Glutathione S-transferase T1 Null Polymorphism Research Articles

SNP’s in xenobiotic metabolism and male infertility

1. Glutathione S-transferases (GST) and cytochrome P450s (CYPs) are xenobiotic metabolizing enzymes participating in the protection of cell. The present study aimed to investigate the relationship between polymorphisms of glutathione S-transferase M1 (GSTM1) null, glutathione S-transferase T1 (GSTT1) null, glutathione S-transferase P1 (GSTP1) Ile105Val, cytochrome P450 1A2 (CYP1A2) 734 C→A, cytochrome P450 2D6 (CYP2D6) 1934 G→A and male infertility.2. A total of 306 azoospermic or oligozoospermic infertile men and 129 normozoospermic or fertile controls were enrolled in the study. Multiplex polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism methods were used for genotyping. There was a significant relationship between male infertility and CYP2D6 GG genotype (p < 0.001). CYP1A2 AA genotype was slightly higher in the infertile group (p = 0.056).3. There was no association between GSTT1 null polymorphisms and male infertility (p = 0.068), GSTM1 null (p = 0.843) and GSTP1 Ile105Val (p = 0.192) genes. GSTM1 null genotype frequency was higher in azoospermic men (p = 0.009). Men carrying CYP1A2 AA genotype had higher risk of infertility risk (OR = 3.14; %95 CI = 1.16–8.54) in the smoker group.4. Our results demonstrated that polymorphisms of CYP2D6 and CYP1A2 may play a role in idiopathic male infertility in our sample population.

Glutathione S-Transferase T1 (GSTT1) Null Polymorphism, Smoking, and Their Interaction in Coronary Heart Disease: A Comprehensive Meta-Analysis.

The association between glutathione S-transferase T1 (GSTT1) null polymorphism and coronary heart disease (CHD) is inconsistent among studies, and data on the GSTT1 null genotype-smoking interplay in CHD is lacking. We conducted this meta-analysis to investigate the relationship between GSTT1 null polymorphism and CHD and to assess the potential interaction between GSTT1 null genotype and smoking. PubMed and EMBASE databases were searched up to 27 January 2016 using the appropriate terms. Odds ratios were pooled using either fixed-effects or random-effects models. Twenty-nine articles including 31 studies with 15,004 cases and 35,597 controls were eligible. The random-effects model showed that the GSTT1 null genotype was associated with increased CHD risk (OR=1.213, 95%CI: 1.004-1.467; I2=90.4%). After excluding 10 studies detected by Galbraith plot, the fixed effects summary estimate also showed an increased risk of CHD (OR=1.14, 95% CI: 1.06-1.22; I2=27.7%). A case-only analysis including eight studies showed a statistically significant positive interaction between GSTT1 null polymorphism and smoking status on CHD (OR=1.34, 95% CI: 1.09-1.64; I2=0%). Sensitivity analyses further supported the associations. No publication bias was observed. This meta-analysis suggests that GSTT1 null polymorphism is associated with the risk of CHD. To our knowledge, this is the first meta-analysis to prove a positive effect of the interaction between GSTT1 null genotype and smoking status on the risk of CHD. Future studies with detailed individual information are needed to confirm our findings.

Associations Among Glutathione S-Transferase T1, M1, and P1 Polymorphisms and the Risk of Oral Leukoplakia.

The potential association between glutathione S-transferase (GST) M1, T1, P1 polymorphisms and the risk of oral leukoplakia (OLK) has been extensively studied. However, the results of previous studies have been contradictory. In an effort to resolve these different findings we performed a meta-analysis. Eligible articles were identified by a search of PubMed, the China National Knowledge Infrastructure (CNKI), MEDLINE, EMBASE, and the Web of Science databases through December 1, 2015. Crude odds ratios (ORs) with 95% confidence intervals were used to evaluate the risk of OLK by tobacco use, ethnicity, and OLK subtype. A total of 3122 cases and 6037 controls were included in the meta-analysis. The results indicated that the glutathione S-transferase Mu1 (GSTM1) and glutathione S-transferase T1 (GSTT1) null polymorphisms increase the risk of OLK (OR = 1.838, 95% CI = 1.582-2.134 and OR = 1.337, 95% CI = 1.132-1.579, respectively), especially in the groups with tobacco use (OR = 2.478, 95% CI = 2.032-3.020 and OR = 2.034, 95% CI = 1.486-2.783, respectively). Conversely the glutathione S-transferase P1 (GSTP1) polymorphism did not demonstrate a significant relationship with OLK risk (OR = 1.139, 95% CI = 0.900-1.442). The GSTM1 and GSTT1 null polymorphisms were identified as being significantly associated with an increased risk of OLK within the German and Indian populations: German subgroup (GSTM1: OR = 11.555, 95% CI = 7.465-17.884), Indian subgroup (GSTM1: OR = 1.333, 95% CI = 1.084-1.638; GSTT1: OR = 1.332, 95% CI = 1.057-1.679). Our findings provide evidence that the GSTT1 and GSTM1 null polymorphisms may be risk factors of OLK, especially for persons who use tobacco, whereas the GSTP1 polymorphism does not contribute to the development of OLK. Thus, detection of GSTT1 and GSTM1 null polymorphisms may be promising biomarkers for the OLK susceptibility.

Glutathione S-transferase T1 and myeloperoxidase -463 G>A genotypes in lung cancer patients of Kumaun region.

Background:Null genetic polymorphism of Glutathione S-transferase T1 (GSTT1) and -463 G>A promoter polymorphism of myeloperoxidase (MPO) were studied for association with lung cancer.Materials and Methods:In a case- control study 26 lung cancer patients and 33 healthy individuals from hilly Kumaun region of northern India were investigated. DNA was extracted from peripheral blood. GSTT1 null polymorphism was detected by duplex PCR, and MPO polymorphism was detected by performing PCR-RFLP.Results:An increased but statistically non- significant risk for lung cancer was found for GSTT1 null genotype. No association for MPO -463G>A genotype was evident.Conclusion:Further study with large sample size may reveal such association in this population.

Quantitative assessment of the influence of glutathione S-transferase T1 null variant on gastric cancer risk

Glutathione S-transferase T1 (GSTT1) catalyzes reactions between glutathione and lipophilic compounds with electrophilic centers, leading to neutralization of toxic compounds, xenobiotics, and products of oxidative stress. In the past decade, a number of case-control studies have been carried out to investigate the relationship between the GSTT1 null polymorphism and gastric cancer (GC), but the results have been inconclusive. To investigate this inconsistency, we performed a meta-analysis of 46 studies involving a total of 9012 GC cases and 14,215 controls for null variant of the GSTT1 gene to evaluate the effect of GSTT1 on genetic susceptibility for GC. Potential sources of heterogeneity including ethnicity, source of control, and sample size were also assessed. Overall, significantly increased GC risk was associated with GSTT1 null polymorphism with OR of 1.20 (95% CI, 1.10-1.32; P < 0.05). In the subgroup analysis by ethnicity, significantly increased risks were found in East Asians and Indians, while no significant associations were found among Caucasian, and Middle Eastern and African populations. By pooling data from 19 studies that considered combinations of GSTT1 and GSTM1 genotypes, a statistically significant increased risk for GC (OR = 2.04, 95% CI, 1.49-2.64; P < 0.05) was detected for individuals with dual deletion in both genes compared with positive genotypes. In addition, we found that cigarette smoking and alcohol drinking may modified the association of GSTT1 null genotypes with the risk of GC. In conclusion, this meta-analysis suggests that GSTT1 null polymorphism is associated with elevated GC risk, but these associations vary in different ethnic populations.

GSTT1 null genotype contributes to hepatocellular carcinoma risk: a meta-analysis

Studies investigating the association between genetic polymorphism of glutathione S-transferase T1 (GSTT1) and hepatocellular carcinoma (HCC) risk have reported conflicting results. Therefore, we conducted this meta-analysis to provide more precise evidence. Databases including PubMed, Embase, SCOPUS, ISI Web of Science, and Wangfang were searched for relevant studies. Potential sources of heterogeneity were also assessed by subgroup analysis. Funnel plots and Egger's linear regression were used to test publication bias among the articles. Finally, a total of 28 studies involving 3,897 HCC patients and 6,117 controls were included in this meta-analysis. In a combined analysis, the summary odds ratio for HCC of the GSTT1 null genotype was 1.43 (95% confidence interval (CI) 1.22–1.68, P < 10(−5)). In the subgroup analysis by ethnicity, significantly increased risks were found in East Asians for GSTT1 null polymorphism, while no significant associations were found among Caucasian, South Asian, and African populations. When stratified by a source of controls, both population- and hospital-based studies get consistent positive results. By pooling data from 10 studies (1,639 cases and 2,224 controls) that considered combinations of GSTT1 and GSTM1 genotypes, a statistically significant increased risk for HCC (odd ratio = 1.85, 95% CI 1.37–2.49) was detected for individuals with combined deletion mutations in both genes compared with positive genotypes. No evidence of publication bias was observed. Our result suggests that the GSTT1 null genotype contributes to an increased risk of HCC in East Asians and that interaction between unfavorable GSTs genotypes may exist.

Association of glutathione S-transferase M1 and T1 null polymorphisms with the development of cervical lesions: a meta-analysis

ObjectivesAn accumulation of evidence suggests that gene-based self-susceptibility may contribute to the development of cancer. Some studies have found that particular polymorphisms of the glutathione S-transferase M1 and T1 genes are associated with increased risk of cervical lesions, but other studies have had contrary results. The present meta-analysis evaluated the association of glutathione S-transferase M1 and T1 null polymorphisms with the development of cervical lesions. In addition, stratified analyses were performed in an attempt to identify any race-specific effects. Study designTwenty-one related studies were included in the meta-analysis, comprising glutathione S-transferase M1 data from 1423 patients with cervical lesions and 2415 healthy matched controls, and glutathione S-transferase T1 data from 2081 patients with cervical lesions and 2287 healthy matched controls. The fixed-effect model (Mantel–Haenszel method) and the random-effect (DerSimonian and Laird) model were used to examine the difference in frequency of glutathione S-transferase M1 and T1 null polymorphisms between pre- and invasive cervical lesions. Subgroup analyses were also conducted to evaluate any race-specific effect on the frequencies of glutathione S-transferase polymorphisms in cervical lesions. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. Heterogeneity was assessed using the heterogeneity metric (I2) and Chi-squared test. ResultsThe glutathione S-transferase M1 null polymorphism was associated with increased risk of low-grade intra-epithelial lesions (OR 1.37, 95% CI 1.05–1.77), but no increased risk of high-grade intra-epithelial lesions (OR 1.29, 95% CI 0.87–1.8) or invasive cervical cancer (OR 1.20, 95% CI 0.99–1.46). The association seemed to be confined to Southeast Asians (OR 1.97, 95% CI 1.44–2.71). No significant associations were found for the glutathione S-transferase T1 null polymorphism for any of the populations. ConclusionsThe glutathione S-transferase M1 null polymorphism significantly increases susceptibility to early-stage cervical lesions in Southeast Asians. However, the glutathione S-transferase T1 null polymorphism does not appear to be a risk factor for cervical lesions in any population.

Stratification for smoking in case-cohort studies of genetic polymorphisms and lung cancer

The risk estimates obtained in studies of genetic polymorphisms and lung cancer differ markedly between studies, which might be due to chance or differences in study design, in particular the stratification/match of comparison group. The effect of different strategies for stratification and adjustment for smoking on the estimated effect of polymorphisms on lung cancer risk was explored in the case-cohort design. We used an empirical and a statistical simulation approach. The stratification strategies were: no smoking stratification, stratification for smoking status and stratification for smoking duration. The study base was a prospective follow-up study with 57,053 participants. In the simulation approach the glutathione S-transferase T1 null polymorphism, as a model of any polymorphism, was added to simulated data in two different ways, assuming either absence or presence of association with smoking. In the empirical approach the risk estimates of the investigated polymorphisms differed between the three different stratification strategies. Simulated data with neither stratification nor adjustment for smoking resulted in low biases and narrow confidence intervals (CI) in the absence of a genotype-smoking association and markedly higher biases in the presence of a genotype-smoking association. In study designs stratified by smoking, low biases and narrow CI spans were found, regardless of a genotype-smoking association. Stratification for smoking seems to be advantageous in case-cohort studies of genetic polymorphisms and lung cancer.

An association study of sodium-lithium countertransport activity with glutathione S transferase (GST) T1 and GST M1 null polymorphisms in Greek dyslipidaemic patients and controls

Previous genomic linkage studies have produced evidence linking sodium-lithium countertransport activity (Na/Li CT) with various chromosomal regions including loci harbouring glutathione S transferase (GST) genes. The aim of this study was to examine the putative association of erythrocyte Na/Li CT activity with GST T1 and M1 gene null polymorphisms. Na/Li CT activity was determined in erythrocytes isolated from 85 individuals, using a standard assay procedure employing atomic absorption spectroscopy. Genotyping of the GST T1 and GST M1 null polymorphisms was accomplished with a multiplex PCR method. A general linear model using age, sex, smoking, dyslipidaemia and hypertension as covariates was used to examine the association of Na/Li CT activity with the GST T1 and GST M1 genotypes. Individuals with the GST T1 null genotype displayed marginally significantly (p=0.049) lower values of Na/Li CT activity compared to those harbouring at least one copy of the GST T1 gene. The significance of this association was eliminated following adjustment for covariates (p=0.150), but survived as a trend when the sample was limited to normotensive and normolipidaemic individuals (p=0.070). No association was detected between the GST M1 null polymorphism and Na/Li CT activity. The suggestive association of the GST T1 null polymorphism with erythrocyte Na/Li CT activity is in line with previously published data from genetic linkage and biochemical analyses and may be of potential prognostic value as regards the behaviour of the countertransport and the development of related pathologies under conditions of oxidative insult.

Exploring SNP‐SNP interactions and colon cancer risk using polymorphism interaction analysis

Several single nucleotide polymorphisms (SNPs) in genes derived from distinct pathways are associated with colon cancer risk; however, few studies have examined SNP-SNP interactions concurrently. We explored the association between colon cancer and 94 SNPs, using a novel approach, polymorphism interaction analysis (PIA). We developed PIA to examine all possible SNP combinations, based on the 94 SNPs studied in 216 male colon cancer cases and 255 male controls, employing 2 separate functions that cross-validate and minimize false-positive results in the evaluation of SNP combinations to predict colon cancer risk. PIA identified previously described null polymorphisms in glutathione-S-transferase T1 (GSTT1) as the best predictor of colon cancer among the studied SNPs, and also identified novel polymorphisms in the inflammation and hormone metabolism pathways that singly or jointly predict cancer risk. PIA identified SNPs that may interact with the GSTT1 polymorphism, including coding polymorphisms in TP53 (Arg72Pro in p53) and CASP8 (Asp302His in caspase 8), which may modify the association between this polymorphism and colon cancer. This was confirmed by logistic regression, as the GSTT1 null polymorphism in combination with either the TP53 or the CASP8 polymorphism significantly alter colon cancer risk (p(interaction) < 0.02 for both). GSTT1 prevents DNA damage by detoxifying mutagenic compounds, while the p53 protein facilitates repair of DNA damage and induces apoptosis, and caspase 8 is activated in p53-mediated apoptosis. Our results suggest that PIA is a valid method for suggesting SNP-SNP interactions that may be validated in future studies, using more traditional statistical methods on different datasets.

Glutathione S-transferase T1 null polymorphism and the risk for head and neck cancer

Conclusions. Inter-regional differences in the distribution of genetic polymorphisms in glutathione S-transferases (GSTs) exist, which may have significant effect on the outcome of other GST polymorphism studies. The GSTT1 null genotype appears to be involved in modulation of the risk for head and neck squamous cell carcinoma (HNSCC). Background. The risk of HNSCC is strongly associated with smoking of cigarettes and consumption of alcohol, resulting in a load of toxins/carcinogens. Detoxification of such exogenous harmful compounds often occurs by phase II enzymes such as GSTs. Proper functioning of these enzymes may be deficient due to the presence of particular genetic polymorphisms in these GSTs, and this may increase the risk for HNSCC. We compared the GSTT1, GSTM1 and GSTP1 genotype frequencies in two groups of healthy blood donors, collected from different but adjacent regions in the Netherlands, with those of a group of patients with HNSCC. Subjects and methods. The GSTM1,GSTT1 and GSTP1 genotype frequencies in two Dutch Caucasian control populations (n=207 and n=285) from different but adjacent geographical regions (Maastricht and Nijmegen; distance, 125 km) and 185 patients with HNSCC from the Maastricht region were determined by PCR-related methods. Results. For the occurrence of the GSTT1 null genotype we found a significant difference (p=0.003) between the two control groups (20.3% vs 33.0% null genotype in the Nijmegen and Maastricht control groups, respectively). Since the HNSCC patients were collected from the Maastricht area, comparison with the Maastricht controls reveals a significant difference for GSTT1 null rates, which are lower in patients vs controls (OR = 0.49, CI = 0.32–0.76).