, GSTM1 null allele, and GSTT1 null allele genotype could not be found in the sample studied; it is assumed that the frequency of carriers of these combined genotypes is less than 1%. CYP1A1*3 and CYP1A1*2 polymorphisms were also evaluated in 50 residents in a community of northern Mexico; the CYP1A1*3 frequency was 54%, similar to that found in the other community studied, and the CYP1A1*2 frequency was 40%, which is high compared to Caucasians and Asians but comparable to the frequency found in Japanese and lower than the frequency found in Mapuche Indians. Haplotype frequencies for these CYP1A1 polymorphisms were estimated, and a linkage disequilibrium value (D) of 0.137 was calculated.

Glutathione S-Transferase M1 and T1 Polymorphisms in Brazilian African Descendants

The glutathione S-transferase gene family has an important role in the biotransformation and detoxification of different xenobiotics and endogenous compounds. Two polymorphic genes of this family, GSTM1 and GSTT1, present null alleles that consequently do not produce the respective enzyme when the genotype is homozygous. These polymorphisms are also interesting for population dynamics studies because they have great frequency variations among different ethnic groups and have been reported worldwide. The distribution of these alleles in urban and Amerindian populations in Brazil has been described, but none of those studies reported on African-descended rural populations. The aim of this study was to analyze the genotype frequency distribution of the GSTM1 and GSTT1 null alleles in an urban sample from the Federal District (n = 91) and in four semi-isolated African-descended populations: Mocambo (n = 55), Rio das Rãs (n = 117), Riacho de Sacutiaba (n = 34), and Kalunga (n = 68). The GSTM1 and GSTT1 null genotype frequencies in these populations range from 17% to 35% for GSTM1 and from 22% to 44% for GSTT1. These values are similar to those described in other African and African-descended populations. Despite this range, there is no distribution difference among the analyzed populations. Combined GSTM1 and GSTT1 null genotype frequencies range from 6% to 13% and are similar to European-derived populations, suggesting admixture with this ethnic group. This can be interpreted as a European contribution to these African-descended populations. Regarding the urban population in the Federal District, our results suggest an important African and European contribution.

Polymorphisms of glutathione-S-transferase M1 and manganese superoxide dismutase are associated with the risk of malignant pleural mesothelioma

Individual response to oxidative stress, due to exposure to asbestos fibres plays a significant role in the malignant pleural mesothelioma (MPM) etiology. The differential impact on MPM risk of polymorphic alleles of glutathione-S-transferases (GSTs) and manganese superoxide dismutase (MnSOD/SOD2) genes involved in the defence against oxidative damage has been investigated. Ninety cases of MPM and 395 controls were genotyped using the arrayed-primer extension technique. Logistic regression analysis was applied to assess the predictive role of single nucleotide polymorphisms (SNPs) potentially involved in MPM carcinogenesis after adjustment for potential confounders. An increased risk of MPM was found in subjects bearing a GSTM1 null allele (OR = 1.69, 95% CI = 1.04-2.74; p = 0.034), and in those with the Ala/Ala genotypes at codon 16 within MnSOD (OR = 3.07, 95% CI = 1.55-6.05; p = 0.001). A stronger effect of MnSOD was observed among patients without a clear exposure to asbestos fibres. No effect was found for GSTA2, GSTA4, GSTM3, GSTP1 and GSTT1 genes. These findings, if replicated, contribute substantial evidence to the hypothesis that oxidative stress and cellular antireactive oxygen species systems are involved in the pathogenesis and in the natural history of MPM.

Polymorphisms of the GSTM1 and GSTT1 genes in patients with allergic diseases in the Czech population

Allergic diseases belong to the most common chronic disorders affecting mankind and their prevalence in population is increasing. Several studies have indicated that oxidative stress impairs pulmonary function and makes existing asthma worse. Members of the glutathione-S-transferase (GST) superfamily of genes are important in protection of cells from reactive oxygen species. Relationships among allergic diseases including asthma and variations in the GST mu (GSTM1) and GST theta (GSTT1) genes were investigated in 1,006 Caucasian subjects. The multiplex polymerase chain reaction protocol was used for simultaneous amplification of both genes for molecular analysis. Genotype frequencies among patients and controls were assessed and the associations of the genotypes with intermediary phenotypes of allergy were statistically determined. The frequencies of GST null genotypes did not differ significantly between patients with allergic diseases (or asthma alone) and healthy controls. However, when compared with patients homozygous or heterozygous for GSTM1 functional allele, asthmatics carrying both GSTM1 null alleles displayed significantly worse lung function, assessed by forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) ratio (Tiffenau index), (P < 0.01). Genetic polymorphisms of the GSTM1 and GSTT1 genes, both individually and in combination, were not associated with the development of allergic diseases including asthma in the Czech population, the GSTM1 gene variability, however, may influence lung functions in our asthmatics.