Glutathione S-transferase GSTM1 Research Articles

Associations of polymorphisms of glutathione-S-transferase and N-acetyltransferase 2 genes in children with acute lymphoblastic leukemia

The development of personalized medicine is inextricably linked with the study of the patient’s genetic profile, which determines not only the features of the course of the disease, but also the risks of its occurrence. Purpose. The aim of the work was to study possible associations between the genetic polymorphisms GSTT1, GSTM1, NAT2 and predisposition to the development of acute lymphoblastic leukemia in children of the East Siberian region. Material and methods. A total of 82 children with acute lymphoblastic leukemia and 227 healthy volunteers with no history of hematological pathology were examined. Deletion polymorphisms in the glutathione S-transferase GSTT1 and GSTM1 genes were detected by polymerase chain reaction (PCR) with electrophoretic detection of amplification products in agarose gel; the type of acetylation was determined by genotyping SNP rs1495741 of the NAT2 gene by conducting a polymerase chain reaction in real time. The material for the study was DNA samples isolated from buccal epithelium samples. Results. Statistical processing allowed us to draw the following conclusions: the rate of acetylation of xenobiotics does not affect the risk of acute lymphoblastic leukemia in children of the Caucasian ethnic group of the East Siberian region. Conclusion. There is no associative relationship between deletions in the GSTM1 and GSTT1 genes and the risk of developing acute lymphoblastic leukemia in children of the Caucasian ethnic group of the East Siberian region. It was found that the risk of developing acute lymphoblastic leukemia in children was significantly higher with the variant of combinations of alleles of the rapid type of NAT2 acetylation and normal activity of GSST1 and GSTM1 (G/G, active, active).

Factors associated with blood mercury concentrations and their interactions with three glutathione S-transferase genes (GSTT1, GSTM1, and GSTP1): an exposure assessment study of typically developing Jamaican children

BackgroundJamaican soil is abundant in heavy metals including mercury (Hg). Due to availability and ease of access, fish is a traditional dietary component in Jamaica and a significant source of Hg exposure. Mercury is a xenobiotic and known neuro-toxicant that affects children's neurodevelopment. Human glutathione S-transferase (GST) genes, including GSTT1, GSTM1, and GSTP1, affect Hg conjugation and elimination mechanisms.MethodsIn this exposure assessment study we used data from 375 typically developing (TD) 2–8-year-old Jamaican children to explore the association between environmental Hg exposure, GST genes, and their interaction effects on blood Hg concentrations (BHgCs). We used multivariable general linear models (GLMs).ResultsWe identified the child’s age, consumption of saltwater fish, canned fish (sardine, mackerel), string beans, grain, and starches (pasta, macaroni, noodles) as the environmental factors significantly associated with BHgCs (all P < 0.05). A significant interaction between consumption of canned fish (sardine, mackerel) and GSTP1 in relation to BHgC using either a co-dominant or recessive genetic model (overall interaction P = 0.01 and P < 0.01, respectively) indicated that consumption of canned fish (sardine, mackerel) was significantly associated with higher mean BHgC only among children with the GSTP1 Ile105Val, Ile/Ile [Ratio of mean Hg (95% CI) = 1.59 (1.09, 2.32), P = 0.02] and Ile/Val [Ratio of mean Hg (95% CI) = 1.46 (1.12, 1.91), P = 0.01] genotypes.ConclusionsSince this is the first study from Jamaica to report these findings, replication in other populations is recommended.

P443: IMPACT OF PHARMACOGENETIC VARIANTS ON CYTARABINE AND ANTHRACYCLINE EFFECT ON OUTCOMES IN ADULT AML PATIENTS

Background: Acute myeloid leukaemia (AML) is primarily treated with combination of cytarabine and anthracyclines. Despite high remission rates, the 5-year overall survival (OS) is <50% and <20% for<60-year-old a ≥60-year-old patients, respectively. This grim clinical outcome could be partly explained by the patients’ genetic variability of proteins involved in metabolic paths of cytarabine and anthracyclines. Pharmacogenetic variants of the main cytarabine membrane transporter SLC29A1 (solute carrier family 29 member 1), DCK (Deoxycytidine kinase) the first enzyme in cytarabine stepwise activation process, genes coding main anthracycline efflux pump ABCB1 (ATP binding cassette) and genes coding glutathione S-transferases GSTM1 and GSTT1, main cytosolic detoxifiers od anthracycline-induced oxidative stress, are shown to influence clinical outcome in AML patients. Aims: to evaluate: 1) the effects of variants in pharmacogenes SLC29A1, DCK, ABCB1, GSTM1 and GSTT1, on complete remission (CR) and relapse rate (RR), disease free survival (DFS) and overall survival (OS), 2) the influence of demographic, laboratory and AML-related parameters on CR, RR, DFS and OS. Methods: 100 newly-diagnosed consenting adults (18-62 years old) diagnosed with AML, except acute promyelocytic leukaemia in Clinic of Haematology UCCS from January 2015 to January 2018, were included in retrospective cohort. Patients received one or two inductions ‘’3 + 7’’ cycles. In patients achieving CR either three consolidation cycles with high/intermediate doses of cytarabine or allogenic SCT in selected patients were performed. Demographic, standard laboratory and AML-related parameters (blood/bone marrow blast percentage, cytologic, flow cytometry and genetic markers enabling ELN risk stratification were collected from patients’ health records. Variants SLC29A1 rs9394992, DCK rs12648166, ABCB1 rs2032582 and GSTM1 and GSTT1 gene deletions were detected by methodology based on PCR, fragment analysis and direct sequencing. The study was approved by the Ethics Committee of the UCCS. The methods of descriptive and analytic statistics were used, while survival analysis was done by the Kaplan-Meier method using the Log-Rank test. Results: 100 patients (53 males) were included in the study, with the median age of 51 (range 18-62). Median laboratory parameters were: WBC 15.5x109/L (range 1-348.8), Hgb 97g/L (range 20-166), Plt 53.5 (range 1-422), LDH 249U/L (1-4169). CD34 was positive in 56% patients. According to ELN 15, 55 and 30 patients were classified in favorable, intermediate and adverse risk group, respectively. CR was achieved in 57 patients (41 after the first and 16 after the second induction cycle). A total of 34% of patients relapsed. Median DFS was 5.3 months (range 0.25-61.5), while median OS was 6 months (range 0.3-75). There was a significant difference in median DFS between CC, CT and TT genotype of SLC29A1: 13, 8 and 1.75 months, respectively (p=0.00037). Median DFS was significantly decreased in null genotype of GSTM1 (9.5 (null) vs 18 months (non-null); p=0.028). Significant difference in OS within ABCB1 genotypes TT, GG, GT and AG+AT was registered: 13, 7, 6.5 and 3 months, respectively (p=0.0036). Other parameters did not differ significantly. Summary/Conclusion: Our results, regarding impact of variants of SLC29A1, GSTM1 on DFS and impact of variant ABCB1 on OS in AML patients, are in line with previous studies. Although further studies, with larger cohorts, are needed, these pharmacogenetic variants show a potential to become prognostic markers in AML.

Desloratadine Efficacy in Relation to GSTM1 and GSTT1 Polymorphic Genes in Chronic Spontaneous Urticaria.

The etiopathogeny of chronic spontaneous urticaria (CSU) is not well defined. Allelism in glutathione S-transferase GSTM1 and GSTT1 has been suggested as a risk factor. Desloratadine is the first-line treatment for this disease. This study aimed to investigate the efficacy of a first-line treatment: desloratadine 5 mg/day on antioxidant status and clinical assessment in Tunisian patients with CSU and to identify possible associations between GSTT1 and GSTM1 genotypes and susceptibility to CSU. Sixty patients with CSU and 60 age- and gender-matched healthy controls were included in the study. We calculated the urticaria activity score (UAS) and assessed the antioxidant parameters (total antioxidant status [TAS], glutathione S-transferase [GST], SOD, CAT, GPx]). Multiplex PCR was performed to find the relationship between GSTM1 and GSTT1 polymorphisms with CSU susceptibility. At baseline, GST, GPx, CAT, SOD activities, and TAS were significantly lower in CSU patients compared to healthy controls (P < 0.05). After treatment, GST, GPx, CAT, SOD activities and TAS were significantly increased in patients compared to those before treatment (P < 0.001). We observed a significant association in null alleles of GSTM1. Before treatment, GST activity was significantly lower in patients having GSTM1+ genotype than those having GSTM1- genotype (P = 0.001). After treatment, TAS and antioxidant enzymes GST, GPx, SOD, and CAT were significantly elevated in patients having GSTM1- genotype than those having GSTM1+ genotype (P < 0.05). These results suggest the impact of GSTM1 and GSTT1 on CSU susceptibility and desloratadine efficacy in Tunisian patients.

Additive and Interactive Associations of Environmental and Sociodemographic Factors with the Genotypes of Three Glutathione S-Transferase Genes in Relation to the Blood Arsenic Concentrations of Children in Jamaica.

Arsenic (As) is a metalloid that has been classified as a xenobiotic with toxic effects on human beings, especially on children. Since the soil in Jamaica contains As, dietary intake is considered the main source of As exposure in Jamaicans. In addition, glutathione S-transferase (GST) genes, including GSTT1, GSTP1, and GSTM1, play an important role in the metabolism of xenobiotics including As in humans. Using data from 375 typically developing children (2–8 years) in Jamaica, we investigated the environmental and sociodemographic factors, as well as their possible interactions with the children’s genotype for GST genes in relation to having a detectable level of blood As concentration (i.e., >1.3 μg/L). Using multivariable logistic regression, we have identified environmental factors significantly associated with blood As concentrations that include a child’s age, parental education levels, and the consumption of saltwater fish, cabbage, broad beans, and avocado (all p < 0.01). Based on the multivariable analysis including gene x environment interactions, we found that among children with the Ile/Ile genotype for GSTP1 Ile105Val, children who consumed avocado had higher odds of having a detectable blood As concentration compared to children who did not eat avocado.

GSTM1 and GSTT1 double null genotypes determining cell fate and proliferation as potential risk factors of relapse in children with hematological malignancies after hematopoietic stem cell transplantation

PurposeThis study aimed to retrospectively evaluate the genetic association of null variants of glutathione S-transferases GSTM1 and GSTT1 with relapse incidence in children with hematological malignancies (HMs) undergoing busulfan (BU)- containing allogeneic hematopoietic stem cell transplantation (HSCT) and to assess the impact of these variants on BU-induced cytotoxicity on the immortalized lymphoblastoid cell lines (LCLs) and tumor THP1 GST gene-edited cell models.MethodsGSTM1- and GSTT1-null alleles were genotyped using germline DNA from whole blood prior to a conditioning BU-based regimen. Association of GSTM1- and GSTT1-null variants with relapse incidence was analyzed using multivariable competing risk analysis. BU-induced cell death studies were conducted in GSTs- null and non-null LCLs and CRISPR–Cas9 gene-edited THP1 leukemia cell lines.ResultsCarrying GSTM1/GSTT1 double null genotype was found to be an independent risk factor for post-HSCT relapse in 86 children (adjusted HR: 6.52 [95% Cl, 2.76–15.42; p = 1.9 × 10–5]). BU-induced cell death preferentially in THP1GSTM1(non−null) and LCLsGSTM1(non−null) as shown by decreased viability, increased necrosis and levels of the oxidized form of glutathione compared to null cells, while GSTT1 non-null cells showed increased baseline proliferation.ConclusionThe clinical association suggests that GSTM1/GSTT1 double null genotype could serve as genetic stratification biomarker for the high risk of post-HSCT relapse. Functional studies have indicated that GSTM1 status modulates BU-induced cell death. On the other hand, GSTT1 is proposed to be involved in baseline cell proliferation.

Glutathione S-transferase gene polymorphisms in association with susceptibility to lead toxicity in lead- and cadmium-exposed children near an abandoned lead-zinc mining area in Kabwe, Zambia.

Interindividual genetic variations determine human's susceptibility to heavy metal-induced toxicity. Thus, we analyzed blood concentrations of lead (Pb) and cadmium (Cd) in 140 lead-exposed children. Genotyping of the glutathione S-transferase (GST) genes, GSTM1, GSTT1, and GSTP1 genes, was carried out to investigate their possible association with heavy metal concentrations and the risk of susceptibility to Pb toxicity. Exposure to both heavy metals was prevalent among the children. The blood Pb level ranged from 3.30 to 74.0 μg dL-1 with an average value of 26.8 μg dL-1 that is five times above its reference level. The average Cd level (0.22 μg L-1) was below its reference level. The metal-gene interaction showed positive correlation between GSTT1 null genotype and Pb and Cd levels (β = 0.11; p = 0.02 and β = 0.10; p = 0.01, respectively). More pronounced effects (β = 0.19; p < 0.01 and β = 0.25; p = 0.04) were found for the mixture of the three putative genes with blood Pb concentration. The susceptibility analysis using 10 μg dL-1 as blood Pb cutoff level showed a high risk of Pb toxicity (OR = 2.54; 95% CI: 1.02-6.32, p = 0.04) for children carrying the GSTP1 Ile/Val genotype. Further, the combined effect of GSTP1 Ile/Val with GSTT1 null genotype was more pronounced and showed an increased risk of susceptibility to Pb toxicity (OR = 11.7; 95% CI: 1.36-102.1, p = 0.02). In summary, this study suggests that GSTT1 null and GSTP1 Ile/Val genotypes are the main genetic factors, and individual and specific combinations of GSTP1 Ile/Val with GSTM1 and GSTT1 GST polymorphisms are associated with susceptibility to Pb toxicity.

Polymorphisms of the GSTT1 and GSTM1 genes in polycystic ovary syndrome.

This study aimed to investigate the deletion polymorphisms of the genes of the glutathione S-transferase family GSTT1 and GSTM1 in patients with Polycystic Ovarian Syndrome (PCOS), comparing them with a control population. Blood was collected from 219 women (110 with PCOS and 109 controls) and genomic DNA was extracted. For the analysis of polymorphisms, the technique used was multiplex PCR. In the statistical analysis, the chi-square test and multiple logistic regression were used. There is no association between the GSTM1 null and GSTT1 null genotypes with PCOS when analyzed separately (P = 0.616 and P = 0.188). The analysis of the combined genotypes showed differences between the groups (P < 0.05), evidencing that the genotypic combination GSTT1 positive and GSTM1 negative is more frequent among patients. In the multivariate analysis, smoking was more frequent in the control group (OR = 0.22; 95% CI - 0.87-0.57; P = 0.002) while the presence of a family history of PCOS (OR = 2, 96; 95% CI - 1.54-5.68; P = 0.001) was more frequent in women with PCOS. In the studied sample, the deletion polymorphisms of the GSTT1 and GSTM1 genes isolated are not associated with PCOS, but in combination, they may be implicated in the etiology of the condition.

Assessment of the Two-Glutathione S-Transferase Genotypes GSTM1 and GSTT1 Polymorphism Frequencies in Epithelial Ovarian Cancer in Nasiriya Province

The family of glutathione S-transferases (GSTs) is composed of multiple isozymes with significant evidenceof functional polymorphic variation. Glutathione S-transferase GSTM1 and GSTT1 are members of theGST family, is responsible for metabolism of xenobiotics and carcinogens. Allelic variant of GST genepolymorphisms might impair detoxification function and increase the susceptibility to cancer. The nullgenetic polymorphism in the gene encoding GST Class µ, GSTM1 and GSTT1, has been reported to besignificantly elevated in cancer patient. This study aimed to investigate if these polymorphisms are usefulmarkers for predicting ovarian cancer susceptibility. 30 cases of epithelial ovarian cancer and 30 controlswas used to investigate the frequency of GSTT1 and GSTM1 genotypes by using multiplex conventionalPCR protocol. The frequency of GSTM1 null allele was significantly elevated (100%, P = 0.004) comparedwith GSTT1 active allele (13% P = 0.037). GSTT1 null showed no significant effect in prognosis epithelialovarian cancer (17%, P = 0.551). We conclude that the GSTs might affect in both risk to ovarian cancer.

Glutathione S-transferase M1 and T1 null allele frequencies among Indonesian ethnics toward improved disease risk assessment

Genetic variations in the glutathione S-transferase genes GSTT1 and GSTM1 have been widely studied, and homozygous deletions or null genotypes have been reported in different populations. Previous studies suggest that individuals who are homozygous-null at the GSTM1 or GSTT1 locus may have an increased risk of environmentally related cancers and drug-induced hepatotoxicity. The aim of the present study was to determine the GSTM1 and GSTT1 polymorphisms in 154 healthy, unrelated individuals from the Javanese-Sundanese and Malay ethnic populations of Indonesia to provide a resource for improving the prognosis of possible susceptibilities in specific populations. The subjects were genotyped for the presence of GSTM1 and GSTT1 using the multiplex polymerase chain reaction technique. The GSTM1-null genotype was more frequent among Javanese-Sundanese ethnics (99%) than among the Indonesian Malay (67.2%). Similarly, Javanese-Sundanese ethnics showed a higher frequency of the GSTT1-null genotype (66.7%) than the Indonesian Malay (36.2%). Analysis of the combined distribution of the GSTM1 and GSTT1 genes revealed that 66.7% of the individuals from the Javanese-Sundanese population lack both the genes, whereas only 21.1% of the Indonesian Malay is GSTM1-null and GSTT1-null. This study contributes significant information on the variability of GSTT1 and GSTM1 gene polymorphisms worldwide, which can provide new knowledge about the relationship between ethnicity and the prevalence of certain diseases.

Maternal dietary antioxidant intake in pregnancy and childhood respiratory and atopic outcomes: birth cohort study

Evidence for a possible protective effect of maternal dietary antioxidant intake during pregnancy on childhood asthma and other atopic outcomes is conflicting, and associations with childhood lung function have been little studied.In the Avon Longitudinal Study of Parents and Children, we analysed associations between maternal intake of fruits, vegetables, vitamins C and E, carotene, zinc, and selenium in pregnancy and current doctor-diagnosed asthma, atopy and lung function in 8915 children at age 7–9 years. Potential modification of associations by maternal smoking and common maternal antioxidant gene polymorphisms was explored to strengthen causal inference.After controlling for confounders, positive associations were observed between maternal intake of zinc and childhood forced expiratory volume in 1 s and forced vital capacity (difference in age-, height- and sex-adjusted sd units per quartile increase in maternal dietary zinc intake β 0.05 (95% CI 0.01–0.08); ptrend=0.01 and 0.05 (95% CI 0.02–0.09); ptrend=0.005, respectively). Weak evidence was found for an interaction between maternal zinc intake and maternal glutathione S-transferase GSTM1 genotype on childhood forced vital capacity (pinteraction=0.05); association among the GSTM1 null group β 0.11 (95% CI 0.05–0.17); ptrend=0.001.Our results suggest that a higher maternal intake of zinc during pregnancy may be associated with better lung function in the offspring.

Transcriptome signature of liver tissue with divergent mutton odour and flavour using RNA deep sequencing

Mutton consumption is less popular in many Asian countries including Indonesia, whose consumers often complain about the unpleasant flavour and odour of the meat. The main causes of mutton odour are the two compounds of branched chain fatty acid (BCFA): methylnonanoic (MNA), phenol, 3-methyl (MP), 4-methylnonanoic (MNA) and 4-ethyloctanoic (EOA) present in all the adipose tissue; and the 3-methylindole (MI) or skatole and indole, which are originated from pastoral diets. It is crucial to understand the genetic mechanism of mutton odour and flavour (MOF) to select sheep for lower BCFA and indole thus reduce the unpleasant flavour of meat. The aim of the present study was to investigate transcriptome profiling in liver tissue with divergent MOF using RNA deep sequencing. Liver tissues from higher (n = 3) and lower (n = 3) MOF sheep were analysed using Illumina HiSeq 2500. The total number of reads produced for each liver sample ranged from 21.37 to 25.37 million. Approximately 103 genes were differentially expressed (DEGs) with significance level of p-adjusted value <0.05. Among them, 60 genes were up-regulated, and 43 were down-regulated (p < 0.01, FC > 1.5) in higher MOF group. Differentially regulated genes in high MOF liver samples were enriched in biological processes such as cellular response to chemical stimulus and endogenous stimulus; cellular components such as such as basement membrane and extracellular matrix; and molecular functions such as haeme binding and oxidoreductase activity. Among the DEGs, metabolic phase I related genes belonging to the cytochrome P450 CYP2A6 were dominantly expressed. Additionally, phase II conjugation genes including UDP glucuronosyltransferases UGT2B18, sulfotransferase SULT1C1, and glutathione S-transferase GSTM1 were identified. The dominant candidate genes for SOF could be cytochrome P450, sodium-channel protein, transmembrane protein, glutathione transferase, UDP glucuronosyltransferases and sulfotransferase. Pathway analysis identified steroid hormone biosynthesis and chemical carcinogenesis by cytochrome P450 pathways which may play important roles in MOF-related molecules metabolism. This work highlighted potential genes and gene-networks that may affect meat off flavour and odour in sheep.

P53 and GSTs Polymorphisms among Bladder Cancer Patients in Iraq

The role of metabolic genes for glutathione S-transferase (gstm1, gstt1) and P53 exon-7 and 8 as risk factors for bladder cancer in Iraqi patients was studied. Thirty five samples from patients attended the Nuclear Medicine Hospital in Baghdad plus fifty samples from apparently healthy individuals were included in the study. DNA extraction was performed using proteinase K/ SDS method PCR techniques were followed to amplify the gene using specific primers for detection of gstm1, gstt1 and albumin as internal control. Single strand conformation polymorphism (PCR-SSCP techniques) for detection of point mutation in P53 exon-7 and 8 were used. Genetic analysis showed that gstm1 null genotype was statistically associated with bladder cancer (14.29%), this association was strengthened when both gstm1 and gstt1 alleles were absent (28.5%). For detection of the point mutations in P53 exon-7 and 8 Single Strand Conformation Polymorphism (PCR-SSCP ) have revealed that there was high association between exon-7 mutations and incidence of bladder cancer (42.86%), while the association between exon-8 mutations and bladder cancer was low (14.28%). In case of combination between exon-7 and 8 mutations, the association was also low (11.42%). Mutations in gstm1 and exon-7 being associated together are more than with exon-8 mutations. The number of mutations in P53 gene was more in patients with combined genotype of gstm1 deletion and null genotypes

Polymorphisms and Protein Expressions of Glutathione S-Transferase M1 and T1 in Non-Small Cell Lung Cancer.

The deletion polymorphisms of glutathione S-transferase (GST) GSTM1 and GSTT1 genes result in the absence of the corresponding protein, which decreases the detoxification of carcinogens. Studies evaluating polymorphisms and protein expressions in the same patients are limited. Therefore, in this study, we aimed to investigate the association between polymorphisms and protein expressions of GSTM1 and GSTT1 in lung tissues of patients with non-small cell lung cancer (NSCLC). For protein expression and gene deletion studies, tumor and surrounding tumor free (normal) tissue of 33 patients with NSCLC were used. In paraffin-embedded tissues, immunohistochemistry was used to detect protein expressions, and multiplex polymerase chain reaction amplification was used to identify gene deletions. GSTM1 and GSTT1 protein expressions were not detected in patients with GSTM1 and GSTT1 gene deletions, whereas protein expressions were detected in lung tissues of all patients carrying GSTM1 and GSTT1 genes. The protein expression level of GSTT1 was 2.0-fold higher in tumors of patients lacking GSTM1 genes than those with GSTM1 genes (p=0.018). Protein expression of GSTM1 was statistically higher in tumor tissues than in normal tissues of patients with GSTM1 genes (p=0.001). These results show that a) there is an association between gene deletions and protein expressions of GSTM1 and GSTT1 in patients with NSCLC, b) in the absence of GSTM1 genes, enhancement of expression of GSTT1 in tumors is likely to show that GSTT1 increases its capacity to detoxify the toxic electrophiles in tumors, and c) GSTM1 protein expression is higher in tumors compared with normal lung tissues of patients with NSCLC.

GSTM1/GSTT1 double-null genotype increases risk of treatment-resistant schizophrenia: A genetic association study in Brazilian patients.

BackgroundThe role of oxidative stress in schizophrenia has been demonstrated, particularly in subjects with treatment-resistant schizophrenia (TRS). In such patients, the decreased levels of antioxidants in conjunction with the increased generation of reactive oxygen species in the brain exposes the neurons to a higher risk of damage.Methods and findingsWe evaluated the association of deletion polymorphisms of two genes of the antioxidant Glutathione S-Transferase family, GSTT1 and GSTM1, with susceptibility to TRS. A total of 54 TRS patients (mean age 38.7 years) and 78 healthy control subjects (mean age 39.0 years) were enrolled in this study. The subjects were matched by sex, age, and smoking and alcohol consumption habits. In the case group, the frequencies of GSTT1-null and GSTM1-null genotypes were 24.1 and 51.9%, respectively, whereas for the control group, the frequencies were 12.8 and 46.2%, respectively. Analysis performed with respect to the risk of developing TRS associated with the GSTT1 and GSTM1 deletion polymorphisms, resulted in odds ratio (OR) values of 2.1 and 1.2, respectively. However, the association was not found to be significant (p = 0.1229 and p = 0.5916, respectively). The analysis performed with respect to the combined genotypes of GSTT1 and GSTM1 revealed that the double-null genotype confers a 4.6-fold increased risk of developing TRS (p = 0.0412).ConclusionThe results of the present study indicate that a combination of GST deficiencies may play a role in enhanced susceptibility to TRS, and the present genotype of one of these genes may buffer the deficiency caused by the lack (null genotype) of the other. The results suggest that combined deletion polymorphisms of GSTT1 and GSTM1 can have implications in the prediction of the clinical course of the disease.

Glutathione S-transferase (GSTM1, GSTT1) polymorphisms and JOAG susceptibility: A case control study and meta-analysis in glaucoma

PurposeGlutathione S transferase (GST) polymorphisms have been considered risk factors for the development of glaucoma. The aim of the present study was to investigate the association of glutathione S-transferase GSTT1 and GSTM1 genotypes with juvenile open-angle glaucoma (JOAG) in Indian patients. MethodsA case-control study was performed to investigate the associations of GSTM1 and GSTT1 in juvenile open-angle glaucoma. The genotype of GSTM1 and GSTT1 were determined in 73 juvenile open-angle glaucoma patients, and 70 controls matched by age and sex by polymerase chain reaction method. We also performed a meta-analysis of sixteen published studies on GSTM1 and GSTT1 and evaluated the association between the GSTM1 and GSTT1 polymorphisms and glaucoma (JOAG & POAG).Published literature from PubMed and other databases were retrieved. All studies evaluating the association between GSTM1 and GSTT1 polymorphisms and glaucoma (JOAG & POAG) risk were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model. ResultsIn the present study, we observed there is no association of GSTM1 (OR=0.680; 95% CI=0.323–1.433; p=0.311) or GSTT1 (OR=0.698; 95% CI=0.307–1.586; p=0.391) with JOAG. In the present meta-analysis, significantly increased glaucoma (JOAG & POAG) risk was found among subjects carrying GSTM1 null genotype (OR=1.177; 95% CI=1.028–1.348; p=0.018) but not among subjects carrying GSTT1 deletion genotype (OR=1.186; 95% CI=0.992–1.417; p=0.061). ConclusionsThe present case-control study found that GSTM1 and GSTT1 polymorphism are not associated with JOAG risk in North Indian population. The present meta-analysis suggested that there might be a significant association of GSTM1 null genotype with glaucoma (JOAG & POAG) risk. To the best of our knowledge, this is the first study in the world to investigate role of GSTM1 and GSTT1 polymorphisms with JOAG susceptibility. Given the limited sample size, the associations between GST polymorphism and glaucoma risk needs further investigation.

Is nullity for Glutathione S-transferase genes GSTT1 and GSTM1 protective against leprosy?

Introduction: Leprosy is a slow and progressive infectious disease caused by Mycobacterium leprae. The generation of free radicals called reactive oxygen species (ROS), which promote destruction of the bacillus within macrophages, is an effective defence mechanism developed by the host. In parallel, the glutathione S-transferase (GST) multifamily of enzymes constitutes an important antioxidant system for ROS detoxification and protection against toxicity. Therefore, GST null genotype individuals could reduce the detoxification of ROS, increasing host effectiveness for M. leprae destruction. Objectives: To evaluate polymorphisms in the GSTT1 and GSTM1 genes as human leprosy susceptibility modulators. Methods: GSTT1 and GSTM1 polymorphisms were genotyped by a multiplex polymerase chain reaction (PCR) in 218 leprosy patients and 244 non-leprosy subjects (control group). Results: The occurrence of the GSTT1/GSTM1 null genotype was significantly higher among control subjects than amongst leprosy patients (P = 0.01). The GSTT1 positive genotype frequency was significantly increased in leprosy patients when compared with control subjects (P = 0.01). Conclusions: The results suggest that GSTT1/M1 nullity may play an important role in leprosy pathogenesis. Significance: Despite these findings, further studies will be necessary to ascertain the exact role of these genes in leprosy and to design any future prevention measures or contributions to drug therapy.

Single nucleotide polymorphisms in glutathione S-transferase P1 and M1 genes and overall survival of patients with ovarian serous cystadenocarcinoma treated with chemotherapy.

The effects of platinum-based drugs are controlled by genes that are involved in DNA detoxification, including glutathione S-transferase (GST)P1 and GSTM1, which have been associated with increased benefits in the chemotherapeutic treatment of patients with ovarian cancer. The present study assessed the effect of single nucleotide polymorphisms in GST genes on the overall survival (OS) of patients with ovarian serous cystadenocarcinoma that were treated with chemotherapy. A total of 95 patients received treatment with a carboplatin-based or alternative chemotherapy. Polymorphisms in the patients were genotyped using the following methods: Pyrosequencing, to identify GSTP1 Ile105Val; a relative quantification method, to identify the copy number variation in GSTM1; and polymerase chain reaction followed by gel electrophoresis, to identify the null vs. non-null genotypes of GSTM1. The association between genotypes and OS of patients was assessed using Kaplan-Meier survival curves and Cox proportional hazards regression analysis. The OS of patients treated with paclitaxel + carboplatin-based chemotherapy was significantly increased, compared with patients treated with alternative forms of chemotherapy (P=0.035). The OS of patients did not differ significantly between different GSTP1 genotypes (log-rank test, P=0.17). Cox proportional hazards regression analysis revealed that, since the start of the treatment, there was not a significant association between the GSTP1 isoleucine allele and the OS for heterozygous carriers of the isoleucine allele [hazards ratio (HR), 1.78; 95% confidence interval (CI), 0.77-4.12; P=0.18] and no homozygous carriers of the valine allele had been detected (HR, 0.00). There was no significant difference between GSTM1 genotypes, according to Kaplan-Meier survival analysis (log-rank test, P=0.83). Patients that possessed ≤1 copy of GSTM1 exhibited no decrease in OS (HR, 0.96; 95% CI, 0.37-2.51; P=0.94), compared with patients that possessed two copies of GSTM1 (HR, 0.71; 95% CI, 0.22-2.28; P=0.56). Overall, the present results suggest that there are no associations between polymorphisms in the GSTP1 and GSTM1 genes and the OS of patients with ovarian cancer following administration of adjuvant chemotherapy.

Glutathione S-Transferase (GST) 유전자 다형성과 항정신병약물로 유발된 하지불안증후군의 연관 연구

Glutathione S-Transferase (GST) 유전자 다형성과 항정신병약물로 유발된 하지불안증후군의 연관 연구

Polymorphic Human Glutathione S-transferase Genes may Predict Susceptibility to Type 2 Diabetes Mellitus: A Minireview

Among the primary human classes of glutathione S-transferase (GST) genes, GSTM1 and GSTT1 genes exhibit a deletion polymorphism that leads to a lack of active isoforms when in homozygous state(the null genotype). Persons with homozygous deletions of either GSTM1 or GSTT1 locus have no functional enzymatic activity of GST and this in turn exacerbate the damage caused by ROS and RNS to pancreatic β-cells. This causes reduced insulin production and, therefore type 2 diabetes. Therefore, GST polymorphic genes (GSTM1null and GSTT1-null) could be used as a biological marker to determine the diabetic risk of individual.