Glutathione S-transferase Variants Research Articles

Association of GSTT1, GSTM1 and GSTP1 (Ile105Val) mRNA Expression with Cardiometabolic Risk Parameters in Women with Breast Cancer and Comorbidities

Breast cancer (BC) and cardiometabolic diseases share a multifactorial and modifiable etiology, modulated by complex molecular pathways. Glutathione S-transferase (GST) plays a critical role, providing protection against xenobiotics and regulating levels of enzymes and proteins in the cell. GST variants have a significant impact on susceptibility to diseases whose pathogenesis involves oxidative stress, as is the case in many inflammatory diseases such as BC and cardiometabolic pathologies. However, the expression of these polymorphic variants has not been studied in BC. This study aimed to evaluate the presence of GST mRNA isoforms and their association with clinical and cardiometabolic parameters in women with BC. This was a case-control study, and a total of 57 participants were recruited. Concentrations of glucose and lipids in blood were measured in all the participants. GST variants (GSTT1, GSTM1 and GSTP1 Ile105Val polymorphism) were evaluated in all the participants by real-time PCR analysis. There was a significant association (p < 0.05) between the frequency of GSTP1 and LDL-c in the BC group. However, the control group showed significant associations between blood pressure with GSTT1 and GSTP1 variants with total cholesterol (TC), LDL-c, VLDL-c and triacylglycerols (TG). Therefore, GSTT1 and GSTP1 variants could be emerging biomarkers to discriminate between BC cases related or not to cardiometabolic disease factors.

Glutathione S-transferases and their implications in the lung diseases asthma and chronic obstructive pulmonary disease: Early life susceptibility?

Our lungs are exposed daily to airborne pollutants, particulate matter, pathogens as well as lung allergens and irritants. Exposure to these substances can lead to inflammatory responses and may induce endogenous oxidant production, which can cause chronic inflammation, tissue damage and remodeling. Notably, the development of asthma and Chronic Obstructive Pulmonary Disease (COPD) is linked to the aforementioned irritants. Some inhaled foreign chemical compounds are rapidly absorbed and processed by phase I and II enzyme systems critical in the detoxification of xenobiotics including the glutathione-conjugating enzymes Glutathione S-transferases (GSTs). GSTs, and in particular genetic variants of GSTs that alter their activities, have been found to be implicated in the susceptibility to and progression of these lung diseases. Beyond their roles in phase II metabolism, evidence suggests that GSTs are also important mediators of normal lung growth. Therefore, the contribution of GSTs to the development of lung diseases in adults may already start in utero, and continues through infancy, childhood, and adult life. GSTs are also known to scavenge oxidants and affect signaling pathways by protein-protein interaction. Moreover, GSTs regulate reversible oxidative post-translational modifications of proteins, known as protein S-glutathionylation. Therefore, GSTs display an array of functions that impact the pathogenesis of asthma and COPD.In this review we will provide an overview of the specific functions of each class of mammalian cytosolic GSTs. This is followed by a comprehensive analysis of their expression profiles in the lung in healthy subjects, as well as alterations that have been described in (epithelial cells of) asthmatics and COPD patients. Particular emphasis is placed on the emerging evidence of the regulatory properties of GSTs beyond detoxification and their contribution to (un)healthy lungs throughout life. By providing a more thorough understanding, tailored therapeutic strategies can be designed to affect specific functions of particular GSTs.

Genetic and environmental risk for lymphoma in boxer dogs.

BackgroundNon‐Hodgkin lymphoma in humans is associated with environmental chemical exposures, and risk is enhanced by genetic variants in glutathione S‐transferases (GST) enzymes.ObjectiveWe hypothesized that boxer dogs, a breed at risk for lymphoma, would have a higher prevalence of GST variants with predicted low activity, and greater accumulated DNA damage, compared to other breeds. We also hypothesized that lymphoma in boxers would be associated with specific environmental exposures and a higher prevalence of canine GST variants.AnimalsFifty‐four healthy boxers and 56 age‐matched nonboxer controls; 63 boxers with lymphoma and 89 unaffected boxers ≥10 years old.MethodsWe resequenced variant loci in canine GSTT1, GSTT5, GSTM1, and GSTP1 and compared endogenous DNA damage in peripheral leukocytes of boxers and nonboxers using the comet assay. We also compared GST variants and questionnaire‐based environmental exposures in boxers with and without lymphoma.ResultsEndogenous DNA damage did not differ between boxers and nonboxers. Boxers with lymphoma were more likely to live within 10 miles of a nuclear power plant and within 2 miles of a chemical supplier or crematorium. Lymphoma risk was not modulated by known canine GST variants.Conclusions and Clinical ImportanceProximity to nuclear power plants, chemical suppliers, and crematoria were significant risk factors for lymphoma in this population of boxers. These results support the hypothesis that aggregate exposures to environmental chemicals and industrial waste may contribute to lymphoma risk in dogs.

GSTM1-null allele predicts rapid disease progression in nondialysis patients and mortality among South Indian ESRD patients.

Chronic kidney disease (CKD) is one of the main causes of early death in humans worldwide. Glutathione S-Transferases (GSTs) are involved in a series of xenobiotics metabolism and free radical scavenging. The previous studies elucidated the interlink between GST variants and to the development of various diseases. The present case-control study performed to ascertain whether GST polymorphisms are associated with the incidence and advancement of CKD. From the Southern part of India, a total of 392 CKD patients (nondialysis, ND; n = 170, end-stage renal disease, ESRD; n = 222) and 202 healthy individuals were enrolled. Patients were followed-up for 70months. Serum biochemical parameters were recorded, and the extraction of DNA was done from the patient's blood samples. To genotype study participants, multiplex PCR for GSTM1/T1 was performed. Statistical analysis was carried out to analyze the relationship between gene frequency and sonographic grading, as well as biochemical parameters for disease development. The GSTM1-null genotype showed threefold increased risk (OR = 2.9304; 95% CI 1.8959 to 4.5296; P < 0.0001) to CKD development and twofold increased risk (OR = 1.8379; 95% CI 1.1937 to 2.8299; P = 0.0057) to ESRD progression. During the mean follow-up of 41months study, multivariate Cox regression analysis revealed that GSTM1-null genotype has 4 times increased the risk for all-cause rapid disease progression to ESRD among ND patients and 3.85-fold increased risk for death among ESRD patients. Survival analysis revealed that patients with GSTM1-present allele showed a significantly diminished risk of mortality compared to patients bearing the GSTM1-null allele among ESRD patients with a hazard ratio of 4.6242 (P < 0.0001). Thus, present data confirm that GSTM1-null genotype increased the risk for all-cause rapid disease progression to ESRD among ND patients. Based on our results, GSTM1-null genotype could be considered as a significant predictor for causing mortality among CKD patients when compared to all other variables.

Effects of GSTA1 and GPX3 Polymorphisms on the Risk of Schizophrenia in Chinese Han Population.

PurposeSeveral lines of evidence support the fact that the presence of oxidative stress plays an important role in the pathophysiological mechanisms of schizophrenia (SCZ). The glutathione peroxidases (GPXs) and glutathione S-transferases (GSTs) are the major antioxidant enzymes. Polymorphic variants of GPX and GST can affect the antioxidant activities of their encoded enzymes. This study explored the possible associations of the GSTA1 and GPX3 gene polymorphisms and schizophrenia in Chinese Han population.MethodsDNA from 648 healthy controls and 617 schizophrenic patients was genotyped for single-nucleotide polymorphisms (SNPs) rs3957357 in GSTA1 and rs736775 in GPX3 using a PCR-LDR genotyping assay. The χ2 test compared differences in genetic distributions between the two groups in a case–control study. The generalized multifactor dimensionality reduction (GMDR) was used to explore the interaction between the GSTA1 gene and the GPX3 gene on the risk of SCZ.ResultsSignificant differences in allelic and genotypic frequencies of GSTA1 rs3957357 were present between SCZ and control groups (GSTA1 rs3957357 χ2=6.172, P=0.046 by genotype, χ2=5.847, P=0.016, odds ratio=1.329, 95% confidence interval=1.055–1.674 by allele). No significant differences in allelic or genotypic frequencies of GPX3 rs736775 were detected between cases and controls (GPX3 rs736775: χ2=2.058, P=0.357 by genotype, χ2=1.853, P=0.173, odds ratio=1.131, 95% confidence interval=0.953–1.342 by allele). Moreover, the GMDR model showed that the interaction between GSTA1 rs3957357 and GPX3 rs736775 was associated significantly with SCZ risk, P=0.0107.ConclusionOur results suggest that GSTA1 rs3957357 SNP has an effect on the risk of SCZ and the interaction between GSTA1 rs3957357and GPX3 rs736775 may affect the development of SCZ in Chinese Han population. However, these results should be validated by replication in different populations with large sample sizes.

Influence of antioxidants' gene variants on risk of diabetes mellitus and its complications: a systematic review.

Oxidative stress has a key role in pathophysiology of type 2 diabetes mellitus (T2DM) and its complications as a most common health problem. Due to controversial evidence regarding the association between antioxidants' gene varients and T2DM, our aim was a systematic review of the current meta-analyses. All meta-analysis' studies which assessed the association of single nucleotide polymorphisms of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX), glutathione S transferase (GST), nitric oxide synthase (NOS) and nicotinamide adenine dinucleotide phosphate oxidase (NOX) with T2DM and its complications were systematically extracted from PubMed, Scopus and Web of Science databases up to January 2016. Results are reported according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). Among 131 articles recorded in initial search, 19 studies were in the topic just for eNOS (endothelial NOS), NOX, GST and SOD gene variants. G894T, 4b/a and T-786C variants (eNOS) were associated with DN (diabetic nephropathy). However no association between 4b/a variant and DR (diabetic retinopathy) was observed. Separate or combination of GSTM1 and GSTT1 null genotypes (GST gene) were associated with T2DM. GSTM1 and combination of GSTM1/GSTT1 null genotypes were associated with DN. Significant association between C242T variant (NOX) and T2DM or DN, and non-significant association with carotid atherosclerosis were seen. C allele of C47T variant (SOD) was protective against DN, DR and microvascular complications of diabetes. Finding gene polymorphisms involved in diabetes and its complications might be helpful in discovering new therapeutic approaches, as well as prevention which is currently as a main focus in personalized medicine.

Role of glutathione S-transferases polymorphisms and monocyte CD64 expression in Egyptian patients with systemic lupus erythematosus

Aim of workTo study the genetic variants of glutathione S-transferases and monocyte CD64 expression in systemic lupus erythematosus patients and to evaluate their role in disease susceptibility, activity and damage. Patients and methodsForty female SLE patients and 40 age matched controls were genotyped for GSTP1, GSTM1 and GSTT1 gene polymorphisms using polymerase chain reaction-restriction fragment length polymorphism, conventional PCR and were assessed for monocyte CD64 expression level using flow cytometry. SLE disease activity index (SLEDAI) and the systemic lupus international. collaborating clinics/damage index (SLICC DI) were considered. ResultsThe patients mean age was 28.13±4.56years and disease duration of 6.4±4.9 with a SLEDAI of 14.4±7.1 and SLICC/DI 3.7±1.5. The frequency of GSTM1 null genotype tended to be higher (55%) in SLE patients compared to the controls (and 42.5%) (p=0.09). The frequency of GSTT1 null genotype was significantly higher in SLE patients (25%) compared to controls (12.5%) (p<0.001) and with a 1.7-fold risk. The genotypes frequencies of GSTP1 polymorphism were comparable between SLE patients and controls. The monocyte CD64 expression was significantly increased in the patients (MFI: 46.23±4.56) compared to the control (MFI: 14.05±2.01) (p=0.001). The GSTM1 and GSTT1 as well as CD64 significantly correlated with the serum creatinine (p=0.005, p=0.01 and p-0.001, respectively). ConclusionThe GST gene polymorphisms together with monocyte CD64 expression level could have a significant relation with SLE and with increased risk in Egyptian patients. The GST gene polymorphisms and monocyte CD64 may form potential biomarkers for renal function.

Effect of GST variants on lung function following diesel exhaust and allergen co-exposure in a controlled human crossover study

BackgroundIsolated exposure to diesel exhaust (DE) or allergen can cause decrements in lung function that are impacted by the presence of genetic variants in the glutathione-S-transferase (GST) family but the effect of GST interactions with DE-allergen co-exposure on lung function is unknown. We aimed to assess the impact of DE and allergen co-exposure on lung function and the influence of GSTM1 or GSTT1 variation MethodsWe used a blinded crossover study design with 17 atopic subjects exposed to filtered air (FA; the control for DE) or DE for 2h. One hour following each exposure to DE or FA, bronchoscopy was performed to deliver a diluent-controlled segmental allergen challenge (SAC). Methacholine challenge and forced expiratory volume in 1s (FEV1) was performed pre-exposure (baseline airway responsiveness) and 24h post-exposure (effect of co-exposure). Additionally, FEV1 was performed hourly after DE/FA exposure and protein carbonyl content was measured in plasma as an oxidative stress marker. ResultsChanges in FEV1 from baseline were dependent on time following allergen exposure. DE, as opposed to FA, led to a significant change in FEV1 at 2h post-allergen exposure in GSTT1 variants only (24.5±19.6% reduction in GSTT1 null individuals vs. 9.2±7.3% reduction in GSTT1 present individuals). Moreover, plasma protein carbonyl level 4h after co-exposure was higher in the individuals who have the GSTT1 null genotype. ConclusionsThis suggests a gene-environment interaction that endangers susceptible populations co-exposed to DE and allergen.

Glutathione S-transferases variants as risk factors in Alzheimer's disease.

Glutathione S-transferase (GST) was suggested as an important contributor to Alzheimer's disease (AD). The GSTs polymorphisms have been investigated as candidate genetic risk factors for AD, yet results remained uncertain. Therefore, we performed a meta-analysis to clarify the relationship of GSTs polymorphismswith the occurrence of AD. PubMed, Embase, Cochrane library and Alzgene databaseswere searched and potential literatures were selected. Pooled analyses and subgroup analyses were conducted, and also publication bias tests and cumulative meta-analysis. This meta-analysis suggested null associations between polymorphisms of GSTM1, GSTT1, GSTM3, GSTP1, GSTO1 and AD risk. GSTs variants may not have an impact on the morbidity of Alzheimer's disease. Further well designed researches are required to confirm these findings of the current study.

Genetic polymorphisms of glutathione S-transferases and cytochrome P450 enzymes as susceptibility factors to systemic lupus erythematosus in southern Brazilian patients.

Systemic lupus erythematosus (SLE) is an autoimmune chronic inflammatory disease that presents several clinical manifestations, affecting multiple organs and systems. Immunological, environmental, hormonal and genetic factors may contribute to disease. Genes and proteins involved in metabolism and detoxification of xenobiotics are often used as susceptibility markers to diseases with environmental risk factors. Cytochrome P450 (CYP) enzymes activate the xenobiotic making it more reactive, while the Glutathione S-transferases (GST) enzymes conjugate the reduced glutathione with electrophilic compounds, facilitating the toxic products excretion. CYP and GST polymorphisms can alter the expression and catalytic activity of enzymes. This study aimed to investigate the role of genetic variants of CYP and GST in susceptibility and clinical expression of SLE, through the analysis of GSTM1 null, GSTT1 null, GSTP1*Ile105Val, CYP1A1*2C and CYP2E1*5B polymorphisms. 371 SLE patients from Hospital de Clínicas de Porto Alegre and 522 healthy blood donors from southern Brazil were evaluated. GSTP1 and CYP variants were genotyped using PCR-RFLP and GSTT1 and GSTM1 variants were analyzed by multiplex PCR. Among European-derived individuals, a lower frequency of GSTP1*Val heterozygous genotypes was found in SLE patients when compared to controls (p = 0.005). In African-derived SLE patients, the CYP2E1*5B allelic frequency was higher in relation to controls (p = 0.054). We did not observe any clinical implication of the CYP and GST polymorphisms in patients with SLE. Our data suggest a protective role of the GSTP1*Ile/Val heterozygous genotype against the SLE in European-derived and a possible influence of the CYP2E1*5B allele in SLE susceptibility among African-derived individuals.

Functional variability of glutathione S‐transferases in basque populations

Glutathione S-transferases (GSTs) are enzymes involved in Phase II reactions. They play a key role in cellular detoxification. Various studies have shown that genes coding for the GST are highly polymorphic and some of these variants are directly associated with a decrease of enzyme activity making individuals more susceptible to different clinical phenotypes. The aim of this study is to investigate the genetic variability of GST genes among human populations. We have focused our attention on the polymorphic variants of the GSTA1, GSTM1, GSTO1, GSTO2, GSTP1, GSTT1, and GSTT2B genes. These polymorphisms were analyzed in a whole sample of 151 individuals: 112 autochthonous Navarrese Basques, and 39 non-autochthonous Navarrese Basques. DNA extraction from plasma was performed by using the phenol:chloroform:isoamylic alcohol method. Genotyping of the gene polymorphisms was performed by PCR Multiplex and the PCR-RFLP method. We applied correspondence analysis and built frequency-maps to compare the genetic structure in worldwide populations. Our results were compared with data available on the Human Genome Diversity Project (HGDP) and on the 1,000 Genomes Project to obtain information on the functional variability of GSTs in Basques. Our data indicated that Basque communities showed a higher differentiation of certain functional GST variants (i.e., GSTM1-positive/null genotype, GSTP1*I105V, and GSTT2B*1/0) than other European and Mediterranean populations. This might account for epidemiological differences in the predisposition to diseases and drug response among Basques and could be used to design and interpret genetic association studies for this particular population.

Expression of glutathione S-transferase variants in human airway wall after long-term response to sulfur mustard

Context: Sulfur mustard (SM) is an alkylating agent identified as a potent chemical warfare agent. More recently, SM was used in the Iraq conflict against Iranian troops and civilians. At present, there are many people suffering from chronic obstructive pulmonary disease (COPD) due to mustard gas in Iran. SM increases the endogenous production of reactive oxygen species (ROS). The oxidant/antioxidant imbalance present in the lungs of these patients also results from the impaired capacity of the antioxidant/detoxification enzymes to detoxify the harmful reactive oxygen metabolites. Objective: One of the major antioxidants in human airways is glutathione S-transferase. They facilitate the detoxification of various environmental of oxidative stress. In this study, we attempted to understand the significance different in expression of GSTs in airway wall of chemical patients and control. Materials and methods: Seven normal and 20 SM induced COPD individuals were studied. Bronchoscopy was performed in all subjects and two specimens were taken from the main bronchus for mRNA extraction, PCR analysis and immunohistochemistry. Results: SM-induced COPD individuals showed expression of GSTA1 2.51 ± 0.83-, GSTM1 2.84 ± 1.71- and GSTP1 5.61 ± 2.59-folds higher than those of controls that revealed. GSTP1-immunoreactivity was strongly expressed in luminal border of normal samples. SM patient samples immunoreactivity for GSTP1 in the same area were negative. Discussion and conclusion: According to these findings, we speculated that overexpression of GSTs mRNA in patients revealed that GSTs plays an important role in cellular protection against oxidative stress of MS in airway wall of patients.

Modifying roles of glutathione S-transferase polymorphisms on the association between cumulative lead exposure and cognitive function

BackgroundGlutathione-S-transferase gene (GST) polymorphisms can result in variable ability of these enzymes to remove electrophilic substrates. We investigated whether the GSTP1 Val105 and GSTM1 deletion polymorphisms modify the lead-cognitive function association. MethodsWe used repeated measures analysis to compare the association between cumulative lead biomarkers—bone lead measured using K-shell X-Ray Fluorescence—and Mini-Mental State Exam (MMSE) score by GST variants, adjusted for covariates, among Normative Aging Study participants, a Boston-based prospective cohort of men. We had complete data for 698 men (providing 1292 observations) for GSTM1 analyses and 595 men (providing 1142 observations) for GSTP1 analyses. ResultsA 15μg/g higher tibia lead concentration (interquartile range of tibia lead) was associated with a 0.24 point decrement in MMSE score among GSTP1 Val105 variant carriers, which was significantly stronger than the association among men with only wild-type alleles (p=0.01). The association among GSTP1 Val105 carriers was comparable to that of 3 years of age in baseline MMSE scores. The association between tibia lead and MMSE score appeared progressively steeper in participants with increasingly more GSTP1 Val105 alleles. A modest association between tibia lead and lower MMSE score was seen among participants with the GSTM1 deletion polymorphism. Neither of the glutathione S-transferase variants was independently associated with cognitive function, nor with lead biomarker measures. The results pertaining to patella lead were similar to those observed for tibia lead. ConclusionOur results suggest that the GSTP1 Val105 polymorphism confers excess susceptibility to the cognitive effects of cumulative lead exposure.

Nullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease

Genetic and environmental factors affect the pathogenesis of Parkinson's disease (PD). Genetic variants of the enzyme glutathione S-transferases (GST) may be related to the disease. This study aimed to evaluate the influence of genetic variants of GST (GSTT1/GSTM1) and their association with the exposure to environmental toxins in PD patients. We studied 254 patients with PD and 169 controls. The GSTM1/GSTT1 variants were analyzed by polymerase chain reaction. We applied the Fisher's exact test and the χ2 test for statistical analysis (p<0.05). The present and absence for GSTT1 and GSTM1 were similar in patients and controls. The null for GSTT1 and GSTM1 (0/0) and exposure to pesticides prevailed in patients (18%) compared to controls (13%, p=0.014). This study suggests the association between PD and previous exposure to pesticides, whose effect may be enhanced in combination with null for GSTT1/GSTM1.

Interaction between glutathione S‐transferase variants, maternal smoking and childhood wheezing changes with age

Maternal smoking increases the risk of respiratory symptoms in children. Glutathione S-transferases (GSTs) detoxify xenobiotics from tobacco smoke, and functional polymorphism in GST gene(s) could predispose children to the detrimental effects of maternal smoking. Our objective was to investigate interactions between GST variants and maternal smoking in relation to the development of wheezing during childhood and whether any such interaction changes with time. In a population-based birth cohort, we assessed maternal smoking and current wheeze at five time points during the first 11 yr of life. DNA was genotyped for GSTP1, GSTM1 and GSTT1 (n = 807). Longitudinal analyses were performed using generalized estimating equations. During early childhood, children whose mothers smoked were more likely to wheeze, with the strongest association observed at age 3 yr (p = 0.006). In a longitudinal model, children with GSTP1 AA and AG genotypes had significantly higher risk of wheeze compared with GG homozygotes. We observed a significant interaction between GSTP1 and maternal smoking where the risk of infantile wheezing was significantly increased in AA homozygotes, but only if their mothers smoked (OR 2.59, [1.08-6.21], p(int) = 0.03). Furthermore, amongst AA carriers, there was a significant interaction between child's age and maternal smoking, with the effect of maternal smoking on the risk of wheeze significantly diminishing with age (p(int) = 0.05); no such findings were observed for GSTM1 and GSTT1. Children with AA genotype for GSTP1 are at increased risk of early-life wheezing if their mothers smoke, but the effect of maternal smoking on wheezing diminishes with time.

Hypertensive nephrosclerosis: not enough of a good thing?

glutathione s -transferases (GSTs) are multifunctional enzymes that are perhaps best known to participate in cell detoxification by catalyzing the conjugation of reduced glutathione to a wide variety of xenobiotics that have electrophilic centers. Production of these adducts promotes cytoprotection

Glutathione S-transferase M1, T1, and P1 polymorphisms and risk of glioma: a meta-analysis

The relationship between genetic polymorphisms of glutathione S-transferase (GST) and the development of glioma has been investigated in several epidemiologic studies. However these studies report inconsistent results. In order to quantitatively summarise the evidence for such a relationship, a meta-analysis is conducted. The PubMed database was searched from inception to January 2012 to identify relevant studies that met pre-stated inclusion criteria. We also reviewed reference lists from retrieved articles. Two researchers evaluated study eligibility and extracted the data independently, and disagreements were resolved by discussion. The principal outcome measure was the odds ratio (OR) with 95% confidence interval (CI) for the risk of glioma associated with GSTM1, GSTT1, GSTP1 I105V or GSTP1 A114V. This meta-analysis included 11 case-control studies, which included 2,404 glioma cases and 6,379 controls. The combined results based on all studies showed that there was no association between any of the GST variants and the risk of glioma (for GSTM1: pooled OR=1.03; 95% CI, 0.92-1.15; for GSTT1: pooled OR=1.12; 95% CI, 0.90-1.40; for GSTP1 I105V: pooled OR=0.92; 95% CI, 0.64-1.31 and for GSTP1 A114V: pooled OR=1.14; 95% CI, 0.97-1.34). Subgroup analyses showed that GSTP1 A114V genotype was associated with an increased risk of other histopathologic glioma except glioblastoma multiforme (GBM) (pooled OR=1.30; 95% CI=1.06-1.60); no relationship was found between other GST variants and histopathologic groups. In conclusion, our meta-analysis suggests no association between GST variants and the risk of glioma. However, the significant risk elevation is present between GSTP1 A114V genotype and other histopathologic glioma except GBM.

Relevance of GSTM1, GSTT1, and GSTP1 gene polymorphisms to gastric cancer susceptibility and phenotype

Human glutathione S-transferases (GSTs) are phase II metabolizing enzymes that play a key role in protecting against cancer by detoxifying numerous potentially cytotoxic/genotoxic compounds. The genes encoding the human GST isoenzymes GSTM(mu)1, GSTT(theta)1 and GSTP(pi)1 harbour polymorphisms, which have been considered important modifiers of the individual risk for environmentally induced cancers such as gastric cancer (GC). However, results are inconsistent among studies from different geographic areas and ethnic groups. Our goal was to perform a nationwide, case-control study in Spain to evaluate the relevance of several functional GST gene polymorphisms and environmental factors to GC risk and phenotype. DNA from 557 GC patients and 557 sex- and age-matched healthy controls (HC) was typed for two deletions in the GSTM1 and GSTT1 genes and two SNPs in the GSTP1 gene (rs1695 and rs1138272) using polymerase chain reaction-restriction fragment length polymorphism methods. Logistic regression analysis identified Helicobacter pylori infection with CagA strains [odds ratio (OR): 2.36; 95% confidence interval (CI): 1.78-3.15], smoking habit (OR: 2.10; 95% CI: 1.48-2.97) and family history of GC (OR: 3.2; 95% CI: 2.02-5.16) as independent risk factors for GC. No differences in the frequencies of GSTM1 or GSTT1 null genotypes were observed between cases and controls (GSTM1: 50.8% vs. 48%; GSTT1: 21.5% vs. 21%). Moreover, simultaneous carriage of both, the GSTM1 and the GSTT1 null genotypes, was almost identical in both groups (10.7% in GC vs. 10.6% in HC). In addition, no significant differences in GSTP1 Ile105Val (rs1695) and GSTP1 Val114Ala (rs1138272) genotype distribution were observed between GC patients and controls. Subgroup analysis for age, gender, Helicobacter pylori status, smoking habits, family history of GC, anatomic location and histological subtype revealed no significant association between GST variants and GC risk. Our results show that the GST polymorphisms evaluated in this study are not relevant when determining the individual susceptibility to GC or phenotype in a South-European population.

An Updated Pooled Analysis of Glutathione S-transferase Genotype Polymorphisms and Risk of Adult Gliomas

Glutathione S-transferases (GSTs) are multifunctional enzymes that play a crucial role in the detoxification of both the endogenous products of oxidative stress and exogenous carcinogens. Recent studies investigating the association between genetic polymorphisms in GSTs and the risk of adult brain tumors have reported conflicting results. The rationale of this pooled analysis was to determine whether the presence of a GST variant increases adult glioma susceptibility by combining data from multiple studies. In our meta-analysis, 12 studies were identified by a search of the MEDLINE, HIGHWIRE, SCIENCEDIRECT and EMBASE databases. Of those 12, 11 evaluated GSTM1, nine evaluated GSTT1 and seven evaluated GSTP1 Ile105Val. Between-study heterogeneity was assessed using χ2-based Q statistic and the I2 statistic. Crude odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to estimate the association between GSTM1, GSTT1 and GSTP1 polymorphisms and the risk of adult gliomas. The quantitative synthesis showed no significant evidence to indicate an association exists between the presence of a GSTM1, GSTT1 or GSTP1 Ile105Val haplotype polymorphism and the risk of adult gliomas (OR, 1.008, 1.246, 1.061 respectively; 95% CI, 0.901-1.129, 0.963-1.611, 0.653-1.724 respectively). Overall, this study did not suggest any strong relationship between GST variants or related enzyme polymorphisms and an increased risk of adult gliomas. Some caveats include absence of specific raw information on ethnic groups or smoking history on glioma cases in published articles; therefore, well-designed studies with a clear stratified analysis on potential confounding factors are needed to confirm these results.

Childhood brain tumors and maternal cured meat consumption in pregnancy: differential effect by glutathione S-transferases.

Some epidemiologic studies suggest that maternal consumption of cured meat during pregnancy may increase risk of brain tumors in offspring. We explored whether this possible association was modified by fetal genetic polymorphisms in genes coding for glutathione S-transferases (GSTs) that may inactivate nitroso compounds. We assessed six GST variants: GSTM1 null, GSTT1 null, GSTP1(I105V) (rs1695), GSTP1(A114V) (rs1138272), GSTM3*B (3-bp deletion), and GSTM3(A-63C) (rs1332018) within a population-based case-control study with data on maternal prenatal cured meat consumption (202 cases and 286 controls born in California or Washington, 1978-1990). Risk of childhood brain tumor increased with increasing cured meat intake by the mother during pregnancy among children without GSTT1 [OR = 1.29; 95% confidence interval (95% CI), 1.07-1.57 for each increase in the frequency of consumption per week] or with potentially reduced GSTM3 (any -63C allele; OR = 1.14; 95% CI, 1.03-1.26), whereas no increased risk was observed among those with GSTT1 or presumably normal GSTM3 levels (interaction P = 0.01 for each). Fetal ability to deactivate nitrosoureas may modify the association between childhood brain tumors and maternal prenatal consumption of cured meats. These results support the hypothesis that maternal avoidance during pregnancy of sources of some nitroso compounds or their precursors may reduce risk of brain tumors in some children.