Association between GSTM1 and GSTT1 Allelic Variants and Head and Neck Squamous Cell Cancinoma

Backgrounds

GSTM1 and GSTT1 are involved in the detoxification of carcinogens such as smoking by-products, and polymorphisms in these two genes with a result of loss of enzyme activity may increase risk of carcinogenesis. Although many epidemiological studies have investigated the association between GSTM1 or GSTT1 null genotype and head and neck squamous cell carcinoma (HNSCC), the results remain conflicting. To elucidate the overall association of GSTM1, GSTT1 and HNSCC, we included all available studies and performed this meta-analysis.

Methodology/Principal Findings

A dataset including 42 articles for GSTM1, 32 articles for GSTT1, and 15 articles for GSTM1 and GSTT1 in combination were identified by a search in PubMed. Associations beween HNSCC and polymorphisms of GSTM1 and GSTT1 alone and in combination were analysed by software RevMan 5.1. Stratification analysis on ethnicity and smoking status, sensitivity analysis, heterogeneity among studies and their publication bias were also tested. Association was found in overall analysis between HNSCC and GSTM1 and GSTT1 null genotype. Stratified by ethnicity, we found increased risks of HNSCC in carriers with GSTM1 null genotype in Asian, GSTT1 null genotype in South American, and dual null genotype in European and Asian. When stratified by smoking, a more significant association of GSTM1 null genotype with HNSCC risk was observed in smokers.

Conclusions/Significance

This meta-analysis presented additional evidence of the association between GSTM1 and GSTT1 polymorphisms and HNSCC risk.     

Genetic Polymorphisms of GSTM1, GSTT1, and GSTP1 with Prostate Cancer Risk: A Meta-Analysis of 57 Studies

Background and Objectives

The GSTM1, GSTT1 and GSTP1 polymorphisms might be involved in inactivation of procarcinogens that contribute to the genesis and progression of cancers. However, studies investigating the association between GSTM1, GSTT1 or GSTP1 polymorphisms and prostate cancer (PCa) risk report conflicting results, therefore, we conducted a meta-analysis to re-examine the controversy.

Methods

Published literature from PubMed, Embase, Google Scholar and China National Knowledge Infrastructure (CNKI) were searched (updated to June 2, 2012). According to our inclusion criteria, studies that observed the association between GSTM1, GSTT1 or GSTP1 polymorphisms and PCa risk were included. The principal outcome measure was the odds ratio (OR) with 95% confidence interval (CI) for the risk of PCa associated with GSTM1, GSTT1 and GSTP1 polymorphisms.

Results

Fifty-seven studies involving 11313 cases and 12934 controls were recruited. The overall OR, which was 1.2854 (95% CI = 1.1405–1.4487), revealed a significant risk of PCa and GSTM1 null genotype, and the similar results were observed when stratified by ethnicity and control source. Further, the more important is that the present study first reported the high risks of PCa for people who with dual null genotype of GSTM1 and GSTT1 (OR = 1.4353, 95% CI = 1.0345–1.9913), or who with GSTT1 null genotype and GSTP1 A131G polymorphism (OR = 1.7335, 95% CI = 1.1067–2.7152). But no association was determined between GSTT1 null genotype (OR = 1.102, 95% CI = 0.9596–1.2655) or GSTP1 A131G polymorphism (OR = 1.0845, 95% CI = 0.96–1.2251) and the PCa risk.

Conclusions

Our meta-analysis suggested that the people with GSTM1 null genotype, with dual null genotype of GSTM1 and GSTT1, or with GSTT1 null genotype and GSTP1 A131G polymorphism are associated with high risks of PCa, but no association was found between GSTT1 null genotype or GSTP1 A131G polymorphism and the risk of PCa. Further rigorous analytical studies are highly expected to confirm our conclusions and assess gene-environment interactions with PCa risk.     

GSTT1 and GSTM1 gene polymorphisms in European and African populations

Glutathione S-transferases (GSTs) are a superfamily of detoxificant enzymes. Pharmacogenomic studies have revealed interethnic differences in GST allelic frequencies. This study is focused on GSTT1 (gene deletion, rs17850155, rs2234953, and rs11550605) and GSTM1 (gene deletion) gene frequency distributions in two population samples of Europe origin (Italy, n = 120; Spain, n = 94) and two population samples of Africa origin (Cameroon, n = 126; Ethiopia, n = 153). Detection of GSTT1 and GSTM1 null genotypes was performed by multiplex PCR analysis, while the other GSTT1 gene polymorphisms were detected using allele specific PCR and sequencing. GSTT1 and GSTM1 null frequencies in the samples analyzed fit with the variability range observed in European and African populations, respectively. The SNP analysis in GSTT1 gene did not highlight any nucleotide substitution in 493 individuals analyzed. The comparisons among GSTM1 and GSTT1 null phenotype frequencies in worldwide populations show different patterns between Asians, Africans, and Europeans. Important insights into the effects of GSTM1 and GSTT1 gene deletions on the pathogenesis of human diseases have been hypothesized. Detailed studies on the geography of GST variants could therefore increase knowledge about the relationship between ethnicity and the prevalence of certain diseases.     

Association of glutathione S-transferase polymorphisms (GSTM1 and GSTT1) with primary open-angle glaucoma: An evidence-based meta-analysis

Studies investigating the associations between glutathione S-transferase (GST) genetic polymorphisms and primary open-angle glaucoma (POAG) have reported controversial results. Therefore, a meta-analysis was performed to clarify the effects of GSTM1 and GSTT1 polymorphisms on POAG risk. Published literatures from PubMed, EMBASE, ISI Web of Science and CBM databases were retrieved. All studies evaluating the association between GSTM1/GSTT1 polymorphisms and POAG were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using fixed- or random-effects model. Eleven studies on GSTM1 (1339 cases and 1412 controls) and seven studies on GSTT1 (958 cases, 1003 controls) were included. Overall analysis showed that the association between GSTM1 and GSTT1 null genotype and POAG risk is not statistically significant. Subgroup analyses showed that the null genotype of GSTM1 increased the risk of POAG in Asians. In GSTM1–GSTT1 interaction analysis, individuals with dual null genotype were associated with a significantly increased risk of POAG when compared with the dual present genotype. In conclusion, the present meta-analysis suggested that GSTM1 null genotypes are associated with increased POAG risk in Asian populations but not in Caucasian and mixed populations. Dual null genotype of GSTM1/GSTT1 is associated with increased risk of POAG. Given the limited sample size, the finding on GST polymorphisms needs further investigation.     

Glutathione S-transferases gene polymorphisms and risk of male idiopathic infertility: a systematic review and meta-analysis

The Glutathione S-transferases (GSTs) polymorphisms have been implicated in susceptibility to male idiopathic infertility, but study results are still controversial. To investigate the genetic associations between GSTs polymorphisms and risk of male idiopathic infertility, a systematic review and meta-analysis were performed. Meta-analysis was performed by pooling odds ratio (OR) with its corresponding 95 % confidence interval (95 % CI) form studies in electronic databases up to March 16, 2012. Glutathione S-transferase M 1 (GSTM1) null genotype, Glutathione S-transferase T 1 (GSTT1) null genotype, and dual null genotype of GSTM1/GSTT1 were analyzed independently. 14 eligible studies with a total of 1,845 idiopathic infertility males and 1,729 controls were included. There were 13 studies on GSTM1 polymorphism, 10 ones on GSTT1 polymorphism and 5 ones on GSTM1-GSTT1 interaction analysis. Meta-analyses of total relevant studies showed GSTM1 null genotype was significantly associated with an increased risk of male idiopathic infertility (OR = 1.40, 95 % CI 1.07–1.84, P _OR = 0.015). The GSTM1-GSTT1 interaction analysis showed dual null genotype of GSTM1/GSTT1 was also significantly associated with increased risk of male idiopathic infertility (OR = 1.85, 95 % CI 1.07–3.21, P _OR = 0.028). Subgroup analyses by ethnicity showed the associations above were still statistically significant in Caucasians (For GSTM1, OR = 1.51, 95 % CI 1.11–2.05, P _OR = 0.009; For GSTM1/GSTT1, OR = 2.10, 95 % CI 1.51–2.91, P _OR < 0.001). This meta-analysis suggests GSTM1 null genotype contributes to increased risk of male idiopathic infertility in Caucasians, and males with dual null genotype of GSTM1/GSTT1 are particularly susceptible to developing idiopathic infertility.     

The Leucocyte Telomere Length,GSTM1 and GSTT1 Null Genotypes and the Risk of Chronic Obstructive Pulmonary Disease

Simple SummaryChronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidative stress, both in the airways and blood, and in other organs. Elevated oxidative stress and inflammation have been reported to affect leucocyte telomere length (LTL). We explored the link between GSTM1 and GSTT1 gene polymorphisms, LTL and COPD risk. For GSTM1 and GSTT1, we genotyped 152 COPD patients and 131 non-affected controls, while for TL, we assessed 91 patients and 88 controls. There was a significant difference in GSTM1 null genotype frequency between the patients and controls (0.59 vs. 0.38, p ≤ 0.000), but such was not found for GSTT1 (p = 0.192). COPD patients carrying the GSTM1 null genotype had shorter telomeres compared to those carrying the non-null genotype (15,720 bp vs. 22,442 bp, p = 0.008); and in controls, the opposite occurred (31,354 bp vs. 17,800 bp, p = 0.020). According to our results GSTM1, but not GSTT1, null genotypes might play role in leucocyte telomere shortening, and thus be involved in the pathogenesis of COPD.AbstractChronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidative stress both in the airways and blood and other organs. Elevated oxidative stress and inflammation have been reported to affect leucocyte telomere length (LTL). Glutathione S-transferase (GST) enzymes are a large family of xenobiotic-metabolizing enzymes that utilize different ROS products. We aimed to explore the link between GSTM1 and GSTT1 gene polymorphisms, LTL and COPD risk. For GSTM1, we genotyped 152 COPD patients and 131 non-affected controls; for GSTT1, we genotyped 149 COPD patients and 130 controls. We were able to assess TL for 91 patients and 88 controls. There was a significant difference in the GSTM1 null genotype frequency between the patients and controls (0.59 vs. 0.38, p ≤ 0.000), but such was not found for GSTT1 (p = 0.192). When combining both polymorphisms, we obtained a significantly greater presence of at least one null genotype among patients (0.12 vs. 0.05, p = 0.027). An association between GSTT1 and LTL was not found. COPD patients carrying the GSTM1 null genotype had shorter telomeres compared to those carrying the non-null genotype (15,720 bp vs. 22,442 bp, p = 0.008); as for the controls, it was the opposite (31,354 bp vs. 17,800 bp, p = 0.020). The significance in both groups remained when combining GSTM1 and GSTT1 (COPD (at least one null) 16,409 bp vs. COPD (non-null) 22,092 bp, p = 0.029; control (at least one null) 29,666 bp vs. control (non-null) 16,370 bp, p = 0.027). The total glutathione level in GSTM1 non-null controls was higher compared to the null genotype (15.39 ng/mL vs. 5.53 ng/mL, p = 0.002). In COPD patients, we found no association (p = 0.301). In conclusion, according to our results, GSTM1, but not GSTT1, null genotypes might play a role in leucocyte telomere shortening, and thus be involved in the pathogenesis of COPD.     

Null genotypes of GSTM1 and GSTT1 contribute to increased risk of diabetes mellitus: A meta-analysis

Diabetes mellitus (DM) is a common disease which results from various causes including genetic and environmental factors. Glutathione S-Transferase M1 (GSTM1) and Glutathione S-Transferase T1 (GSTT1) genes are polymorphic in human and the null genotypes lead to the absence of enzyme function. Many studies assessed the associations between GSTM1/GSTT1 null genotypes and DM risk but reported conflicting results. In order to get a more precise estimate of the associations of GSTM1/GSTT1 null genotypes with DM risk, we performed this meta-analysis. Published literature from PubMed, Embase and China Biology Medicine (CBM) databases was searched for eligible studies. Pooled odds ratios (OR) and corresponding 95% confidence intervals (95%CI) were calculated using a fixed- or random-effects model. 11 publications (a total of 2577 cases and 4572 controls) were finally included into this meta-analysis. Meta-analyses indicated that null genotypes of GSTM1/GSTT1 and dual null genotype of GSTM1–GSTT1 were all associated with increased risk of DM (GSTM1: OR _{random-effects} = 1.60, 95%CI 1.10–2.34, P_OR = 0.014; GSTT1: OR _{random-effects} = 1.47, 95%CI 1.12–1.92, P_OR = 0.005; GSTM1–GSTT1: OR _{fixed-effects} = 1.83, 95%CI 1.30–2.59, P_OR = 0.001). Subgroup by ethnicity suggested significant associations between null genotypes of GSTM1 and GSTT1 and DM risk among Asians (GSTM1: OR _{random-effects} = 1.77, 95%CI 1.24–2.53, P_OR = 0.002; GSTT1: OR _{random-effects} = 1.58, 95%CI 1.09–2.27, P_OR = 0.015). This meta-analysis suggests null genotypes of GSTM1/GSTT1 and dual null genotype of GSTM1–GSTT1 are all associated with increased risk of DM, and null genotypes of GSTM1/GSTT1 and dual null genotype of GSTM1–GSTT1 are potential biomarkers of DM.     

Glutathione S-transferase M1 and T1 genotypes and myocardial infarction

Myocardial infarction (MI), which is the most important manifestation of coronary artery disease, is the leading cause of morbidity and mortality in the world. Glutathione S transferases (GSTs) are enzymes responsible for the metabolism of numerous xenobiotics and are known to be polymorphic in humans. We investigated the association between the GSTM1 and GSTT1 gene polymorphisms and MI. The study consists of 296 healthy controls and 324 consecutive patients who had undergone coronary angiography for suspicion of coronary artery disease and with a past history of myocardial infarction. DNA was extracted from whole blood of patient and control. GSTM1 and GSTT1 gene polymorphisms were examined using multiplex PCR. We found that the null GSTM1 was associated with protective effect on MI, although this increase was not significant for GSTM1 (p < 0.054). However, GSTT1 genotype was associated with an increase in the risk of developing MI. In addition to after adjusting other all coronary risk factors, the interactive effect of GSTT1 null genotype remained statistically significant (p < 0.001) for MI disease but GSTM1 null genotype was not statistically significant. Patients, who smoke having the null genotypes of GSTM1, were at a higher risk for developing MI (p < 0.001, OR = 0.41, 95 % CI = 0.240–0.207). There was an effect of interaction of GSTM1 null genotype and smoking on MI development between patient and control groups (p < 0.001). Our results showed that individuals with the null genotypes for GSTM1 had protective effect, while GSTT1 was at a higher risk for MI disease. In addition, there was additional effects of smoking when smoking and non-smoking groups were compared.     

Null Genotypes of GSTM1 and GSTT1 and Endometriosis Risk: A Meta-Analysis of 25 Case-Control Studies

Endometriosis is one of the most frequent benign gynecological disorders. Numerous studies have shown an association between GSTM1 and/or GSTT1 polymorphisms and endometriosis susceptibility. However, these associations remain inconclusive. To derive a more precise estimation, we conducted a comprehensive search to identify all existing studies and then performed a meta-analysis. Electronic literature searches of the PubMed, Chinese Biomedical, and China National Knowledge Infrastructure databases were performed up to December 2013. GSTM1-, GSTT1-, and dual-null genotypes were analyzed independently, and pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated by comparing the null genotype with other genotypes using the random-effects or fixed-effects model. Twenty-five and 16 independent studies on GSTM1 and GSTT1 polymorphisms, respectively, and five GSTM1-GSTT1 interaction analyses were identified and included in this meta-analysis. Both GSTM1- and GSTT1-null genotypes increased risk of endometriosis (OR = 1.54, 95% CI: 1.30–1.83, P<0.001; OR = 1.41, 95% CI: 1.10–1.82, P = 0.007; respectively). Moreover, we found a significant positive association between the dual null genotype GSTM1-GSTT1 and endometriosis susceptibility (OR = 1.33, 95% CI: 1.03–1.72, P = 0.027). This meta-analysis provides evidence that null genotypes of GSTM1 and/or GSTT1 contribute to risk of endometriosis. Further investigations are required to confirm these findings.     

Genetic polymorphism of GST, NAT2, and MTRR and susceptibility to childhood acute leukemia

Polymorphisms of xenobiotic-metabolizing genes correlate with hereditary predisposition to neoplasia in some cases. The frequencies of polymorphisms of xenobiotic-metabolizing genes were determined in 332 children with acute lymphoblastic leukemia, 71 children with acute myelogenous leukemia, and 490 healthy donors by allele-specific hybridization on a biochip. The frequencies of the GSTT1 null genotype and the GSTT1/GSTM1 double null genotype were significantly increased in children with acute leukemia as compared to healthy donors (OR = 1.9, P = 4.7E-5, and OR = 3.1, P = 2.5E-8, respectively). The frequency of NAT2 genotype 341T/T, 481C/C, 590G/G was increased 1.8-fold in children with acute leukemia as compared to healthy controls (P = 0.026). Analysis of gene-gene interactions showed that the combination of NAT2 genotype 341T/T, 481C/C, 590G/G with the GSTT1 and/or GSTM1 null genotypes was significantly more frequent in patients with acute leukemia than in the population control. In addition, the frequency of MTRR genotype 66G/G was reduced in girls with acute leukemia as compared to healthy female donors (OR = 0.50, P = 0.0015). The GSTT1 and/or GSTM1 null genotypes combined with MTRR genotype 66A/-were considered to be a risk factor for acute leukemia in girls. Thus, the polymorphisms of GSTT1, GSTM1, NAT2, and MTRR proved to influence the risk of childhood acute leukemia in residents of European Russia.     

Glutathione S-Transferase Gene Polymorphisms and Treatment Outcome in Cervical Cancer Patients under Concomitant Chemoradiation

Purpose

Cisplatin based concomitant chemoradiation (CRT) is the standard treatment for locally advanced cervical cancer (CC). Glutathione S-transferase (GST), a phase II antioxidant enzyme is induced by oxidative stress generated by drugs and reactive oxidants. The present study was undertaken to evaluate the association of GSTM1, T1 and P1 polymorphisms with the outcome of CRT treatment in CC patients.

Methods

A total of 227 cervical cancer patients with stages IIB-IIIB treated with the same chemoradiotherapy regimen were enrolled and genotyped for GSTM1, T1 and P1 gene polymorphisms by multiplex polymerase chain reaction (mPCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). Overall survival was evaluated using Kaplan-Meier survival function and Cox proportional hazards model. All data were analyzed using SPSS (version 21.0).

Results

Stratified analysis showed that GSTM1 null (M1-) genotype was associated with a significantly better survival among patients with stage IIB cervical cancer (log-rank P = 0.004) than cases with stage IIIA/IIIB. Death and recurrence were significantly higher in patients with GSTM1 present genotype (M1+) (P = 0.037 and P = 0.003 respectively) and those with M1- showed reduced hazard of death with an adjusted hazard ratio ‘HR’ of 0.47 (95% CI, 0.269–0.802, P = 0.006). Women with M1- genotype as well as in combination with GSTT1 null (T1-), GSTP1 (AG+GG) and GSTT1 null/GSTP1 (AG+GG) showed better survival and also reduced risk of death (HR = 0.31, P = 0.016; HR = 0.45, P = 0.013; HR = 0.31, P = 0.02 respectively).

Conclusions

To the best of our knowledge, this is the first study to correlate the association of GSTM1, T1 and P1 gene polymorphisms with treatment outcome of CRT treated CC patients. Our results suggested that individuals with GSTM1 null genotype and in combination with GSTT1 null and GSTP1 (AG+GG) had a survival advantage. Such genetic studies may provide prognostic information in CRT treated CC patients.     

Genetic polymorphisms in GSTM1, GSTT1, GSTP1, GSTM3 and the susceptibility to gallbladder cancer in North India

Abstract

The glutathione S-transferase (GSTs) are polymorphic supergene family of detoxification enzymes that are involved in the metabolism of numerous potential carcinogens. Several allelic variants of polymorphic GSTs show impaired enzyme activity and are suspected to increase the susceptibility to various cancers. To find out the association of GST variants with risk of gallbladder cancer, the distribution of polymorphisms in the GST family of genes (GSTT1, GSTM1, GSTP1, and GSTM3) were studied in 106 cancer patients and 201 healthy controls. Genotypes were analysed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP). The frequencies of GSTM1 null and GSTM3*BB genotypes did not differ between patients and controls. The overall frequency of GSTT1 null was lower in cases as compared with controls (p=0.003, Odds ratio (OR)?=?0.2, 95% confidence interval (CI), 0.1–0.6). After sex stratification, the GSTT1 null frequency was reduced only in female patients (p=0.008, OR?=?0.2, 95% CI?=?0.1–0.6). However, the GSTP1, ile/val genotype and the val allele were significantly higher in cases than controls (p=0.013, OR?=?1.9, 95% CI?=?1.1–3.1; p=0.027, OR?=?1.5, 95% CI?=?1.0–2.1), respectively. To study gene–gene interactions, a combined risk of gallbladder cancer due to ile/val or val/val were calculated in combination with null alleles of GSTM1 and GSTT1 or the *B allele of GSTM3, but there was no enhancement of risk. Gallstones were present in 57.5% of patients with gallbladder cancer, but there were no significant differences between allelic/genotype frequencies of the studied GST genes polymorphisms between patients with or without gallstones. To best of our knowledge, this is the first paper showing ile/val genotypes and val allele of GSTP1 to be associated with higher risk of gallbladder cancer.     

Polymorphisms of methylenetetrahydrofolate reductase and glutathione S-transferase are not associated with the risk of papillary thyroid cancer in Korean population

Korea has the highest incidence of thyroid cancer of any nation. We conducted a population-based, case–control study of the association between the risk of papillary thyroid cancer (PTC) in the Korean population and polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T, glutathione S-transferase class mu (GSTM1), and glutathione S-transferase class theta (GSTT1). The study subjects consisted of 2,194 newly diagnosed PTC cases and 1,669 population-based healthy controls. Odds ratios adjusted by age, sex, body mass index, smoking, drinking, serum thyroid-stimulating hormone level, family history of thyroid cancer, and previous history of thyroid disease, with 95 % confidence intervals, were estimated using logistic regression analysis. The frequencies of MTHFR 677TT genotypes, and null genotypes of GSTM1 and GSTT1 were 19.2, 56.8, and 51.4 % among PTC cases and 17.4, 54.1, and 50.6 % among the controls, respectively. No significant associations between PTC and TT genotypes of MTHFR C677T, null genotypes of GSTM1 and GSTT1, or double-null (GSTM1-GSTT1) genotypes were found. These findings suggest that polymorphisms of the MTHFR C677T, GSTM1 and GSTT1 genotypes do not contribute to the development of PTC susceptibility in the Korean population.     

Association of GST Genetic Polymorphisms with the Susceptibility to Hepatocellular Carcinoma (HCC) in Chinese Population Evaluated by an Updated Systematic Meta-Analysis

Background

Due to the possible involvement of Glutathione S-transferase Mu-1 (GSTM1) and Glutathione S-transferase theta-1 (GSTT1) in the detoxification of environmental carcinogens, environmental toxins, and oxidative stress products, genetic polymorphisms of these two genes may play important roles in the susceptibility of human being to hepatocellular carcinoma. However, the existing research results are not conclusive.

Methods

A systematic literature search using databases (PubMed, Scopus, Embase, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Wanfang Data, etc.) for the eligible studies meeting the inclusion criteria including case-control studies or cohort studies is evaluated using an updated systematic meta-analysis.

Results

Significant increase in the risk of HCC in the Chinese population is found in GSTM1 null genotype (OR = 1.47, 95% CI: 1.21 to 1.79, P<0.001) and GSTT1 null genotype (OR = 1.38, 95% CI: 1.14 to 1.65, P<0.001). Analysis using the random-effects model found an increased risk of HCC in GSTM1-GSTT1 dual null population (OR = 1.79, 95% CI: 1.26 to 2.53, P<0.001). In addition, subgroup analyses showed a significant increase in the association of GST genetic polymorphisms (GSTM1, GSTT1, and GSTM1-GSTT1) with HCC in southeast and central China mainland. However, available data collected by this study fail to show an association between GST genetic polymorphisms and HCC in people from the Taiwan region (for GSTM1: OR = 0.78, 95% CI: 0.60 to 1.01, P = 0.06; for GSTT1: OR = 0.94, 95% CI: 0.78 to 1.14, P = 0.546; for GSTM1-GSTT1: OR = 1.04, 95% CI: 0.81 to 1.32, P = 0.77). Sensitivity analysis and publication bias diagnostics confirmed the reliability and stability of this meta-analysis.

Conclusions

Our results indicate that both GSTM1 and GSTT1 null genotypes are associated with an increased HCC risk in Chinese population. Peoples with dual null genotypes of GSTM1-GSTT1 are more susceptible to developing HCC. In conclusion, GST genetic polymorphisms play vital roles in the development of HCC in the Chinese population.     

Association of polymorphisms in glutathione-S-Transferase and DNA repair genes with ovarian cancer risk in the Russian population

Polymorphism of glutathione-S-transferase (GSTA1, GSTM1, GSTM3, GSTP1, and GSTT1) and DNA repair (ERCC1, ERCC2, and XRCC1) genes in samples of ovarian cancer patients and healthy women of the Russian ethnic group was studied. A trend in the allele frequency variation of ERCC2 gene single nucleotide polymorphism (rs13181, A > C) was revealed. The A allele frequency was higher in the sample of patients (60,6% versus 52,9%, P = 0.058).     

GSTM1 and GSTT1 gene polymorphisms as major risk factors for bronchopulmonary dysplasia in a Chinese Han population

Bronchopulmonary dysphasia (BPD) is a complex multifactorial disease with an obvious genetic predisposition. Oxidative stress plays an important role in its pathogenesis. Glutathione S-transferases (GSTs) detoxify metabolites produced by oxidative stress within the cell and protect the cells against injury. In the present study, the hypothesis that polymorphisms in the GSTM1 and GSTT1 genes are associated with BPD in Chinese Han infants was examined. Sixty infants with BPD and 100 gestational age and birth weight-matched preterm infants without BPD were recruited. Genotyping for GSTM1 and GSTT1 was performed by multiplex polymerase chain reaction (PCR). The GSTM1 null genotype was more prevalent in BPD infants (65.0%) than in the control subjects (48.0%), which yielded higher risk towards BPD (odds ratio (OR): 2.012, 95% confidence interval (CI) = 1.040–3.892, p = 0.037). There was no statistically significant association of GSTT1 genotype with BPD (OR: 1.691, 95% CI = 0.884–3.236, p = 0.111), although the frequency of GSTT1 null genotype was higher among the BPD subjects (60.0%) than in the control patients (47.0%). GSTM1 and GSTT1 double null genotype was also higher in BPD group (38.3%) than in controls (21.0%) with a higher risk towards BPD (OR: 2.338, 95%CI = 1.151–4.751, p = 0.017). The results suggest that null genotypes of GSTM1 and GSTT1 genes may contribute to the development of BPD in our Chinese Han population.     

Investigation of glutathione S-transferase M1 and T1 deletions in lung cancer

Glutathione S-transferases (GSTs) M1 and T1 are known to be polymorphic in humans. Both polymorphisms are due to gene deletions which are responsible for the existence of null genotypes. Previous studies have suggested that GST genotypes may play a role in determining susceptibility to a number of unrelated cancers, including lung cancer. The GSTM1 and GSTT1 polymorphisms were determined by PCR-based analysis in 75 lung cancer patients and 55 controls. The unconditional logistic regression analysis was used to calculate ORs and 95% CI. The frequencies of GSTM1 and GSTT1 null genotypes were 37.3 and 22.7% in lung cancer patients and 27.3 and 16.4% in controls, respectively. When analyzed by histology the GSTM1 null genotype was more prevalent in squamous-cell carcinoma and adenocarcinoma patients. Whereas, GSTT1 null genotype frequency was lower in small-cell lung cancer patients than controls. But these differences were not statistically significant. According to smoking status, null genotype for both gene are associated with an increase in risk for lung cancer. Our results suggest that GSTM1 and GSTT1 polymorphisms may play a role in the development of lung cancer for some histological subtypes and modifies the risk of smoking-related lung cancer.     

Genetic polymorphism of lysyl oxidase,glutathione S-transferase M1, glutathione-S-transferase T1, and glutathione S-transferase P1 genes as risk factors for lung cancer in Egyptian patients

Lung cancer is a lethal malignancy and is affected by genetic polymorphisms that contribute to an individual’s susceptibility to developing the disease. Several studies on lung cancer showed conflicting results. The aim of this study is to investigate whether individual or combined modifying effects of LOX G/A, GSTM1 active/null, GSTT1 active/null and GSTP1 Ile/Val polymorphisms are related to the risk of lung cancer in relation to smoking in the Egyptian population. This study is a hospital-based case control study that included 200 patients and 200 control subjects. Genotyping of the 4 studied genes was determined by Multiplex PCR for GSTM1 and GSTT1 and Taq man SNP assay for GSTP1 and LOX genes. The LOX G/A and GSTP1 Ile/Val in both homozygous and heterozygous variants, and the GSTM1 and GSTT1 null genotype showed significant association with lung cancer. Combination between gene polymorphism and smoking increased the risk of developing cancer by 2.7 fold in the LOX GA+AA variant, 1.9 fold in the GSTM1 null variant, 4.8 fold in the GSTT1 null variant and 4.3 fold in the GSTP1 Ile/Val+Val/Val variant. The genetic combination (LOX GA+AA/GSTT1 active, LOX GG/GSTT1 null, LOX GA+AA/GSTT1 null, LOX GA+AA/GSTP1 Ile/Ile, LOX GG/GSTP1 Ile/Val+Val/Val and LOX GA+AA/GSTP1 Ile/Val+Val/Val) led to a higher lung cancer risk, compared to the reference group. The LOX GA/AA, GSTM1 null, GSTT1 null and GSTP1 Ile/Val, Val/Val genotypes contributed to increased lung cancer susceptibility. To the best of our knowledge, this is the first study of LOX genotyping in the Egyptian population. The combination of genotypes increased the risk of cancer, indicating the importance of gene–gene interaction and giving a targeted preventive approach.

     

GSTM1 and GSTT1 Null Polymorphisms and Childhood Acute Leukemia Risk: Evidence from 26 Case-Control Studies

Several molecular epidemiological studies have been conducted to examine the association between glutathione S-transferase mu-1 (GSTM1) and glutathione S-transferase theta-1 (GSTT1) null polymorphisms and childhood acute leukemia; however, the conclusions remain controversial. We performed an extensive meta-analysis on 26 published case-control studies with a total of 3252 cases and 5024 controls. Crude odds ratios (ORs) with 95% confidence interval were used to assess the strength of association between childhood acute leukemia risk and polymorphisms of GSTM1 and GSTT1. With respect to GSTM1 polymorphism, significantly increased risk of childhood acute leukemia was observed in the overall analysis (OR = 1.30; 95%CI, 1.11-1.51). Furthermore, a stratification analysis showed that the risk of GSTM1 polymorphism are associated with childhood acute leukemia in group of Asians (OR = 1.94; 95%CI, 1.53-2.46), Blacks (OR = 1.76; 95%CI, 1.07-2.91), ALL (OR = 1.33; 95%CI, 1.13-1.58), ‘< 100 cases and <100 controls’ (OR = 1.79; 95%CI, 1.21-2.64), ‘≥ 100 cases and ≥ 100 controls’ (OR = 1.25; 95%CI, 1.02-1.52), and population-based control source (OR = 1.40; 95%CI, 1.15-1.69). With respect to GSTT1 polymorphism, significant association with childhood acute leukemia risk was only found in subgroup of Asian. This meta-analysis supports that GSTM1 null polymorphism is capable of causing childhood acute leukemia susceptibility.     

Null genotypes of GSTM1 and GSTT1 contribute to risk of cervical neoplasia: an evidence-based meta-analysis

Background and Objectives

Glutathione S-transferases (GSTs) are multifunctional enzymes that play a key role in the detoxification of varieties of both endogenous products of oxidative stress and exogenous carcinogens.

Methods

In this meta-analysis, twenty-five studies were identified by searching PubMed, EMBASE, ISI Web of Science and CBM databases: 23 evaluated GSTM1 and 19 evaluated GSTT1. Crude odds ratios with corresponding 95% confidence intervals were used to estimate the association between GSTM1 and GSTT1 polymorphisms and risk of cervical neoplasia. Subgroup analyses were conducted by pathological history, ethnicity, source of DNA for genotyping, quality score, and matching variable.

Results

The null genotypes of GSTM1 and GSTT1 polymorphisms were associated with a significantly increased risk of cervical neoplasia (for GSTM1: OR = 1.40; 95%CI, 1.19–1.65; for GSTT1: OR = 1.30; 95%CI, 1.05–1.62, respectively). Subgroup analyses showed that the null genotype of GSTM1 increased the risk of cervical neoplasia in Asians, studies with DNA isolation from white blood cells and tissue samples, both high and low quality studies, and matched studies. In GSTM1-GSTT1 interaction analysis, individuals with dual null genotype were associated with a significantly increased risk of cervical neoplasia (OR = 1.72; 95%CI, 1.18–2.51).

Conclusion

These findings indicate that GSTM1 and GSTT1 polymorphisms, particularly GSTM1-GSTT1 interaction, may play critical roles in the development of cervical neoplasia. A conservative manner should be adopted to interpret these results because of obvious heterogeneity between-study, unadjusted data, and relatively small sample size in this meta-analysis. Well designed studies with larger sample size are of great value to confirm these results.