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Oxidative stress is one of the main risk factors for asthma development. Glutathione S-transferases play an important role in antioxidant defences and may influence asthma susceptibility. In particular, GSTM1 and GSTT1 positive/null genotypes and the GSTP1*Ile105 Val polymorphism have been analyzed in a number of genetic association studies, with conflicting outcomes. Two previous meta-analyses have attempted to clarify the associations between GST genes and asthma, but these studies have also showed contrasting results. Our aim was to perform a meta-analysis that included independent genetic association studies on GSTM1, GSTP1, and GSTT1, evaluating also the effect of potential confounding variables (i.e. ethnicity, population age, and urbanization). Systematic review and meta-analysis of the effects of GST genes on asthma were conducted. The meta-analyses were performed using a fixed or, where appropriate, random effects model. The meta-analysis of the GSTM1 ( n = 35), GSTT1 ( n = 31) and GSTP1 ( n = 28) studies suggests that no significant associations with asthma susceptibility were observed for GSTM1 and GSTP1 gene polymorphisms, whereas a significant outcome was detected for the GSTT1 positive/null genotype (pooled OR = 1.33, 95 %CI = 1.10-1.60). However, high between-study heterogeneity was identified in all the general analyses ( p < 0.05). The stratification analysis seems to explain the heterogeneity only in few cases. This picture is probably due to the interactive process of genetics and environment that characterizes disease pathogenesis. Further studies on interactions of GST genes with the potential oxidative stress sources and with other antioxidant genes are needed to explain the role of GST enzymes in asthma. [ABSTRACT FROM AUTHOR]

Glutathione-S-transferases (GSTs) play a protective role during spermatogenesis and GST genes may be involved in impaired spermatogenesis. A case-control study was performed to explore the association of genes GSTM1 and GSTT1, two members of GST gene family, with spermatogenesis impairment. The deletion polymorphism distribution of genes GSTM1 and GSTT1 was investigated in 353 patients with azoospermia or oligospermia and 201 fertile controls in Chinese population using multiplex PCR. As a result, the frequencies of null genotype of genes GSTM1 (67.4% versus 57.7%, p = 0.022, OR = 1.516, 95% CI = 1.001-2.168) and GSTT1 (61.8% versus 46.8%, p = 0.001, OR = 1.838, 95% CI = 1.295-2.610) in patients were significantly higher than those in controls. After stratifying patients, the frequencies of null genotype of gene GSTM1 in oligospermia (68.3% versus 57.7%, p = 0.027, OR = 1.580, 95% CI = 1.051-2.375) and GSTT1 in azoospermia (66.9% versus 46.8%, p < 0.001, OR = 2.299, 95% CI = 1.484-3.562) as well as oligospermia (57.9% versus 46.8%, p = 0.025, OR = 1.567, 95% CI = 1.057-2.322) were still significantly higher compared with controls. The results suggested that null genotypes of GSTM1 and GSTT1 are associated with spermatogenesis impairment and may contribute to susceptibility to spermatogenesis impairment and male infertility in Chinese population. [ABSTRACT FROM AUTHOR]

Recent studies on the association between glutathione S-transferase T1 ( GSTT1) polymorphism and risk of esophageal cancer showed inconclusive results. To clarify this possible association, we conducted a meta-analysis of published studies. Data were collected from the following electronic databases: Pubmed, Embase, and Chinese Biomedical Database (CBM). The odds ratio (OR) and its 95 % confidence interval (95 % CI) was used to assess the strength of this association. We summarized the data on the association between GSTT1 null genotype and risk of esophageal cancer in the overall population, and performed subgroup analyses by ethnicity. Finally, a total of 24 independent studies including a total of 7,801 subjects (2,965 cases and 4,836 controls) were eligible for meta-analysis. In the overall analysis, there was no significant association between GSTT1 null genotype and esophageal cancer risk (OR = 1.15, 95 % CI 0.99-1.33, P = 0.067). However, meta-analysis of adjusted ORs showed a significant association between GSTT1 null genotype and increased risk of esophageal cancer (OR = 1.30, 95 % CI 1.08-1.56, P = 0.005). Subgroup analyses by ethnicity showed there was an obvious association between GSTT1 null genotype and increased risk of esophageal cancer in East Asians (OR = 1.24, 95 % CI 1.10-1.39, P < 0.001), but not in Caucasians (OR = 0.89, 95 % CI 0.71-1.11, P = 0.300). There was no obvious risk of publication bias in this meta-analysis (Egger's test, P = 0.784). This meta-analysis demonstrates that GSTT1 null genotype is independently associated with increased risk of esophageal cancer, and a race-specific effect may exist in this association. [ABSTRACT FROM AUTHOR]

Backgrounds: Compared with previously published meta-analyses, this is the first study to investigate the combined effects of glutathione-S-transferase polymorphisms (GSTM1, GSTT1 and GSTP1 IIe105Val) and type 2 diabetes mellitus (T2DM) risk; moreover, the credibility of statistically significant associations was assessed; furthermore, many new original studies were published. Objectives: To determine the relationship between GSTM1, GSTT1, and GSTP1 polymorphisms with T2DM risk. Methods: PubMed, Embase, Wanfang, and China National Knowledge Infrastructure Databases were searched. We quantify the relationship using crude odds ratios and their 95% confidence intervals Moreover, the Venice criteria, false-positive report probability (FPRP), and Bayesian false discovery probability (BFDP) were used to validate the significance of the results. Results: Overall, significantly increased T2DM risk was found between individual and combined effects of GSTM1, GSTT1, and GSTP1 polymorphisms on T2DM risk, but, combined effects of the GSTT1 and GSTP1 polymorphisms was not statistically significant. GSTT1 gene polymorphism significantly increases the risk of T2DM complications, while GSTM1 and GSTP1 polymorphisms had no statistical significance. The GSTM1 null genotype was linked to a particularly increased risk of T2DM in Caucasians; the GSTT1 null genotype was connected to a significantly higher risk of T2DM in Asians and Indians; and the GSTP1 IIe105Val polymorphism was related to a substantially increased T2DM risk in Indians. Moreover, the GSTM1 and GSTT1 double null genotype was associated with substantially increased T2DM risk in Caucasians and Indians; the combined effects of GSTM1 and GSTP1 polymorphisms was associated with higher T2DM risk in Caucasians. However, all significant results were false when the Venice criteria, FPRP, and BFDP test were used (any FPRP >0.2 and BFDP value >0.8). Conclusion: The current analysis strongly suggests that the individual and combined effects of GSTM1, GSTT1 and GSTP1 polymorphisms might not be connected with elevated T2DM risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Wang, Tang, Wang, Zheng, Wei, Li and He.)

Background: Several meta-analyses have analyzed the association of GSTM1 present/null, GSTT1 present/null, and GSTP1 IIe105Val polymorphisms with leukemia risk. However, the results of these meta-analyses have been conflicting. Moreover, they did not evaluate the combined effects of the three aforementioned gene polymorphisms. Furthermore, they did not appraise the credibility of the positive results. Finally, many new studies have been published. Therefore, an updated meta-analysis was conducted. Objectives: To further explore the relationship of the three aforementioned gene polymorphisms with leukemia risk. Methods: The crude odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the association of the individual and combined effects of the three aforementioned genes. Moreover, the false-positive report probability (FPRP) and Bayesian false discovery probability (BFDP) were applied to verify the credibility of these statistically significant associations. Results: Overall, the individual GSTM1, GSTT1, and GSTP1 IIe105Val polymorphisms added leukemia risk. On combining GSTM1 and GSTT1, GSTM1 and GSTP1, and GSTT1 and GSTP1 polymorphisms, positive results were also observed. However, no significant association was observed between the combined effects of these three polymorphisms with leukemia risk in the overall analysis. Moreover, when only selecting Hardy-Weinberg equilibrium (HWE) and medium- and high-quality studies, we came to similar results. However, when the FPRP and BFDP values were applied to evaluate the credibility of positive results, the significant association was only observed for the GSTT1 null genotype with leukemia risk in Asians (BFDP = 0.367, FPRP = 0.009). Conclusion: This study strongly suggests a significant increase in the risk of leukemia in Asians for the GSTT1 null genotype., Competing Interests: Author WW was employed by the company Beijing Zhendong Guangming Pharmaceutical Research Institute. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Wang, Zhang, Liu, Wang, Shi, Wang, Shen and He.)

Objectives: This study investigated the role of glutathione-S-transferase gene (GSTM1 and GSTT1) polymorphisms in the predisposition of type 2 diabetes mellitus (T2DM) with or without diabetic retinopathy (DR)., Methods: The case-control study included 188 subjects: 50 T2DM with DR, 63 T2DM without DR, and 75 healthy individuals' presenting no clinical signs or evidence of diabetes mellitus. Zinc and magnesium levels were measured using a flame atomic absorption spectrophotometer, and the lipid profile was evaluated using standard methods. The gene polymorphism of GSTs was performed by the multiplex-PCR method., Results: Compared to the control, DR and T2DM had considerably greater total cholesterol, LDL-C, and decreased HDL-C levels. Magnesium levels were significantly lower in DR and T2DM than in control. Total cholesterol, LDL, TG, and magnesium levels didn't differ significantly between DR and T2DM groups. In DR, the GSTT1-null genotype was more prevalent than in T2DM subjects and controls (26.0%, 12.7%, and 10.7%, respectively). GSTT1-null genotype was considerably more common in DR than in controls and associated with 2.94-folds enhancing the chance of developing DR (OR = 2.94; 95% CI = 1.12-7.75;  p  = 0.02). However, the recurrence of GSTM1-null genotype was not clearly distinguishable among these three populations (28.0%, 38.1% and 29.3%, respectively) and not particularly prone to the risk of DR compared to T2DM subjects and controls (OR = 0.63; 95% CI = 0.28-1.41; p  = 0.26; OR = 0.94; 95% CI = 0.42-2.07; p  = 0.87, respectively)., Conclusions: Taken together, these findings suggest the potential role of GSTT1 deletion mutation as a risk factor for the vulnerability of DR among T2DM patients in the Bangladeshi population., Competing Interests: Conflicts of interestAuthors declares that there has no conflict of interest., (© The Author(s), under exclusive licence to Tehran University of Medical Sciences 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Glutathione S-transferase Mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1) enzymes are glutathione-S-transferases with broad significance for susceptibility or resistance to multifactorial human diseases, as well as detoxification of environmental chemicals and drugs. Moreover, some individuals may have a complete deletion of GSTM1 and GSTT1 genes, which can contribute to patient-to-patient variability in drug safety and efficacy. GSTM1 and GSTT1 gene deletion frequencies can vary according to ethnicity and continental origin of the studied population with implications for achieving the goal of precision/personalized medicine in clinical practice. We report here a worldwide systematic review of the null genotypes in these two clinically important genes by continents, ethnicities, and therapeutic areas (TAs). Searches were performed in the PubMed database covering the period from 1992 to 2020. Out of the 1925 articles included, most studies analyzed European individuals, corroborating the literature failure for not adequately considering the non-European ethnicities. The frequency of GSTM1 and GSTT1 null genotypes was higher in patients than in healthy volunteers. Conversely, in East Asians, higher frequencies of the null genotypes were observed in healthy volunteers than patients. Oncology was the most intensively studied TA (57% of the articles) in relation to GSTM1 and GSTT1 . In all, these results demonstrate that there is an important gap in the literature in terms of failure to consider a broader range of populations, as well as diseases wherein GSTM1 and GSTT1 variations have clinical and biological implications. To achieve precision/personalized medicine on a global/worldwide scale, with equity and inclusiveness, this knowledge/research gap ought to be remedied in studies of GSTM1 and GSTT1 null genotypes. To the best of our knowledge, this is the largest systematic review conducted to date addressing the GSTM1 and GSTT1 null genotypes worldwide. The analyses from the 1925 articles highlighted the current knowledge gaps in different TAs, ethnicities, and populations. Filling these gaps is of importance, given the role these genes play in relation to the metabolism of substances to which we have frequent contact with, the associations observed between their deletion and diseases such as cancer, in addition to the interethnic differences observed for the deletion frequencies of these genes.

In Peru, 24,581 people were diagnosed with tuberculosis (TB) in 2020. Although TB treatments are effective, 3.4-13% are associated with significant adverse drug reactions (ADRs), with drug-induced liver injury (DILI) considered the most predominant. Among the first-line antituberculosis drugs, isoniazid (INH) is the main drug responsible for the appearance of DILI. In the liver, INH is metabolized by the enzymes N-acetyltransferase-2 (NAT2), cytochrome P450 2E1 (CYP2E1), and glutathione S-transferase (GST) with two isoforms, GSTT1 and GSTM1. Based on previous studies, we hypothesized that interactions between the GSTT1 and GSTM1 null genotypes induce DILI in TB patients. In this cross-sectional study of 377 participants who completed their anti-TB treatment, we genotyped by revealing the presence or absence of 215- and 480-bp bands of GSTM1 and GSTT1 , respectively. We found that the prevalence of the GSTM1 genotype was 52.79% and 47.21% for presence and null, respectively, and for GSTT1 it was 69.76% and 30.24% for presence and null, respectively. Neither genotype was prevalent in the patients who developed DILI ( n = 16). We did not confirm our hypothesis; however, we found that the combination of GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype had a significant risk for the development of ADR (OR 11; p = 0.017; 95% CI: (0.54-186.35)). We propose that the presence of the GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype in the Peruvian population could be considered a risk factor for the development of ADR due to therapeutic drug intake., Competing Interests: The authors declare no conflict of interest.

The associations of organochlorine pesticides (OCPs) with semen quality from human studies are conflicting, and also it is largely unknown whether the associations are modified by genetic polymorphisms. We aimed to evaluate the associations between serum concentrations of 18 OCPs and semen quality among 387 Chinese men, and further to examine the modifying effects by genetic polymorphisms in cytochrome P450 (CYP2E1) and glutathione S-transferase (GSTT1). Multivariable linear regressions were used to evaluate the relationships between serum OCP concentrations and semen quality, and the role of CYP2E1 and GSTT1 polymorphisms in modifying the associations were assessed. Multiple testing was adjusted using the false discovery rate (FDR). We observed that men with detectable concentrations of serum ɤ-HCH had a decrease in sperm motility of 7.07% (95% CI: -10.9%, -3.24%) compared to those with undetectable concentrations (FDR-P value = 0.02). Men with TT of CYP2E1 rs 915906 genotypes had higher median concentrations of serum dieldrin compared with those with CT/CC of CYP2E1 rs 915906 genotypes. There were interactions between CYP2E1 and GSTT1 polymorphisms and certain OCPs namely ɤ-HCH, δ-HCH, dieldrin, endosulfan I, and endrin aldehyde on semen quality. For example, elevated dieldrin levels in relation to decreased sperm concentration, sperm count, and sperm motility were only observed among men with CC of CYP2E1 rs2031920 genotypes (all P interaction < 0.05). However, these interactions were not statistically significant after the FDR adjustment. Our results suggested that CYP2E1 and GSTT1 polymorphisms may modify the effects of OCP exposures on semen quality. Due to the relatively small size samples, further investigation is warranted to confirm the findings., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Abstract: 1,3-Butadiene (BD) has been classified as a human carcinogen, group I; however, the relationship between polymorphisms of glutathione S-transferases that metabolize BD and chromosomal damage is not clear. The present study used sister chromatid exchange (SCE) and cytokinesis-block micronucleus (CBMN) assays to detect chromosomal damage in peripheral lymphocytes of 44 BD-exposed workers and 39 non-exposed healthy controls. PCR and PCR-RFLP were employed to detect three known glutathione S-transferase polymorphisms GSTT1, GSTM1, and GSTP1 (Ile105Val). The data demonstrated that the micronucleus (CBMN) frequency in BD-exposed workers was significantly higher than that in controls (frequency ratio (FR)=1.48, 95% CI: 1.14–1.91, P <0.01), and the CBMN frequency was higher in workers exposed to higher cumulative BD levels (FR=1.70, 95% CI: 1.28–2.27, P <0.01). However, differences in SCE frequency were not observed (FR=1.14, 95% CI: 0.81–1.61, P >0.05). Among exposed workers, chromosomal damage was related to BD exposure levels (FR=1.35, 95% CI: 1.02–1.80, P <0.05); age, older workers exhibited higher MN frequencies than younger workers (FR=1.45, 95% CI: 1.14–1.84, P <0.05); and years of work, those with more years of work exhibited higher MN frequencies than those with fewer years (FR=1.40, 95% CI: 1.10–1.77, P <0.05). Multivariate Poisson regression analysis showed that those who carried GSTM1 (−) (FR=1.48, 95% CI: 1.14–1.92) or GSTT1 (−) (FR=1.42, 95% CI: 1.10–1.83) genotypes, and especially those who carried both (FR=2.10, 95% CI: 1.43–3.09) exhibited significantly higher MN frequencies than those carrying GSTM1 (+), GSTT1 (+) genotypes or their combination. The GSTP1 Val genotype did not affect MN frequency (P >0.05). Our results suggested that higher levels of BD exposure in the workplace resulted in increased chromosomal damage, and that polymorphisms in GSTT1 and GSTM1 genes might modulate the genotoxic effects of BD exposure. Furthermore, the GSTT1 and GSTM1 polymorphisms exhibited an additive effect. Finally, urinary DHBMA was found to provide a biomarker that correlated with airborne BD levels. [Copyright &y& Elsevier]

Abstract: The relationship of NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms with mild elevation of liver biomarkers was investigated in individuals under anti-tuberculosis drug therapy. Tuberculosis outpatients (18–70y) with (n=59) and without (n=40) mild increase of liver enzymes (MILE) at two-month treatment were selected. Blood samples were obtained for DNA extraction and evaluation of serum markers of liver function. NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms were detected by DNA sequencing, PCR-RFLP, and PCR multiplex. Frequency of NAT2*5/*5 genotype was higher in MILE than in non-MILE group (p=0.04). Patients carrying NAT2*5/*5 genotype had increased susceptibility to MILE (OR: 9.00, 95CI: 1.46–55.48, p=0.018). CYP2E1*5B allele (*1A/*5B plus *5B/*5B genotypes) carriers had a trend for reduced risk for MILE (OR: 0.34, 95CI: 0.11–1.03, p=0.056) that was confirmed by lower levels of liver markers than CYP2E1*1A/*1A carriers after treatment (p<0.05). Moreover, increased post-treatment ALT, AST and total bilirubin were associated with GSTM1*1/GSTT1*1 genotypes (p<0.05). Patients taking CYP2E1 inhibitors had increased susceptibility to MILE (OR: 7.39, 95CI: 1.93–28.29, p=0.003), which was independent of the studied polymorphisms. These results are suggestive that NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms and concomitant use of CYP2E1 inhibitors contribute to the susceptibility to mild alterations in liver enzymes in patients under anti-tuberculosis drug therapy. [Copyright &y& Elsevier]

Abstract: There is substantial evidence found in the literature that supports the fact that the presence of oxidative stress may play an important role in the pathophysiology of schizophrenia. The glutathione S-transferases (GSTs) forms one of the major detoxifying groups of enzymes responsible for eliminating products of oxidative stress. Interindividual differences observed in the metabolism of xenobiotics have been attributed to the genetic polymorphism of genes coding for enzymes involved in detoxification. Thus, in this study we investigated the association of glutathione S-transferase Mu-1 (GSTM1) and glutathione S-transferase theta-1 (GSTT1) gene deletion polymorphisms and schizophrenia in a Tunisian population. A case–control study including 138 schizophrenic patients and 123 healthy controls was enrolled. The GSTM1 and GSTT1 polymorphisms were analyzed by multiplex polymerase chain reaction (PCR). No association was found between the GSTM1 genotype and schizophrenia, whereas the prevalence of the GSTT1 active genotype was significantly higher in the schizophrenic patients (57.2%) than in the controls (45.5%) with (OR=0.6, IC 0.37–0.99, p =0.039). Thus, we noted a significant association between schizophrenia and GSTT1 active genotype. Furthermore, the combination of the GSTM1 and GSTT1 null genotypes showed a non-significant trend to an increased risk of schizophrenia. The present finding indicated that GSTT1 seems to be a candidate gene for susceptibility to schizophrenia in at least Tunisian population. [Copyright &y& Elsevier]

Glutathione S-transferases (GSTs) are postulated to be involved in the detoxification of potential carcinogens, and gene variation may alter susceptibility to lymphomas. Results from several previous epidemiologic studies have been inconsistent. Hence a meta-analysis was conducted to verify the role of GST genetic polymorphisms in lymphoma risk. Eleven trials involving 1626 patients and 2892 controls were analyzed. Pooled results showed that the GSTT1 null polymorphism might increase the risk of lymphoma (odds ratio [OR] 2.26, 95% confidence interval [CI] 1.20, 4.24; p = 0.01; random-effects model), whereas the impact of GSTM1 and GSTP1 Ile105Val polymorphisms was not significant. Subgroup analysis showed the GSTT1 null genotype to be a risk factor for non-Hodgkin lymphoma (NHL) (OR 2.75, 95% CI 1.17, 6.45; p = 0.02; random-effects model) but not for Hodgkin lymphoma (HL), and the effect remained evident in females (OR 1.43, 95% CI 1.04, 1.97; p = 0.03; I2 = 41.0%, p for heterogeneity = 0.15; fixed-effects model). An effect of GSTM1 and GSTT1 double null genotype on lymphoma risk was also shown (OR 2.09, 95% CI 1.31, 3.33; p = 0.01; random-effects model). In conclusion, the GSTT1 null genotype appears to be associated with a modest increase in the risk of NHL, whereas the GSTM1 and GSTP1 Ile105Val polymorphisms are unrelated to lymphoma risk. [ABSTRACT FROM AUTHOR]

Objective: To analyse patients that developed in time three different malignant tumors. Material and Methods: We included 23 cases with at least three primitive malignant tumors among more than 5000 patients with a cancer admitted in our hospital during last 7.5 years, 8 males and 14 females. At least one tumor was diagnosed and treated in our hospital. We made a genetic analysis of glutathione S-transferases of class mu, pi and theta for all of them. Results: We did not find association of mutated GSTs in our group of patients diagnosed with three malignant primaries. Conclusion: The GSTs may play a role in carcinogenesis, but not in all cases. [ABSTRACT FROM AUTHOR]

Oxidative stress is thought to be involved in the pathogenesis of asthma. Glutathione S-transferase (GST) enzymes play an important role in the antioxidant defence mechanism and therefore may influence asthma risk. Polymorphism of GSTT1 and GSTM1 genes has been associated with asthma in children and adults, but results are inconsistent across studies. The aim of the present study was to examine the association of GSTT1 and GSTM1 gene genotypes and the risk of asthma among 44 stable asthmatic children in comparison to 30 healthy control subjects. Genotyping was performed using the multiplex PCR technique. GSTT1 null genotype was significantly associated with an increased risk of asthma by more than 9-fold. GSTM1 polymorphism did not appear to play a major role in the development of bronchial asthma in children. Neither was associated with patients' phenotype. [ABSTRACT FROM AUTHOR]

The results from the published studies on the association between glutathione S-transferases (GST) gene polymorphism and hepatocellular carcinoma (HCC) in Asian population are still conflicting. GSTM1, GSTT1 and GSTP1 are the mainly mutant sites reported at present. This meta-analysis was performed to evaluate the relationship between GST gene polymorphism and HCC risk in Asians. Association studies were identified from the databases of PubMed, Embase, Cochrane Library and CBM-disc (China Biological Medicine Database) on February 1, 2012, and eligible investigations were synthesized using meta-analysis method. Results were expressed with odds ratios (OR) for dichotomous data, and 95 % confidence intervals (CI) were also calculated. Twenty-five investigations were identified for the analysis of association between polymorphic deletion of GSTM1 and HCC, consisting of 3,547 patients with HCC and 6,132 controls. There was a marked association between GSTM1 null genotype and HCC susceptibility (OR 1.48, 95 % CI 1.19-1.85, P = 0.0004). GSTM1 null genotype was associated with HCC risk in Chinese. Furthermore, null genotype of GSTT1 was associated with HCC susceptibility in Asians. For the GSTM1-GSTT1 interaction analysis, the dual null genotype of GSTM1/GSTT1 was significantly associated with HCC susceptibility in Asian population. However, GSTP1 ile105 val gene polymorphism was not associated with HCC risk in Asian population. In conclusion, GSTM1/GSTT1 null genotype is associated with the HCC susceptibility. However, GSTP1 gene polymorphism is not associated with HCC risk. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To estimate the prevalence and importance of GSTT1, GSTM1, and CYP1B1 genotypes in renal cell carcinoma (RCC), and to identify their value as a prognostic factor. Materials and methods: Cross-sectional study of a group of patients diagnosed with RCC (n = 133) and a control group (n = 208) with benign conditions and no history of tumor. Controls were selected by cumulative samples and mixed pairing. All subjects pertained to the catchment area for our hospital. Sociodemographic variables, anatomical pathology features, and presence of GSTT1, GSTM1, and CYP1B1 polymorphisms by multiplex PCR and sequencing techniques. Results: There were no differences in the genotype distribution of the GSTT1 and GSTM1 genes between cases and controls. In the case of CYP1B1, the GG genotype (Ala119) was more prevalent in patients with RCC (OR = 2.08; 95% CI: 1.32–2.28) and may be implicated in 34.3% (95% CI: 16.3–52.2) of RCCs. In patients with GSTT1 deletion, TNM stages III to IV were more common (39.1%); whereas in Val432 homozygous patients in CYP1B1, Fuhrman grades 3 to 4 (54.6%) were more common. Because this was a cross-sectional study, longitudinal studies are needed in the future to confirm these data. Conclusions: No relationship between GSTT1 and GSTM1 genotypes and RCC risk was observed. Homozygous subjects with Ala119 in CYP1B1 had twice the risk of RCC as homozygous for Ser119 or heterozygotes. Patients with GSTT1 deletion had tumors of more advanced stages, and those with Val432 polymorphism in CYP1B1 had tumors of higher Fuhrman grade. [Copyright &y& Elsevier]

The present study investigated the impact of metabolic gene polymorphisms in modulating lung cancer risk susceptibility. Gene polymorphisms encoding Cytochrome 1A2 (CYP1A2) and Glutathione-S-transferases (GSTT1 and GSTM1) are involved in the bioactivation and detoxification of tobacco carcinogens and may therefore affect lung cancer risk. In order to assess association between lung cancer and GSTT1, GSTM1 and CYP1A2-2467T/ delT, variant allele (CYP1A2"1D) polymorphisms, a case-control study of healthy and smoking lung cancer patients in Tunisian population was conducted. Polymorphisms of GSTs were assayed by multiplex PCR. Genotype polymorphism of CYP1A2"1D was determined by PCR-RFLP assay. Odds Ratio was used for analysing results. There was no association with any increase of lung cancer risk in GSTT1 null genotype [OR: 0.83 (0.47-1.45)] as well as in GSTM1 null genotype [OR: 0.78 (0.37-1.62)]. However, a significant association between lung cancer and the homozygous mutate variant of the CYP1A2 [(OR =4.7 (1.55- 29.78)] was observed These results demonstrated that the strong and significant association between CYP1A2"1D and lung cancer appears to be relevant in this Tunisian population, suggesting that CYP1A2 metabolic genetic factor may, in partly, play a role in modulating lung cancer susceptibility. [ABSTRACT FROM AUTHOR]

What is Known and Objective: The pathogenic mechanism of antituberculosis drug-induced hepatotoxicity (ATDH) is thought to involve drug-metabolizing enzymes including N-acetyl transferase2 (NAT2), cytochrome P4502E1 (CYP2E1) and glutathione S-transferase (GST) M1, T1. The associations between genetic polymorphisms of those genes and ATDH have been reported but with inconsistent results. Moreover, most studies were hospital-based retrospective studies and not prospective. We aimed to investigate possible associations of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms with ATDH using a more robust case-control study nested in a population-based prospective antituberculosis treatment cohort. Methods: A total of 4304 patients with smear-positive tuberculosis (TB) who received standard short-course chemotherapy were monitored for 6-9 months. Incidence density sampling method was adopted to select controls and 4 : 1 matched with each ATDH cases by age (±5 years), sex, treatment history, disease severity and drug dosage. The CYP2E1, GSTM1 and GSTT1 polymorphisms were genotyped using PCR-RFLP and multiplex PCR methods. Conditional logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P-values. Results and Discussion: A total of 89 ATDH cases and 356 controls were included in this study. There was no statistically significant association between CYP2E1 RsaI c1/ c1 genotype or DraI C/C genotype and ATDH (OR = 0·99, 95% CI:0·62-1·59; OR = 1·13, 95% CI: 0·40-3·20, respectively) compared with CYP2E1 RsaI c1/c2 or c2/c2 genotypes or DraI D/D genotype, or between GSTM1/ GSTT1 null genotypes and ATDH (OR = 1·22, 95% CI: 0·76-1·96; OR = 0·96, 95% CI: 0·60-1·52, respectively) compared with non-null genotypes. What is new and Conclusion: This is the first study of the involvement of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms in ATDH using a nested case-control population-based prospective cohort design. We could not confirm positive associations of genetic polymorphisms of CYP2E1 RsaI, CYP2E1 DraI, GSTM1 null and GSTT1 null with ATDH reported by various groups, in our Chinese TB population. [ABSTRACT FROM AUTHOR]

Lung cancer, which is mainly affected by environmental factors, is a lethal malignancy. It is also important to investigate the effect of genetic factors on lung cancer aetiology. In this study, we aimed to investigate the distribution of CYP1A1*2C, GSTT1 and GSTM1 polymorphisms in Turkish lung cancer patients to determine whether any promoting effect of polymorphisms could cause development of lung cancer. For this purpose, genomic DNA samples obtained from peripheral blood of 128 patients with lung cancer and 122 healthy subjects were analyzed. Genotyping of polymorphic enzymes were carried out by polymerase chain reaction–restriction fragment length polymorphism methods. Although there were no significant differences between groups in terms of CYP1A1 polymorphism, the carriers of CYP1A1Ile/Val genotype (odds ratio [OR] = 1.224, 95% confidence interval [CI]: 0.585–2.564) or CYP1A1Val/Val genotype (OR = 3.058, 95% CI: 0.312–30.303) had an increased risk of lung cancer development. There was no statistical difference between groups in terms of both GSTT1 null genotype (OR = 1.114, 95% CI: 0.590–2.105) and GSTM1 null genotype (OR = 0.776, 95% CI: 0.466–1.290). This is the first case–control study investigating CYP1A1Ile/Val, GSTT1 and GSTM1 polymorphisms in Turkish lung cancer patients. Although we suggest that other genes in addition to the proposed genes could play a role in lung cancer development, the results of our study will contribute to the possible associations between CYP1A1Ile/Val, GSTT1 and GSTM1 gene polymorphism on the risk of lung cancer. [ABSTRACT FROM AUTHOR]

Genetic alterations in the genes expressing drug metabolizing enzymes can make an individual susceptible to various cancers. This study detects the polymorphisms at CYP1A1, GSTM1, and GSTT1 genes in a section of North Indian population and determines the susceptibility to oral submucous fibrosis (OSF). In this case-control study one hundred and two OSF patients were genotyped to detect the GSTM1, GSTT1, CYP1A1 polymorphism. Two hundred healthy controls were also included. Genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. The frequency of GSTM1 and GSTT1 genotype was higher in OSF patients, as compared to controls. A trend risk analysis showed 7.6 fold increase in risk, when both the genes were absent. The frequency of CYP1A1 (m1) and CYP1A1 (m2) genotypes was higher in controls. No polymorphic alleles were detected in the m4 site. CYP1A1 (m1) wild genotype in the absence of GSTM1 null genotype, falls under the highest risk group (OR 3.74). Our findings suggest that CYP1A1 (m1) genotype and (m2) genotype singly acts as a protective factor but in the absence of GSTM1 and/or GSTT1 gene significantly alters risk towards OSF. [ABSTRACT FROM AUTHOR]

The results from the published studies on the relationship between GSTM1/GSTT1 null genotypes and renal cell carcinoma (RCC) risk are still conflicting. This meta-analysis was performed to evaluate the relationship between GSTM1/GSTT1 null genotypes and RCC susceptibility. Association studies were identified from the databases of PubMed, Embase, Cochrane Library, and CBM-disc (China Biological Medicine Database) on 1 February 2012, and eligible investigations from 1950 to 2012 were synthesized using meta-analysis method. Results were expressed as odds ratios (ORs) for dichotomous data, and 95% confidence intervals (CIs) were also calculated. Six studies were identified for the analysis of association between polymorphic deletion of GSTM1/GSTT1 and RCC risk. There was no association between GSTM1/GSTT1 null genotype and RCC susceptibility (GSTM1: N = 6, p-heterogeneity = 0.07, OR = 1.07, 95% CI: 0.85-1.35, p = 0.57; GSTT1: N = 6, p-heterogeneity < 0.00001, OR = 0.98, 95% CI: 0.58-1.65, p = 0.94). Interestingly, null genotype of GSTT1 was associated with RCC risk in Caucasians and Asians (Caucasians: N = 4, p-heterogeneity = 0.38, OR = 0.76, 95% CI: 0.61-0.95, p = 0.01; Asians: N = 1, OR = 2.39, 95% CI: 1.63-3.51, p < 0.00001). For the GSTM1-GSTT1 interaction analysis, the dual null genotype of GSTM1/GSTT1 was not significantly associated with RCC susceptibility ( N = 4, p-heterogeneity = 0.006, OR = 1.17, 95% CI: 0.98-1.39, p = 0.09). However, the dual null genotype of GSTM1-GSTT1 was associated with RCC risk in Asians ( N = 1, OR = 2.06, 95% CI: 1.36-3.13, p = 0.007). In conclusion, our study results suggest that GSTT1 null genotype is associated with the RCC susceptibility in Caucasians and Asians, and the dual null genotype of GSTM1-GSTT1 is associated with RCC risk in Asians. However, more genetic epidemiological investigations are required to further explore this relationship. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The present study was aimed at examining the local distribution of GSTM1, GSTT1, MDR1, and VEGF gene polymorphisms as possible risk factors contributing to the development of bladder cancer among the population from Canary Islands, Spain. Materials and methods: The genotypes were determined by PCR-based methods in a hospital-based case-control study consisting of 119 cases and 110 controls. The socio-demographic and clinicopathologic data were collected, including the smoking habits of the population covered in the study. Results: The observed allelic frequencies were (%): GSTM1-GSTT1, (positive) 54 and (null) 46 in cases, and 65 and 35, respectively, in controls (P = 0.144); MDR1 C3435T, (C) 57 and (T) 43 in cases, and 54 and 46, respectively, in controls (P = 0.633); VEGF A2578C, (A) 40 and (C) 60 in cases, and 51 and 49, respectively, in controls (P = 0.221). Among Canary Islands subjects, GSTT1-null genotype appeared as a significant risk factor for bladder cancer (odds ratio (OR) 2.0; 95% confidence interval (CI), 1.0–3.7; P = 0.041), in multivariate analysis adjusted by age and smoking habits. No statistical changes in genotype distribution of GSTM1, MDR1 C3435T, and VEGF A2578C gene polymorphisms were observed between cases and controls. The distribution of the initial clinical stage, clinical grade, or recurrence status was not significantly different among the polymorphic variants in the case group (P = NS). Conclusions: Subjects with the GSTT1-null genotype might be at an increased risk of bladder cancer in Canary Islands, Spain. However, extensive studies are required for accurate confirmation of these results. [Copyright &y& Elsevier]

Many studies have investigated the association between glutathione S-transferase T1 ( GSTT1) null genotype and risk of coronary heart disease (CHD), but the impact of GSTT1 null genotype on CHD is still unclear owing to the obvious inconsistence among those studies. This study aims to quantify the strength of association between GSTT1 null genotype and risk of CHD. We searched the PubMed, Embase and Wangfang databases for studies relating the association between GSTT1 null genotype and risk of CHD. We estimated summary odds ratio (OR) with their 95 % confidence interval (95 % CI) to assess the association. 24 case-control studies with 13, 884 CHD cases and 30, 719 controls were included into this meta-analysis. Meta-analysis of total 24 studies showed GSTT1 null genotype was not associated risk of CHD (random-effects OR = 1.17, 95 % CI 0.97-1.42, P = 0.101). After adjustment for heterogeneity, meta-analysis showed GSTT1 null genotype was associated increased risk of CHD both in total population and Caucasians (for total population, fixed-effects OR = 1.12, 95 % CI 1.05-1.21, P = 0.001; for Caucasians, fixed-effects OR = 1.10, 95 % CI 1.02-1.19, P = 0.010). There was no significant association in the other populations. No evidence of publication bias was observed. Meta-analyses of available data suggest the GSTT1 null genotype contributes to increased risk of CHD in Caucasians. [ABSTRACT FROM AUTHOR]

Glutathione S-transferases (GSTs) are phase II enzymes that detoxify hazardous xenobiotics including carcinogens. Inter-individual variations in GSTM1 and GSTT1 loci have been associated with several types of cancer, including leukemias. In this study, we investigated the possible association between GSTM1 and GSTT1 polymorphisms and susceptibility to chronic myeloid leukemia (CML) in a Turkish population. In a case-control study, 106 CML patients and 190 healthy controls were evaluated for GSTM1 and GSTT1 polymorphisms. GSTM1 null ( GSTM1-) genotype frequencies in CML cases and controls were 45.3% and 42.6%, respectively. GSTT1 null ( GSTT1-) genotype frequencies were 44.3% and 18.4%, respectively. The frequency of the GSTT1- genotype among CML patients was significantly higher than in controls [odds ratio (OR) 3.53, 95% confidence interval (CI) 2.08-6.00; P < 0.0001]. Individuals with the GSTM1- genotype did not have increased risk of CML [OR: 1.11; 95% CI: 0.69-1.80; P = 0.714]. The combined GSTM1-/ GSTT1- genotype was significantly associated with risk of CML compared to the GSTM1+/GSTT1+ genotype which was most frequent in both cases and controls [OR: 9.47; 95% CI: 3.61-24.87]. Similar findings have only been obtained in Turkish and Indian populations but not elsewhere. The GSTM1+/ GSTT1- genotype was associated with a 2.5-fold increased risk compared with the GSTM1-/ GSTT1+ genotype, the second most frequent genotype (OR; 2.46; 95% CI: 1.17, 5.20), suggesting a complex interaction between GSTM1 and GSTT1. Our results indicate an association between the GSTT1- genotype, either alone or in combination with GSTM1- genotype, and risk of CML, suggesting a possible interaction between GSTM1 and GSTT1. These findings, which are possibly restricted to Turkey and India, warrant further research. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present study was to investigate the role of some polymorphisms in GSTs (GSTM1, GSTT1 and GSTP1) which are very important protective mechanisms against oxidative stress and in OGG1 gene which is important in DNA repair, against the risk of type 2 diabetes mellitus (T2DM). 127 T2DM and 127 control subjects were included in the study. DNA was extracted from whole blood. Analyses of GSTM1 and GSTT1 gene polymorphisms were performed by allele specific PCR and those of GSTP1 Ile105Val and OGG1 Ser326Cys by PCR‐RFLP. Our data showed that GSTM1 null genotype frequency had a 2–6 times statistically significant increase in a patient group (OR=3.841, 95% CI=2.280–6.469, p <0.001) but no significance with GSTT1 null/positive and GSTP1 Ile105Val genotypes was observed. When T2DM patients with OGG1 Ser326Cys polymorphism were compared with patients with a wild genotype, a 2–3 times statistically significant increase has been observed (OR 1.858, 95% CI=1.099–3.141, p =0.021). The combined effect of GSTM1 null and OGG1 variant genotype frequencies has shown to be statistically significant. Similarly, the risk of T2DM was statistically increased with GSTM1 null (OR=3.841, 95% CI=2.28–6.469), GSTT1 null+ GSTP1 (H+M) (OR=4.118, 95% CI=1.327–12.778) and GSTM1 null+ OGG1 (H+M) (OR=3.322, 95% CI=1.898–5.816) and GSTT1 null+ OGG1 (H+M) (OR=2.179, 95% CI=1.083–4.386) as compared to the control group. According to our study results, it has been observed that the combined evaluation of GSTM1–GSTT1–GSTP1 and OGG1 Ser326Cys gene polymorphisms can be used as candidate genes in the etiology of T2DM, especially in the development of T2DM. [Copyright &y& Elsevier]

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. A number of studies have examined the role of genetic polymorphisms in the risk of DLBCL, and several variants have been identified as potential susceptibility genes, of those glutathione-S-transferases T1 and M1 (GSTT1 and GSTM1). Aim of the work: The aim of the current study was to investigate the influence of inherited genetic polymorphisms of GSTM1 and GSTT1 genes on the susceptibility to DLBCL in Egypt. Methods: Genotyping of the candidate genes was performed for 71 Egyptian DLBCL patients and 100 age- and gender-matched healthy controls by multiplex polymerase chain reaction technique. Results: The frequencies of GSTT1 null, GSTM1 null, and dual null genotypes among DLBCL patients were 47.9, 52.1, and 23.9 % respectively. Conclusion: GSTT1 null genotype conferred almost fourfold increased risk of DLBCL (OR = 3.9, 95 % CI = 1.97-7.75), and the risk increased when confined to male patients (OR = 4.4, 95 % CI = 1.57-12.63), while GSTM1 null genotype was not associated with DLBCL risk. Further studies on the functional consequences of GSTT1 and GSTM1 genetic polymorphisms would pave the way to declare their role in the pathogenesis of DLBCL or as possible predictors for response to therapy. [ABSTRACT FROM AUTHOR]

Genetic polymorphisms in genes encoding glutathione S-transferase T1 ( GSTT1, a member of class theta) and M1 ( GSTM1, a member of class mu) have been defined. Previous studies have revealed that there was significant difference between populations for allelic frequency of several members of GSTs. In order to find the prevalence of null genotypes of GSTM1 and GSTT1 in Afghanis populations the present study was carried out. The total study subjects consisted of 656 unrelated healthy Afghanis refugees living in Fars province (southern Iran). From these 257, 217, 120, and 62 individuals were Pashtuns, Tajiks, Hazaras, and Uzbeks, respectively. Genetic polymorphisms for GSTT1 and GSTM1 were detected by multiplex PCR. The prevalence of null genotype of GSTM1 in Pashtuns, Tajiks, Hazaras, and Uzbeks was 42.4, 48.4, 52.5, and 40.3 %, respectively. There was no significant difference between these populations for the genotypic distribution of the GSTM1 polymorphism (χ = 4.67, df = 3, P = 0.197). The frequency of GSTT1 null genotype in Pashtuns, Tajiks, Hazaras, and Uzbeks was 7.4, 25.3, 25.0, and 29.0 %, respectively. The observed difference between populations for prevalence of GSTT1 null genotype was statistically significant (χ = 35.54, df = 3, P < 0.001). In comparison with European and Asian populations, Afghanistan populations like Iranian populations showed intermediate frequency for GSTT1 and GSTM1 null genotypes. [ABSTRACT FROM AUTHOR]

The article discusses a research study which examined the association of glutathione S-transferase T1 (GSTT1) and M1 gene polymorphisms with ischemic stroke risk in the Chinese Han population compared to healthy controls. The researchers used polymerase chain reactions, electrophoresis and imaging analysis to determine GSTT1 and GSTM1 genotypes. Analysis revealed an increase in the risk of stroke when hypertension or diabetes was accompanied by GSTT1-null and GSTM1-null genotypes.

Abstract: Introduction: Oxidative stress plays key role in pathogenesis of Alzheimer''s disease. Glutathione S-transferases (GSTs), a family of phase-II isoenzymes, play a critical role in providing protection against electrophiles and products of oxidative stress. Among different classes of GSTs, GSTM1 (Mu) and GSTT1 (theta) are found to be genetically deleted which results in decreased expression of the concerned enzyme. This study aims at preliminary analysis of the frequency of deletion of GSTM1 and GSTT1 and their association with late-onset Alzheimer''s disease. Material and methods: In this study, association of the deletion type polymorphism of GST M1 and T1 as possible risk factors for dementia of Alzheimer''s type was studied in 50 patients and 100 controls. Dementia was diagnosed by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria, Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scale. Genotyping was done by multiplex Polymerase Chain Reaction (PCR). Associations between null genotype of either GSTM1 and GSTT1 or both with Alzheimer''s disease were analyzed by Chi-Square test. Results: Deletion of GSTT1 was found significantly associated with Alzheimer''s disease (χ 2 =5.08, p =0.02*). Conclusions: The odds of Alzheimer''s disease in null GSTT1 is found to be increased by 2.47 times in comparison to positive GSTT1. [Copyright &y& Elsevier]

It is proposed that lead concentrations in the blood are related to intracellular glutathione and lead might be conjugated with glutathione non-enzymatically or enzymatically via glutathione S-transferase (GST). Essential hypertension is a complex, multifactorial and polygenic disease in which the underlying genetic components remain unknown. This study was aimed to investigate GST-mu1 ( GSTM1) and GST-theta1 ( GSTT1) gene polymorphisms in lead-exposed workers and their relationship with blood lead levels and leadrelated hypertension. To address the possible association, GSTM1 and GSTT1 (homozygous deletion vs. non-deleted) polymorphisms in 755 lead-exposed male workers were analyzed. GSTM1 and GSTT1 polymorphisms were determined using a Multiplex PCR. We observed significant association in positive alleles of GSTT1 (OR=1.593, 95% CI=1.157-2.194). However, no significant association in GSTM1 was observed with lead-related hypertension. For combined analysis with GSTM1 and GSTT1, both positive type (+/+) and GSTT1 positive (−/+) group showed significant differences between groups. These data suggest that the GSTT1 positive type polymorphism might be associated with lead-related hypertension in the lead-exposed male workers. [ABSTRACT FROM AUTHOR]

Abstract: The pathogenesis of cataract is influenced by a number of factors including oxidative stress. Glutathione-S-transferase (GST) catalyses the nucleophilic addition of the thiol of GSH to electrophilic acceptors. It is important for detoxification of xenobiotics in order to protect tissues from oxidative damage. In humans, GSTT1 and GSTM1 deletion genotypes are associated with a variety of pathological conditions including certain ophthalmic diseases. In the present study, it is aimed to determine the risk of genetic polymorphisms of GSTM1 and GSTT1 isoforms of GST for developing of age related cataracts (ARCs). We compared the prevalence of GSTT1 and GSTM1 deletion genotypes, which were determined by multiplex polymerase chain reaction, in 455 patients with ARCs (108 with nuclear (NC), 105 with cortical (CC), 96 with posterior subcapsular, (PSC) and 146 with mixed type (MT)) and 205 age and sex matched controls. The GST activity in erythrocytes (RBC) and cataractous lenses was measured spectrophotometrically using 1-chloro-2,4-dinitrobenzene (CDNB) as substrate. The frequency of GSTM1 positive individuals was significantly higher in MT cataracts followed by NC, CC and PSC types with corresponding decrease in the GSTM1 null genotypes as compared to controls. Considering the GSTT1 locus, GSTT1 null genotypes showed high frequency in patients in general as compared to controls with corresponding reduction in the GSTT1 positive genotype. The activity of GST in RBC was higher in all the types of cataracts as compared to that in controls and in cataractous lenses the mean values were slightly higher in cases of NC cataracts as compared to CC, PSC and MT. The data suggests that GSTM1 positive, GSTT1 null and double null (GSTM1 null and GSTT1 null) genotypes may confer risk for the development of ARC. The increased activity of GST found in the present study could be due to a compensatory mechanism operating in response to increased oxidative stress. [Copyright &y& Elsevier]

Abstract: Simple aromatic hydrocarbon benzene occurs naturally in crude oil and petroleum. Benzene has been internationally recognised as a haematotoxin and carcinogen. The involvement of oxidative stress is a major susceptibility factors for benzene hematotoxicity in humans. Advanced oxidation protein products (AOPPs) and advanced glycation end products (AGEs) are modified structures which can serve as markers of oxidative stress. The aim of this study is to assess modification of circulating AOPPs and AGEs, as early markers of oxidative stress, in subjects exposed to low dose of benzene. Furthermore the genetic polymorphism of glutathione-S-transferase (GST) may be related to health effects of benzene exposure, in fact both genotype T1 (GSTT1) and M1 (GSTM1) are involved in the detoxification of benzene oxide. The study was performed on 54 workers oil refinery employees. A group of 32 healthy age-matched subjects was included as controls. The AOPPs serum levels in oil refinery employees were higher in a statistically significant way than those measured in controls, but there were no significant changes in serum AGE levels between both groups. However, GST polymorphisms had not influence on serum levels of both biomarkers, so demonstrating that production of circulating AGEs and AOPPs in benzene parity-exposed workers levels is not dependent by GST genotypes. We can conclude that, in this condition, AOPPs are more sensitive marker of low benzene exposure than AGEs. [Copyright &y& Elsevier]

The relationships between some metabolic (including EPHX1, GSTs and NQO1) gene polymorphisms and colorectal adenoma (CRA) risk have been commonly studied, and no conclusions are available up to now. Therefore, we quantitatively studied the relationships by a metaanalysis. The databases of Medline and Embase were retrieved updated to June 15th, 2011. Crude or adjusted odds ratio (crude OR or adjusted OR) and 95% confidence interval (95%CI) were calculated to present the strength of the associations. Overall, nine case-control studies for EPHX1 Tyr113His and His139Arg, five case-control studies for GSTM1, four studies for GSTP1 Ile105Val, two studies for GSTP1 Ala114Val, six studies for GSTT1 and four studies for NQO1 Pro187Ser were included in this metaanalysis. The results of combined analyses indicated that EPHX1 Tyr113His and His139Arg, GSTT1, GSTM1, GSTP1 Ile105Val and Ala114Val were not associated with CRA risk [crude OR (95%CI): 0.98 (0.90-1.07) and P = 0.65 for EPHX1 His carriers vs. Tyr/Tyr; 1.05 (0.97-1.15) and P = 0.21 for EPHX1 Arg carriers vs. His/His; 1.05 (0.92-1.20) and P = 0.47 for GSTT1 Null vs. Present; 1.01 (0.90-1.13) and P = 0.90 for GSTM1 Null vs. Present; 1.04 (0.92-1.17) and P = 0.56 for G carriers vs. AA for GSTP1 Ile105Val; 0.88 (0.70-1.11) and P = 0.28 for T carriers vs. CC for GSTP1 Ala114Val]. In contrast, Ser allele of NQO1 Ser187Pro might be a modest risk factor for CRA development [1.19 (1.06-1.33) and P = 0.003 for Ser carriers vs. Pro/Pro]. To get more precise evidences, adjusted ORs (95%CI) for EPHX1 Tyr113His, His139Arg, GSTP1 Ile105Val and NQO1 Ser187Pro were also calculated based on adjusted ORs (95%CIs) reported in primary studies. The results still indicated that EPHX1 Tyr113His, His139Arg and GSTP1 Ile105Val were not associated with CRA risk except for NQO1 Ser187Pro. When subgroup analyses were performed for population-based case-control studies or studies in HWE for EPHX1 Tyr113His and His139Arg, and NQO1 Ser187Pro polymorphisms, the results were persistent. Although with modest limitations and biases, this metaanalysis suggests that EPHX1 Tyr113His and His139Arg, GSTT1, GSTM1, GSTP1 Ile105Val and Ala114Val polymorphisms may be not risk factors for CRA development, while Ser allele of NQO1 Ser187 Pro may be a modest risk factor for CRA development, and may be used with other genetic markers for screening CRA in the future. [ABSTRACT FROM AUTHOR]

Polymorphisms of the Glutathione-S Transferase (GST) family may influence the prognosis in lymphoma patients. We aimed to validate the impact of GSTT1 and GSTM1 deletions and of the GSTP1Ile105Val polymorphism on outcome and toxicity in 140 patients with advanced Hodgkin's lymphoma enrolled in the prospective multicenter HD2000-GISL trial, comparing ABVD, BEACOPP and CEC regimens. Carriers of the GSTP1Ile105Val polymorphism had a higher rate of grade 3-4 anemia following treatment. Overall, our study failed to validate GST genotyping as prognostic factor for progression-free survival (PFS). Only the small cohort of patients with an international prognostic score (IPS) >3 and undeleted GSTT1 and/or GSTM1, treated with ABVD had worse progression-free survival (PFS) (GSTT1 ++ vs GSTT1−: HR 5.02, 95% C.I., 1.16-21.8, p == 0.031, GSTM1 ++ /GSTT1 ++ vs GSTM1−and/or GSTT1−: HR 4.61, 95% C.I. 1.28- 16.6, p == 0.019, respectively). No differences were observed for patients treated with intensified regimens, as BEACOPP and CEC. In conclusion, the prognostic role of GST polymorphism, if at all, is limited to a small subgroup of patients treated with standard ABVD regimen. [ABSTRACT FROM AUTHOR]

The aim of this study is to understand the multifactorial causes of age-related macular degeneration (ARMD), and, therefore, it is reasonable to investigate whether genetic polymorphisms of antioxidant enzymes ( GSTM1 and GSTT1) contribute to the development of ARMD. This study consisted of 112 subjects (44 females, 68 males) with exudative ARMD, who were recruited from Khalili Hospital ophthalmic clinic in Shiraz (southern Iran), referred by vitreoretinal surgeon. Also 112 sex-matched controls (44 females, 68 males) were randomly selected from unrelated volunteers in the same clinic. We excluded patients and controls with cataract or past history of cataract surgery, asthma, past history of malignancy, cardiovascular disease that on medication and known cases of glaucoma, because these traits were associated with GSTM1 and/or GSTT1 polymorphisms. There was no association between polymorphisms of neither GSTM1 nor GSTT1 and risk of ARMD. The combination genotypes of GSTM1 and GSTT1 were not associated with the risk of ARMD. We considered the time of deterioration of vision as the time of onset of exudative ARMD. The Kaplan-Meier analysis revealed that there was significant difference between genotypes of GSTM1 (log rank statistic = 7.03, df = 1, P = 0.008). The age at onset among GSTM1 null genotype was lower than the active genotype of GSTM1. Our results support the hypothesis that the protein encoded by the GSTM1 gene might have a protective function against oxidative stress in retina. Since the age at onset is influenced by the GSTM1 polymorphism, this implies that GSTM1 is a modifier gene. [ABSTRACT FROM AUTHOR]

Abstract: Studies investigating the association between glutathione S-transferase T1 (GSTT1) gene polymorphism and laryngeal cancer susceptibility have reported conflicting results. The aim of the present study was to conduct a meta-analysis assessing the possible association of GSTT1 gene polymorphism with laryngeal cancer risk. The relevant studies were identified through a search of PubMed, Embase, ISI Web of Knowledge and Chinese National Knowledge Infrastructure until May 2011. Twelve studies were included in the present meta-analysis, which described a total of 2124 laryngeal cancer cases and 2059 controls. The overall odds ratio (OR) for GSTT1 null genotype was 1.40 (95% CI=0.90–2.16). When stratifying for race, the pooled ORs for GSTT1 null genotype were 1.07 (95% CI=0.81–1.41) in Caucasians and 5.63 (95% CI=1.00–31.83) in Asians. The pooled ORs for GSTT1 null genotype were 1.03 (95% CI=0.71–1.49) in population-based studies and 2.39 (95% CI=0.73–7.86) in hospital-based studies, stratifying for study design. This meta-analysis suggested that there was lack of association between GSTT1 gene polymorphism and laryngeal cancer risk. However, larger scale primary studies are still required to further evaluate the interaction of GSTT1 gene polymorphism with laryngeal cancer risk. [Copyright &y& Elsevier]

Abstract: Background: Associations between polymorphisms for gene encoding enzymes involved in biotransformation of xenobiotics and susceptibility to several cancers have been shown in several studies. The aim of the present study was to evaluate the association of polymorphisms of cytochrome P450 (CYP1A1) and GST deletions with the incidence of Polycythemia vera (PV) among the Jordanian population. Methods: The study included 61 PV patients and 70 cancer-free healthy controls. CYP1A1 (m1, m2, m3, m4) and GST (T1, M1) genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism. The risk of cancer associated with gene polymorphisms was estimated by calculations of odds ratio (ORs) and confidence intervals (95% CIs) using Mantel–Haenszel statistics. Results: A statistically significant difference between the PV group and the control group was observed in the case of GSTM1 null genotype with 3.38 fold increase in risk of developing PV (95% CI=1.63–7.01, p =0.001) while GSTT1 null genotype showed no significance (OR=1.11; 95% CI=0.50–2.44, p =0.38). No significant association was found between the CYP1A1 mutant genotypes (m1, m2, m4) and PV. The m3 genotype was absent in both patients and controls. Interestingly, a substantial significant increase of PV risk for the combination of GSTM1 null genotype and CYP1A1 m1 (T6235C) genotype was observed (OR=4.38; 95% CI=1.15–16.73, p =.02). Furthermore, the present case–control study showed that the studied Jordanian population generally resembles Caucasian populations with respect to the frequencies of CYP1A1 polymorphisms. Conclusion: Our data suggests that GSTM1 null genotype alone and in combination with CYP1A1 m1 genotype may be predisposing risk factors for PV in the Jordanian population. [Copyright &y& Elsevier]

Enzymes belonging to the glutathione-S-transferase (GST) and cytochrome P450 (CYP) families are involved in a 2-stage detoxification process of a wide range of environmental toxins and carcinogens. In order to investigate whether there is a genetic association of the biotransformation enzymes and idiopathic male fertility, we studied GSTT1, GSTM1, and CYP1A1*2A polymorphisms in 150 infertile men and 200 healthy men as controls from Northern Iran. Genotyping of the GSTT1 and GSTM1 genes were performed using the multiplex polymerase chain reaction (PCR). However, the CYP1A1 polymorphism was determined using PCR-restriction fragment length polymorphism (RFLP). The GSTM1 and GSTT1 null genotypes were present at frequencies of 0.61 and 0.34 in infertile cases, whereas in controls the frequencies were 0.33 and 0.17, respectively. Double-null genotype was found to be elevated among infertile men (odds ratio [OR] = 3.75, 95% confidence interval [CI] = 2.42-6.45; P < .0001). The frequency of TT, TC, and CC genotypes of CYP1A1 polymorphism in the controls were 42.5%, 45.5%, and 12%, respectively, while those in the infertile men were 38.7%, 48%, and 13.3%. The CYP1A1*2A did not display any association with male infertility. We observed an association between male infertility and the GSTM1 and GSTT1 null deletion, but not with the CYP1A1 polymorphism in North Iranian men with idiopathic infertility. [ABSTRACT FROM PUBLISHER]

Abstract: B cell responses to minor histocompatibility antigens (mHags) have not been extensively studied after allogeneic hematopoietic stem cell transplantation (HSCT). Glutathione S-transferase T1 (GSTT1) is a drug metabolizing enzyme encoded by a single gene that is highly expressed in liver and kidney. Anti-GSTT1 antibodies have been described in the context of antibody-mediated rejection in kidney and liver transplantation, due to a mismatch between donor and recipient. The aim of the present study was to investigate the specific immune response against GSTT1 in HSCT with production of antibodies and their influence in the development of hepatic graft-versus-host-disease (GVHD). Forty patients and their respective donors were included in the study. The median follow-up time was 35.6months (range 0.6–76months) and a total of 349 serum samples were tested for the presence of anti-GSTT1 antibodies by ELISA test. Statistical analysis was performed by defining the GSTT1 null donor/positive recipient as mismatch compared with the other three genetic combinations regarded as GSTT1-matched. Antibodies were found in three patients within the group of null donor/positive recipient and one within the null/null group. Development of liver GVHD, particularly its acute form, was highly associated with the GSTT1-mismatch (P =0.0178) and with the presence of post-transplant anti-GSTT1 antibodies (P =0.0076). We conclude that GSTT1 could be considered as a new mHag in hepatic GVHD. The fact that three donors were parous females and the rapid production of antibodies after HSCT suggests the existence in the graft of memory B-cells specific for the GSTT1 antigen. [Copyright &y& Elsevier]

We examined the influence of the CYP1A1 A4889G and T6235C, GSTM1 and GSTT1 polymorphisms, involved in carcinogen metabolism, on the head and neck (HN) squamous cell carcinoma (SCC) risk. DNA from 142 HNSCC patients and 142 controls was analysed by polymerase chain reaction (PCR)-restriction fragment length polymorphism or multiplex-PCR for the polymorphisms analyses. Excesses of the CYP1A1 4889AG+GG and 4889AG+GG plus GSTT1 null genotype were seen in patients with heavy tobacco habit compared with controls (41.9% versus 26.8%, P = 0.03; 26.2% versus 10.3%, P = 0.04, respectively). Carriers of the referred genotypes and heavy tobacco consumption were under a 2.0-fold and 2.8-fold increased risks for HNSCC than others, respectively. The CYP1A1 6235TC+CC plus GSTM1 and GSTT1 null genotypes were more common in pharyngeal SCC patients than in controls (5.3% versus 0.7%, P = 0.04). Carriers of the combined genotype had 16.0-fold increased risk for the disease than others. The frequency of one null genotype of the GSTM1 or GSTT1 gene was higher in patients with pharyngeal SCC and heavy smoking status than in controls (76.3% versus 57.7%, P = 0.04). Carriers of the referred genotype and heavy tobacco status had a 2.4-fold increased risk for pharyngeal SCC than others. In contrast, the CYP1A1 6235TC+CC genotype was more common in controls than in laryngeal SCC patients (35.9% versus 21.6%, P = 0.01). Carriers of the genotype had a 0.2-fold decreased risk for the disease than others. Our data present preliminary evidence that inherited combined CYP1A1 A4889G and T6235C abnormalities and GSTM1 and GSTT1 pathways are important determinants of HNSCC, particularly pharyngeal SCC in heavy smoking individuals from south-eastern Brazil. [ABSTRACT FROM AUTHOR]

Abstract: Background: Difference in the capacity of xenobiotic metabolising enzymes might be an important factor in genetic susceptibility to cancer. Methods: A case control study involving forty one gastric cancer patients and one hundred and thirty controls was carried out to determine the frequency of GSTM1 and GSTT1 null genotypes. The frequency of GSTM1 and GSTT1 null genotype was observed by carrying out multiplex PCR. Results: There was no difference in the frequencies of the GSTM1 and GSTT1 null and the combined GSTM1 and GSTT1 null genotype between patients and control. Conclusions: Our data suggest that GSTM1 and GSTT1 status may not influence the risk of developing gastric cancer. [Copyright &y& Elsevier]

Abstract: The association between present/null polymorphism of glutathione S-transferase T1 (GSTT1) and breast cancer risk are still inconclusive. We performed a meta-analysis to derive a more precise estimation of the relationship. A total of 48 studies including 17,254 cases and 21,163 controls were involved in this meta-analysis. When all studies were pooled into the meta-analysis, significantly elevated breast cancer risk was associated with null genotype (OR=1.138, 95% CI=1.051–1.232). When stratified by ethnicity, significantly increased risks were found for Caucasians (OR=1.185, 95% CI=1.075–1.306), but no statistically significantly increased risks were found in Asians (OR=1.017, 95% CI=0.846–1.223) and Africans (OR=1.160, 95% CI=0.815–1.650). In the subgroup analysis by controls source, statistically significantly elevated risks were both found in population-based studies (OR=1.123, 95% CI=1.014–1.243) and hospital-based studies (OR=1.181, 95% CI=1.056–1.321). When stratified by menopausal status, no statistically significantly increased risks were found in premenopausal women (OR=1.115, 95% CI=0.925–1.345) and postmenopausal women (OR=1.077, 95% CI=0.992–1.169). In summary, this meta-analysis suggests that the GSTT1 null genotype is a risk allele for breast cancer development. However, large sample and representative population-based studies with homogeneous breast cancer patients and well matched controls are warranted to confirm this finding. [Copyright &y& Elsevier]

Exposure to endocrine-disrupting chemicals (EDCs) and maternal endogenous estrogen may cause hypospadias, common congenital anomaly. Several organochlorine pesticides (OCPs) have been reported to possess an endocrine-disrupting potential. Cytochrome P4501A1 (CYP1A1) and glutathione S-transferases (GSTM1 and GSTT1) of xenobiotic metabolizing enzyme family are involved in the metabolism of various environmental toxicants and steroidal hormones. Hence, the present study was designed to evaluate the role of CYP1A1, GSTM1, GSTT1 genes polymorphism, OCPs levels and risk of hypospadias. A total of 80 hypospadiac and 120 age-matched control boys were included. OCP levels in blood were determined using Gas Chromatograph equipped with electron capture detector (GC-ECD) and polymorphism in CYP1A1, GSTM1 and GSTT1 genes was evaluated by RFLP and multiplex PCR method. We observed significant high levels of β-hexachlorohexane (HCH), γ-HCH, and p,p′-dichlorodiphenyl-dichloroethylene (p,p’-DDE) in the cases. CYP1A1 polymorphisms were not significantly different among cases and controls, whereas concomitant deletion of GSTM1 and GSTT1 genotypes was significantly higher in cases as compared to controls. However, after adjusting for low birth weight and maternal occupational exposure, the results did not remain significant but odds of risk was higher (OR = 1.72, p = 0.14) among cases. In conclusion, our study suggests irrespective of genetic predisposition, higher level of some OCPs may be associated with increased risk of hypospadias. [ABSTRACT FROM PUBLISHER]

Abstract: DNA damage was evaluated by alkaline comet assay in peripheral blood lymphocytes of 115 coal-tar workers occupationally exposed to polycyclic aromatic hydrocarbons (PAHs) and 105 control subjects. The effect of polymorphisms of glutathione S-transferase (GST) genotypes on the DNA damage was assessed. The mean tail moment (TM) value in the coal-tar workers was significantly higher as compared to the control subjects (12.06±0.55 versus 0.44±0.31; P <0.05). No significant association (P >0.05) between the GSTT1 and GSTM1 genotypes and the TM values was found, however highest mean rank TM value was reported in GSTM1 null and GSTT1 null genotypes in both control and exposed subjects. Our results suggest that there is increased DNA damage in coal-tar workers due to PAHs exposure. Polymorphisms in GSTM1 and GSTT1 genes do not show significant effect (P >0.05) on DNA damage. [Copyright &y& Elsevier]

Summary: The highest rates of oral squamous cell carcinomas are observed in south Asia, particularly in India, where complex forms of tobacco and alcohol exposures exist. Genetic polymorphisms contribute significantly to observed differences in cancer susceptibility. We examined the association of 13 variants in eight genes (rs4646903, rs2031920, rs3813867, GSTM1 null, GSTT1 null, rs1695, rs1138272, rs1799782, rs25487, rs1799791, rs1799793, rs13181 and rs1052133) involved in various stages of tobacco and alcohol metabolism and the risk of leukoplakia and oral cancer (OC) in a case–control study involving 219 oral leukoplakia, 665 OC and 802 age, sex and habit-matched controls. GSTT1 null and rs1695 were inversely associated with oral leukoplakia while GSTM1 null, GSTT1 null, rs2031920, rs3813867 (CYP2E1), and rs13181 were associated with OC. We report that genetic variants associated with premalignant and malignant conditions of the oral cavity differ. The associations appeared to be consistent among smokeless tobacco users, a characteristic risk factor in these parts. [ABSTRACT FROM AUTHOR]

Glutathione S-transferases are a superfamily of multifunctional enzymes that play a key role in Phase II metabolism, detoxifying therapeutic drugs, and various carcinogens by conjugation with glutathione. We undertook a case-control study in Central-Eastern Portuguese population to evaluate the association of null genotype in GSTM1 and GSTT1 along with the polymorphism in GSTP1 (A/G) and susceptibility to breast cancer. The population sample consisted of 85 patients with histological diagnosis of breast cancer and 102 healthy women. Genomic DNA was extracted from blood samples, and genotyping analyses were performed by PCR-based methods. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by unconditional logistic regression. We found a increased breast cancer risk associated with GSTM1 null genotype (OR = 3.597; 95% CI = 1.849-6.999; P = 0.0001) and GSTT1 (OR = 2.592; 95% CI = 1.432-4.690; P = 0.002), but the presence of valine alleles compared to isoleucine alleles in codon 105 in GSTP1 did not increase the risk of breast cancer development. The two-way combination of GSTM1 and GTTT1 null genotypes resulted in 8-fold increase for breast cancer risk (OR = 8.287; 95% CI = 3.124-21.980; P = 0.0001) and the three-way combination of GSTP1 105AA/AG and null genotypes for both GSTM1 and GSTT1 resulted in 5-fold increase for breast cancer risk (OR = 5.040; 95% CI = 1.392-18.248; P = 0.016). Our results suggest that GSTM1 and GSTT1 null genotype alone, both combined or combined with GSTP1 valine alleles, are associated with higher susceptibility to breast cancer development. [ABSTRACT FROM AUTHOR]