GSTT1 Null Genotype Research Articles

Abstract 4347: A randomized phase 2 clinical trial of PEITC on detoxification of tobacco-specific and non-specific carcinogens and toxicants

Abstract Abstract Background: Cigarette smoke contains the tobacco-specific lung carcinogen NNK and other carcinogens and toxicants. 2-Phenethyl isothiocyanate (PEITC), a natural product found as a conjugate in cruciferous vegetables, can inhibit the metabolic activation and lung carcinogenicity of NNK in rodents. Intake of a broccoli sprout beverage containing high levels of sulforaphane can increase urinary excretion of benzene and acrolein metaboites. Glutathione S-transferases (GST) catalyze the conjugation of carcinogens and toxicants with glutathione enhancing their urinary excretion, thus functional GST genotypes may modify the effect of PEITC. Methods. The goal of this randomized phase 2 clinical trial with a crossover was to determine if PEITC inhibits the metabolic activation of NNK and enhances the detoxification of benzene, acrolein and crotonaldehyde. Eighty-two smokers were completed the trial. The smokers smoked cigarettes containing deuterium labeled [pyridine-D4]NNK to allow measurement of metabolic activation. The subjects were randomly assigned to one of two arms: PEITC-placebo, or placebo-PEITC. During the 1-week treatment period, each subject took PEITC (10 mg in 1 ml of olive oil, 4 times per day). There was a 1-week washout period between the PEITC and placebo periods. Three 24h urine samples were collected during each of the 2 treatment periods. The NNK metabolic activation ratio: [pyridine-D4]hydroxy acid/total [pyridine-D4]NNAL, and the mercapturic acids of benzene, acrolein and crotonaldehye in urine were quantified using validated LC-ESI-MS/MS methods. The linear mixed model with random effect was used to examine the PEITC effect. Results. Overall, PEITC treatment significantly reduced the NNK metabolic activation ratio by 7.7% (P = 0.023), and increased the detoxification metabolites of benzene by 24.6% (P = 0.002) and acrolein by 15.1% (P = 0.005), but had no effect on crotonaldehyde (5.5%, P = 0.148). PEITC had stronger effects in subjects with GST null genotype. PEITC reduced the NNK metabolic activation ratio by 15.6% (P = 0.039), and increased detoxification metabolites of benzene by 95.4% (P <0.001), acrolein by 32.7% (P = 0.034), and crotonaldehyde by 29.8% (P = 0.006) among the subjects with null genotype of both GSTM1 and GSTT1, but had no effect in those possessing both genes (Pinteraction < 0.05). Conclusion. The results of this trial demonstrate that PEITC inhibits the metabolic activation of NNK in smokers, and has a stronger effect on the detoxification of environmental carcinogens and toxicants such as benzene, acrolein, and crotonaldehyde. A more pronounced effect of PEITC in subjects lacking both GSTM1 and GSTT1 genes supports the epidemiological findings of stronger protection of dietary isothiocyanates against the development of lung cancer in such individuals. [Grant support: NCI R01CA122244]. Citation Format: Jian-Min Yuan, Jian-Min Yuan, Irina Stepanov, Sharon E. Murphy, Sharon E. Murphy, Renwei Wang, Steven G. Carmella, Heather H. Nelson, Heather H. Nelson, Dorothy Hatsukami, Stephen S. Hecht. A randomized phase 2 clinical trial of PEITC on detoxification of tobacco-specific and non-specific carcinogens and toxicants. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4347.

Traffic-related air pollution exposure is associated with allergic sensitization, asthma, and poor lung function in middle age

Traffic-related air pollution (TRAP) exposure is associated with allergic airway diseases and reduced lung function in children, but evidence concerning adults, especially in low-pollution settings, is scarce and inconsistent. We sought to determine whether exposure to TRAP in middle age is associated with allergic sensitization, current asthma, and reduced lung function in adults, and whether these associations are modified by variants in Glutathione S-Transferase genes. The study sample comprised the proband 2002 laboratory study of the Tasmanian Longitudinal Health Study. Mean annual residential nitrogen dioxide (NO2) exposure was estimated for current residential addresses using a validated land-use regression model. Associations between TRAP exposure and allergic sensitization, lung function, current wheeze, and asthma (n=1405) were investigated using regression models. Increased mean annual NO2 exposure was associated with increased risk of atopy (adjusted odds ratio [aOR], 1.14; 95% CI, 1.02-1.28 per 1 interquartile range increase in NO2 [2.2ppb]) and current wheeze (aOR, 1.14; 1.02-1.28). Similarly, living less than 200m from a major road was associated with current wheeze (aOR, 1.38; 95% CI, 1.06-1.80) and atopy (aOR, 1.26; 95% CI, 0.99-1.62), and was also associated with having significantly lower prebronchodilator and postbronchodilator FEV1 and prebronchodilator forced expiratory flow at 25% to 75% of forced vital capacity. We found evidence of interactions between living less than 200m from a major road and GSTT1 polymorphism for atopy, asthma, and atopic asthma. Overall, carriers of the GSTT1 null genotype had an increased risk of asthma and allergic outcomes if exposed to TRAP. Even relatively low TRAP exposures confer an increased risk of adverse respiratory and allergic outcomes in genetically susceptible individuals.

Association of GSTT1 and GSTM1 gene polymorphisms with coronary artery disease in North Indian Punjabi population: a case-control study

BackgroundGlutathione S-transferases are metabolic enzymes which are responsible for detoxification of endogenous (products of oxidative stress) as well as exogenous (drugs, pesticides, herbicides, environmental pollutants and carcinogens) products. Dysfunctional detoxification...

Analysis of the glutathione S-transferase genes polymorphisms in the risk and prognosis of renal cell carcinomas. Case-control and meta-analysis

BackgroundThe Glutathione S-transferases (GSTs) genes deletion polymorphisms have been associated with the progression of several cancers. The association studies between the 2 GSTs (GSTM1 and GSTT1) null polymorphisms with the susceptibility to renal cell carcinoma (RCC) have been inconclusive. Therefore, with the inclusion of our own data, we performed a comprehensive meta-analysis to assess the association between these 2 polymorphisms and the risk of RCC. MethodsA systematic literature search was carried out for studies published in the PubMed, EMBASE, Cochrane library, and Google Scholar from 1997 to December 2014. Results were stated as pooled odds ratios (ORs) for nonparametric data after heterogeneity analysis with 95% CI using fixed effect or random effect model. ResultsWe systematically selected 13 relevant studies after thorough searches from the databases. Data showed no association between the GSTM1 and the GSTT1 null genotypes and the risk of RCC (OR = 1.01; CI: 0.92–1.11; P = 0.89 for GSTM1 and OR = 1.14; CI: 0.91–1.42; P = 0.25 for GSTT1). No association was found when the data were stratified according to the geographical/ethnic basis, source of control, and the risk factor evaluation. Subgroup analysis of occupational exposure to pesticides showed an inverse association of the active genotypes of both GSTM1 and GSTT1 polymorphisms with the exposed group of RCC (P<0.00001 and P<0.00001, respectively). The combined null genotype of the GSTM1/GSTT1 significantly increased the susceptibility to RCC by 1.4-fold (P = 0.001). This association remained significant for the Asian populations in subgroup analysis (OR = 1.8; CI: 1.30–2.49; P = 0.0004). ConclusionIn conclusion, this meta-analysis suggests that the 2 GSTs deletion polymorphisms independently have no association with the risk of RCC. However, combination of both deletions increases the risk of developing the RCC.

Simulation of interindividual differences in inactivation of reactive para-benzoquinone imine metabolites of diclofenac by glutathione S-transferases in human liver cytosol.

Diclofenac is a widely prescribed NSAID that causes severe idiosyncratic drug induced liver injury (IDILI) in a small part of the patient population. Formation of protein-reactive metabolites is considered to play a role in the development of diclofenac-induced IDILI. Therefore, a high hepatic activity of enzymes involved in bioactivation of diclofenac is expected to increase the risk for liver injury. However, the extent of covalent protein binding may also be determined by activity of protective enzymes, such as glutathione S-transferases (GSTs). This is supported by an association study in which a correlation was found between NSAID-induced IDILI and the combined null genotypes of GSTM1 and GSTT1. In the present study, the activity of 10 different recombinant human GSTs in inactivation of protein-reactive quinoneimine (QI) metabolites of diclofenac was tested. Both at low and high GSH concentrations, high activities of GSTA1-1, A2-2, A3-3, M1-1, M3-3 and P1-1 in the inactivation of these QIs were found. By using the expression levels of GSTs in livers of 22 donors, a 6-fold variation in GST-dependent inactivation of reactive diclofenac metabolites was predicted. Moreover, it was shown in vitro that GSTs can strongly increase the efficiency of GSH to protect against the alkylation of the model thiol N-acetylcysteine by reactive diclofenac metabolites. The results of this study demonstrate that variability of GST expression may significantly contribute to the inter-individual differences in susceptibility to diclofenac-induced liver injury. In addition, expression levels of GSTs in in vitro models for hepatotoxicity may be important factors determining sensitivity to diclofenac cytotoxicity.

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

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

Association of glutathione S-transferase T1, M1, and P1 polymorphisms in the breast cancer risk: a meta-analysis.

BackgroundSeveral case–control studies investigating the relationship between genetic polymorphisms of glutathione S-transferase (GST) M1, GSTT1, and GSTP1 (rs1695) and the risk of breast cancer have reported contradictory results. We therefore performed a meta-analysis to clarify this issue.Materials and methodsAn updated meta-analysis using PubMed and Web of Knowledge databases for the eligible case–control studies was performed. Random- or fixed-effects model was used.ResultsA total of 10,067 cancer cases and 12,276 controls in 41 independent case–control studies from 19 articles were included in this meta-analysis. Significant increase in risk of breast cancer for Asians was found in GSTM1-null genotype (P=0.012, odds ratio [OR] =1.17, 95% confidence interval [CI] =1.04–1.32) and GSTT1-null genotype (P=0.039, OR =1.19, 95% CI =1.01–1.41). In addition, our results showed that the GSTP1 (rs1695) polymorphisms can significantly increase the risk among Caucasians (P=0.042, OR =1.16, 95% CI =1.01–1.34). Sensitivity analysis and publication bias further confirmed the dependability of the results in this meta-analysis.ConclusionOur results demonstrate that both GSTM1- and GSTT1-null polymorphisms are associated with an increased risk of breast cancer in Asians and that GSTP1 Val105Ile (rs1695) polymorphism is associated with an increased breast cancer risk in Caucasians.

Glutathione S-Transferase Deletion Polymorphisms in Early-Onset Psychotic and Bipolar Disorders: A Case-Control Study.

To examine glutathione S-transferase (GST) deletion polymorphisms in development of early-onset severe mental disorders, with the hypothesis that patients with GSTM1-null and GSTT1-null genotypes will develop psychotic disorders at a younger age. We identified GSTM1 and GSTT1 deletion polymorphisms by multiplex polymerase chain reaction (PCR) in 93 patients with early onset severe mental disorders and 278 control individuals. The diagnoses were confirmed by Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version and Schedule for Affective Disorders and Schizophrenia-Life-Time Version (K-SADS-PL) interviews. Individuals with the GSTM1-null genotype were at 3.36-fold higher risk of developing early-onset severe mental disorders than carriers of a corresponding active genotype. The risk of those disorders was increased by 6.59-fold in patients with GSTM1-null/GSTT1-active genotype. Patients with the GSTM1-null genotype were at approximately 2-fold increased risk for developing early-onset schizophrenia-spectrum disorder (EOS), early-onset bipolar disorder (EOBD) with psychotic symptoms, or early-onset first-episode psychosis (EOFEP), compared with patients with the GSTM1-active genotype. The GSTM1-null genotype might be associated with higher risk for early onset severe mental disorders.

Comparative Hepatotoxicity of Aflatoxin B1 among Workers Exposed to Different Organic Dust with Emphasis on Polymorphism Role of Glutathione S-Transferase Gene.

AIM:The study aimed to investigate effects of organic dust exposure from different sources on aflatoxin B1-albumin adducts (AFB1/Alb), and role of glutathione S-transferase (GST) gene polymorphism in hepatotoxicity of (AFB1) among exposed workers.MATERIAL AND METHODS:Liver enzymes, AFB1/Alb, and GST polymorphism were estimated in 132 wheat flour dust and 87 woods sawmill workers, and 156 controls.RESULTS:Results revealed that AFB1/Alb and liver enzymes were significantly elevated in exposed workers compared to controls, and were significantly higher in sawmill workers compared to flour workers. AFB1/Alb in flour and sawmill workers with GSTT1 and GSTM1&GSTT1 null genotypes were significantly higher than controls, and in sawmill workers with GSTM1&GSTT1 null than flour workers. Liver enzymes (ALT and AST) in sawmill workers were significantly higher than flour workers and controls in all GST polymorphism; except in GSTT1 polymorphism, where these enzymes were significantly higher in the two exposed groups than controls.CONCLUSIONS:In conclusion, organic dust exposure may cause elevation in AFB1/Alb and liver enzymes of exposed workers, and GST gene polymorphism plays an important role in susceptibility to hepatic parenchymal cell injury; except in workers with GSTT1&GSTM1 null genotype, gene susceptibility seemed to have little role and the main role was for environmental exposures.

Association of glutathione S-transferases M1, T1 and P1 gene polymorphisms with attention deficit and hyperactivity disorder in Korean children

Attention deficit and hyperactivity disorder (ADHD) is highly heritable disorder and common in school-age children characterized by inattention, hyperactivity and impulsivity. Although its heritability was estimated at 80–90% from family, adoption and twin studies, the molecular etiology of this disorder has not elucidated. Meanwhile, an impaired balance of oxidant-antioxidant status and increased oxidative stress is observed in ADHD, and it may imply a possible relationship between oxidative stress and etiology of ADHD. Glutathione S-transferase (GST) is antioxidant enzymes that play a key role in the cellular detoxification. In the present study, we examined the association between the genetic polymorphisms of GSTM1, GSTP1 and GSTT1, and ADHD in Korean children. Case–control study was conducted with 243 ADHD children and 327 controls. There were no significant associations between the polymorphisms and the incidence of ADHD (p>0.05). However, significant associations were observed in the stratified analyses. The frequency of GSTP1 Ile/Ile genotype is reached to the significant level in the hyperactivity subtype (88.2%) compared to controls (64.8%) (p=0.035) and the frequency of GSTT1-null genotype is significantly higher in the inattentive boys (p=0.005). Similarly, GSTT1-null genotype showed significant associations in combined subtype (p=0.016) and hyperactivity subtype (p=0.036) of the ADHD girls. Thus our result imply that the polymorphisms in the GST genes may affect ADHD, however, replication study for larger sample set and functional studies are crucial to confirm these findings.

Association study of Glutathione S-Transferase polymorphisms and risk of endometriosis in an Iranian population

Endometriosis influenced by both genetic and environmental factors. Associations of glutathione S-transferases (GSTs) genes polymorphisms in endometriosis have been investigated by various researchers; however, the results are not consistent. We examined the associations of GSTM1 and GSTT1 null genotypes and GSTP1 313 A/G polymorphisms with endometriosis in an Iranian population. In this case-control study, 151 women with diagnosis of endometriosis and 156 normal healthy women as control group were included. The genotyping was determined using multiplex PCR and PCR- RFLP methods. The GSTM1 null genotype was significantly higher (p=0.027) in the cases (7.3%) than the control group (1.3%). There was no significant difference between the frequency of GSTT1 genotypes between the cases and controls. The GSTP1 313 AG genotype was significantly lower (p=0.048) in the case (33.1%) than the control group (44.4%). Our results showed that GSTM1 and GSTP1 polymorphisms may be associated with susceptibility of endometriosis in Iranian women.

Among a panel of polymorphisms in genes related to oxidative stress, CAT-262 C>T, GPX1 Pro198Leu and GSTP1 Ile105Val influence the risk of developing BCR-ABL negative myeloproliferative neoplasms

Objectives: To analyze the relationship between six polymorphisms in genes related to oxidative stress, namely CAT-262 C>T, MnSOD Ala16Val, GPX1 Pro198Leu, GSTM1 and GSTT1 null genotypes, and GSTP1 Ile105Val, and the occurrence of BCR-ABL negative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, and primary myelofibrosis).Methods: We genotyped for these polymorphisms 328 patients with a known mutation status for JAK2 V617F, MPL and CALR, and 363 controls, using molecular genetics assays.Results: The CAT-262 C>T and GPX1 Pro198Leu polymorphisms were seen significantly less frequently, while the GSTP1 IleVal105 polymorphism was seen significantly more frequently in patients with BCR-ABL negative myeloproliferative neoplasms, regardless of the molecular sub-type (e.g. JAK2 V617F or CALR mutated).Discussion and conclusion: Our study provides evidence that variation in genes related to oxidative stress might modulate the risk of developing BCR-ABL negative myeloproliferative neoplasms.

Interactions between CYP2E1, GSTZ1 and GSTT1 polymorphisms and exposure to drinking water trihalomethanes and their association with semen quality

Trihalomethanes (THMs) have been reported to be associated with altered semen quality, and this association may be modified by inherited differences in cytochrome P450 (CYP2E1) and glutathione S-transferase (GSTZ1 and GSTT1), which metabolize THMs. We conducted a cross-sectional study to examine the interactions between CYP2E1, GSTZ1 and GSTT1 polymorphisms and exposure to THMs on semen quality among 401 men from the Reproductive Center of Tongji Hospital in Wuhan China. The baseline blood concentrations of four individual THMs, chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM) and bromoform (TBM), were measured as biomarkers of exposure to drinking water THMs. Genotypes were determined by real-time PCR, and semen-quality parameters were evaluated according to the World Health Organization guidelines. GSTT1 genotype significantly modified the association between exposure to Br-THMs (sum of BDCM, DBCM and TBM) and below-reference sperm motility (Pint=0.02). Men with above-median blood Br-THM levels had an increased odds ratio (OR) of below-reference sperm compared to men with below-median blood Br-THM levels (OR=2.15, 95% CI: 1.11, 4.19) in the GSTT1 null genotype only. In addition, we found that men with a TT of CYP2E1 rs 915,906 had higher blood TCM and TTHM (sum of TCM, BDCM, DBCM and TBM) concentrations than men with a CT/CC of CYP2E1 rs 915,906. Our results suggest that GSTT1 polymorphisms modify Br-THM exposure relation with semen quality, and CYP2E1 polymorphisms are associated with internal levels of exposure to THMs.

No association between GSTM1 and GSTT1 genetic polymorphisms and susceptibility to opium sapdependence.

Glutathione S-transferases (GSTs; EC: 2.5.1.18) are a ubiquitous family of eukaryotic and prokaryotic phase II metabolic isozymes. Genes encoding GSTM1 (OMIM: 138350), and GSTT1 (OMIM: 600436) are members of class mu and theta, respectively. The most common polymorphism in the GSTM1 is a deletion of the whole GSTM1 gene with a lack of enzyme activity. A homozygous deletion in the GSTT1 has also been reported (null genotypes of GSTT1). The aim of the present study was to investigate the association between GSTM1 and GSTT1 polymorphisms and risk of dependency to opium sap. The present study was performed in Shiraz (southern Iran). In total, 71 males dependent to opium sap and 590 healthy males (as a control group) were included in this study. The genotypes of GSTM1 and GSTT1 polymorphisms were determined by PCR. Our data indicate that neither GSTM1 (OR=0.78, 95% CI: 0.47-1.27, P=0.325) nor GSTT1 (OR=1.25, 95% CI: 0.70-2.21, P=0.442) null genotypes significantly associated with the risk of opium sapdependence. There is no additive effect of the null genotypes of GSTT1 and GSTM1 in relation to the risk of dependency to opium sap. The present study indicated that the null genotypes of GSTT1 and GSTM1 are not risk factor for opium sapdependence.

Impact of null genotypes of GSTT1 and GSTM1 with uterine leiomyoma risk in Iranian population.

Few studies have investigated the role of the GSTM1 and GSTT1 genes in uterine leiomyoma. Therefore, in the current study the distribution of these genotypes in Iranian women and susceptibility to uterine leiomyoma was investigated. Blood samples of 50 patients with uterine leiomyoma and 50 healthy individual controls were collected in this cross-sectional study. Genomic DNA was extracted, and subsequently GSTM1 and GSTT1 null genotypes were detected by the Gap-polymerase chain reaction method. A total of 42% of patients appeared to lack GSTM1 enzyme activity due to the presence of an extended deletion (GSTM1 0/0 genotype), compared with 18% in a control group (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.35-9.37; P < 0.010). In addition, the prevalence of the GSTT1 null genotype in patients was higher than that in the control group (42% to 14%, P < 0.009). Also, it was shown that individuals with both null genotypes (-/-) had a 19.23-fold higher risk of developing the disease in comparison to people who showed both present genotypes (+/+). (P = 0.007; 95%CI, 2.20-167.41). Besides, it was observed that at least one null genotype increases the risk of myoma to 2.6 compared to the both present genotype (P-value < 0.03, 95%CI, 1.05-6.82). To our knowledge, this is first significant correlation between risk of uterine leiomyoma and null GSTM1 and GSTT1 genotypes among Iranian patients. Our data support the involvement of GSTM1 and GSTT1 in uterine leiomyoma liability, and especially its role as a genetic factor in the occurrence of this disease.

Distribution of genetic variants of oxidative stress metabolism genes: Paraoxonase 1 (PON1) and Glutathione S-transferase (GSTM1/GSTT1) in a population from Southeastern Mexico

Background: Paraoxonase 1 (PON1) and glutathione S-transferases (GSTs) are involved in the biotransformation of xenobiotics. Variation in the enzyme concentration and activity suggests individual differences for the degree of protection against oxidative stress.Aim: This study analysed the distribution of SNPs Q192R, L55M (PON1) and variants in GSTM1 and GSTT1 genes in a population from Southeastern Mexico.Subjects and methods: One hundred and fifty-one Mexican Mestizo healthy volunteers were included. PON1 polymorphisms were determined by Taqman allele discrimination real time-PCR, whereas GSTM1 and GSTT1 genes were determined with a multiplex PCR-based method.Results: All genotypes were in Hardy-Weinberg equilibrium, except for GSTM1. The genotypic distributions of Q192R and L55M were 22% QQ, 48% QR, 30% RR, 62% LL, 34% LM and 4% MM, respectively, whereas the allele frequencies were 0.46 (Q), 0.54 (R), 0.79 (L) and 0.21 (M). The most frequent haplotype was R/L (46.7%). It was found that 31% and 9% of the individuals had the GSTM1 and GSTT1 null genotype, respectively. The frequency of the combined null genotype GSTM1*0/GSTT1*0 was 4.64%.Conclusion: The results showed that the frequencies of polymorphisms of PON1, GSTM1 and GSTT1 in the Yucatán population differ to those observed in other ethnic groups and provide useful data for epidemiological studies.

GSTT1 Null Genotype Significantly Increases the Susceptibility to Urinary System Cancer: Evidences from 63,876 Subjects

GSTT1 gene plays an important role in detoxification and clearance of reactive oxygen species(ROS). A null variant in this gene has been demonstrated to confer cancer susceptibility. Although many studies have demonstrated the association between GSTT1 null polymorphism and urinary system cancer susceptibility, several publications reported opposite conclusions. For better understanding the effects of this polymorphism on the risk of urinary system cancer, a updated meta-analysis was performed with a total of 26,666 cases and 37,210 controls extracted from 117 studies, by following the latest meta-analysis guidelines (PRISMA). The results suggested that the GSTT1 null genotype was significantly associated with an increased risk of urinary system cancer (OR=1.13, 95%CI=1.05-1.22). Furthermore, stratified analyses by the type of cancer, ethnicity, source of control and quality score presented a significantly increased risk associated with GSTT1 null genotype in bladder and prostate cancer subgroup, Caucasians and Indians subgroup, population-based(PB) subgroup, medium quality and low quality subgroup. Overall, our meta-analysis suggested that GSTT1 null genotype is a potential cancer susceptibility variant. Well-designed and large-cohort studies are needed to confirm the association between GSTT1 null genotype and urinary system cancer risk.

Investigation on glutathione-S-transferase M1 and T1 gene polymorphisms as risk factor in cervical cancer

Glutathione S-transferases (GSTM1 and GSTT1) detoxify tobacco smoke constituents and polymorphisms within GSTM1 and GSTT1 genes, can result in a complete lack of enzyme activity. In this hospital based case-control study, 230 cervical cancer patients (cases) and 230 controls were studied to determine the risk of the disease due to polymorphisms at GSTM1 and GSTT1 locus. For GSTM1 null genotype (?² =8.97, df=1, p=0.003) and GSTT1 null genotype (?² =8.33, df=1, p=0.004), the association was found to have statistically significant between cases and controls. The GSTM1 null genotype had 2.5 times increased risk for cervical cancer (OR= 2.57 p<0.001, 95% CI = 1.36 to 4.85), whereas GSTT1 null genotype had 1.8 times higher risk of getting cervial cancer (OR = 1.83; 95% CI = 1.21 to 2.75). GSTM1 null genotype showed significant distribution for Gudakhu habit in case and control groups (?2=7.734, df=1, p=0.005). Tobacco chewing and alcohol drinking habit did not show any associations with the occurrence of cervical cancer.These findings indicate that GSTM1 and GSTT1 polymorphisms play crucial role in the development of cervical cancer.

The synergy of tobacco and alcohol and glutathione S-transferase θ 1 gene deletion and oral squamous cell carcinoma.

Background:Oral squamous cell carcinoma (OSCC) is the leading cancer among males in India. It is related to tobacco habits and alcohol consumption as well as the individual susceptibility for xenobiotic metabolizing enzyme polymorphisms. Glutathione S-transferase θ 1 (GSTT1) is a Phase II metabolic enzyme which is directly involved in catalyzing chemicals to mutagenic intermediates. This gene is characterized by genetic polymorphism resulting in complete gene deletion and subsequent absence of the enzyme, which ultimately dictates the risk of cancer development. Scraping buccal mucosa to obtain DNA from the cells is a simple, readily acceptable and rapid method to detect and assess the gene.Aim:To assess GSTT1 gene deletion in individuals giving a history of tobacco smoking and/or chewing and alcohol consumption and absence of clinically detectable lesions; and in OSCC cases to gauge if GSTT1 gene deletion confers protection to an individual and whether it can be used as a “single” marker to arrive at this conclusion. To validate the use of buccal scrape for determining the genotype of an individual by assessing the polymorphism at GSTT1 gene locus (22q11.2).Materials and Methods:Fifty-two cases were evaluated using buccal mucosal scrapes of tobacco habituates for 8 or more years, without clinically evident lesion (Group I) and from mucosa of tobacco habituates with clinically evident and histopathologically confirmed OSCC (Group II). DNA extraction and genotype at GSTT1 gene locus was determined by polymerase chain reaction assay.Statistical Analysis:The results were statistically analyzed using Chi-square test.Results:90.66% of subjects had GSTT1 null genotype in Group I subjects. In Group II, subjects with both clinically and histopathologically diagnosed oral cancer, about 76.96% had GSTT1 null genotype.Conclusion:GSTT1 null genotype confers protection to individuals with tobacco habits and alcohol consumption, predominantly to those who used chewable form of tobacco and especially among female population. However, the influence of many other environmental, genetic and epigenetic factors should be considered for the genesis/occurrence of cancer.

Analysis of the prevalence of polymorphisms in the glutathione S transferase gene (GST) in cataract patients from Goiânia

The aim of this study was to determine the prevalence of polymorphisms in the glutathione S-transferase genes GSTM1 and GSTT1 in patients with lens opacity (cataract). Peripheral blood samples were obtained from male and female patients (N = 23) with cataract. The GSTM1 and GSTT1 polymorphic regions were amplified by polymerase chain reaction, and the amplification products were electrophoresed on a 2% agarose gel. The obtained bands were by staining with ethidium bromide. The results were compared by a chi-square test using the BioEstat software (v.5.0). The frequencies of the GSTM1- and GSTT1-null genotypes were higher than those of the GSTM1- and GSTT1-present genotypes. The frequency of GSTT1-null genotypes was approximately 1.7 times higher than that of GSTM1, which was a statistically significant difference (P = 0.0019). Although a consensus remains to be reached on the correlation between genetic polymorphisms in GSTs and cataract susceptibility, the observations from most scientific studies are similar to those reported in this study. Thus, we conclude that the absence of these genes, particularly GSTT1, is correlated with the development of lens opacity.