GSTM1 Genotypes Research Articles

Polymorphism of Glutathione Sand#8209;Transferase M1 and T1 Genes and Susceptibility to Childhood Asthma: A Study from North India

Objectives: Glutathione S-transferases (GSTs) enzymes play an important role in the xenobiotic biotransformation of endogenous or exogenous toxicants and thought to protect the airways from oxidative stress, inflammation, and genotoxicity. Polymorphisms in the GST genes may lead to an increased imbalance in antioxidant systems and may influence the pathogenesis of asthma. We examined the association of the GST gene polymorphism to ascertain whether high-risk genotypes of GSTM1/GSTT1 could influence the susceptibility to childhood asthma in the N orth Indian population. Methods: The study constituted of 100 childhood asthmatic cases and 180 age-matched controls. The GSTT1 and GSTM1 null genotypes were identified by multiplex PCR in peripheral blood DNA samples. Statistical analysis was done by using SPSS 20.0 soft ware. Results: No association was seen either the null genotype of the GSTM1 or GSTTT1 (P > 0.05); however, in atopy patients significant association were observed with null genotype of GSTT1 (OR=2.67; P<0.05) for risk of child hood asthma. In combined analysis of GSTM1/GSTT1, presence of null genotypes of GSTM1 G P<0.05) compared to positive genotypes of GSTM1 and GSTT1. When compared among gender, GSTT1 null genotype was found to be statistically significant in male (OR=2.71; P<0.005) as compared to female childhood asthmatic patients. Conclusion: In conclusion, null genotype of GSTT1 exhibits significant association for the risk of childhood asthma, especially in disease predisposition and initiation.

Genetic Variation of Glutathione S-Transferase M1 Is Associated with Patients with Ovarian Endometriosis and Endometriosis-Related Primary Infertility

Background: The aim of the study was to investigate the role of the genetic variation of glutathione S-transferase M1 (GSTM1) in the development of ovarian endometriosis and endometriosis-related primary infertility risk. Methods: This case-control study included 564 women with ovarian endometriosis and 576 normal women in the control group in northern China. The polymorphism of GSTM1 was genotyped by polymerase chain reaction (PCR)/ligase detection reaction method. To assess the biological significance of polymorphisms, the level of GSTM1 mRNA expression in patients’ endometrial tissues with different genotypes was detected by quantitative real-time PCR (qRT-PCR). Results: Compared with the positive genotype, the null genotype of GSTM1 was associated with the risk of developing ovarian endometriosis (OR = 1.29, 95% CI = 1.02–1.62). Further analysis showed that patients with a null genotype also had a significantly higher risk of primary infertility than patients with positive genotypes (OR = 1.59, 95% CI = 1.01–2.49). In addition, we found that GSTM1 mRNA expression was present in the endometrial tissue of all patients, but the expression level of patients with a positive genotype was nearly 10 times higher than that of patients with a negative genotype. Conclusion: Our results suggest that the GSTM1 polymorphism is not only related to the genetic susceptibility to ovarian endometriosis but also a potential molecular marker of primary infertility in patients with ovarian endometriosis.

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.

Association of Glutathione S-Transferase theta 1 and mu 1 Genes Polymorphisms with the Susceptibility of Myocardial Infarction in Bangladesh.

Myocardial infarction is one of the leading causes of morbidity and mortality worldwide. Oxidative stress plays a vital role in the pathogenesis of atherosclerosis leading to myocardial infarction and Glutathione S-transferases (GSTs) act as detoxifying enzymes to reduce oxidative stress. The aim of the present study was to investigate the associations of the GST (T1 & M1) gene polymorphism with the susceptibility of myocardial infarction in the Bangladeshi population. A case-control study on 100 cardiac patients with MI and 150 control subjects was conducted. The genotyping of GST (T1 & M1) gene was done using conventional Polymerase Chain Reaction. The percentage of GSTM1 genotypes was significantly (p< 0.01) lower in patients compared to control subjects while the GSTT1 genotypes were not significantly different between the study subjects. The individual with GSTM1 null allele was at 2.5-fold increased risk {odds ratio (OR)= 2.5; 95 % confidence interval (95 % CI)= 1.4 to 4.3; p< 0.01} of experiencing MI while individual with either GSTM1 or GSTT1 genotypes was at lower risk. In the case of GST M1 and GST T1 combined genotype, patients having both null genotypes for GST M1 and GST T1 gene showed significantly (p< 0.01) higher risk of experiencing MI when compared to control subjects (OR= 3.5; 95% CI= 1.7-7.2; p< 0.001). Thus our recent study suggested that GSTM1 alone and GSTM1 and T1 in combination augments the risk of MI in Bangladeshi population.

Evaluation of glutathione S-transferase polymorphism in Iranian patients with type 2 diabetic microangiopathy

BackgroundOverproduction of reactive oxygen species as a result of hyperglycemia in diabetes mellitus leads to microvascular complications. Glutathione S-transferases play important detoxifying roles with antioxidant potentials. This study aimed to assess whether the glutathione S-transferase M1 and T1 genotypes were associated with type 2 diabetes mellitus microangiopathic complications in the Iranian population.ResultsIn this case-control study, the frequencies of null GSTM1 and GSTT1 genotypes were 4/72 (5.56%) and 12/72 (16.67%) respectively, in uncomplicated DM group. The frequencies of null GSTM1 and GSTT1 genotype in complicated DM group were 16/134 (11.94%) and 37/134 (27.61%), respectively. The proportion of GSTM1 null genotypes was higher in diabetic nephropathy compared to non-nephropathy (19.3% vs. 6.04 %, P = 0.006). At GSTT1 locus, patients with diabetic peripheral neuropathy had a higher frequency of deletion compared to those of without neuropathy (30.39% vs. 23.49%) (P = 0.02).ConclusionSelective polymorphisms encoding GSTM1 and GSTT1genes may prove useful as genetic markers to recognize individuals with an increased trend in developing diabetic nephropathy and neuropathy, respectively. This will help better identify individuals at higher risk toward microvascular complications of type 2 diabetes due to genetic susceptibility.

Genotype of Null Polymorphisms in Genes GSTM1, GSTT1, CYP1A1, and CYP1A1*2A (rs4646903 T>C)/CYP1A1*2C (rs1048943 A>G) in Patients with Larynx Cancer in Southeast Spain.

Simple SummaryEpidemiological studies have shown that individual susceptibility to cancer is mediated by genetic and environmental factors. The aim of the present study is to evaluate the individuals’ metabolic genetic susceptibility to toxic habits (smoking and alcohol consumption) by detecting polymorphisms CYP1A1 rs1048943 T>C and CYPA1A2 rs4646903 A>G, and null polymorphisms in GSTM1 and GSTT1 genotypes, comparing a group of healthy control subjects with a population of larynx cancer patients from southeastern Spain. As results patients with larynx cancer present more gene GSTM1 and GSTT1 null polymorphisms, and CYP1A1 rs4646903 T>C polymorphisms.Background: some types of cancer have been associated with the presence of single nucleotide polymorphisms (SNPs) of some genes that encode enzymes: glutathione-S transferase (GST), whose alteration leads to loss of function and a lower capacity to eliminate toxic GSTM1 and GSTT1 null genotypes; SNPs causing loss of function of CYP1A1 or CYP1A1–2 cytochrome P450 enzymes related with a lower capacity to deactivate hydrocarbons related to smoking, which involves a higher risk of developing some smoking-dependent cancers including larynx cancer. Objective: to compare the presence of null SNPs in genes GSTM1, GSTT1, and CYP1A1 rs 4646903 T>C, and CYP1A1–2 RS1048943 A>G in patients with hypopharyngeal and larynx cancer with a healthy control group. Materials and method: The study included a total of 80 patients with hypopharyngeal and laryngeal cancer and 23 healthy subjects. Genomic DNA was obtained from saliva samples, determining genotype GSTM1 (present +, or null −), GSTT1 (present + or null −). Polymorphisms (SNP) in CYP1A1 T>C (present + CC, or absent − TC/TT), and CYP1A1–2 A>G (present + GG, or absent − AG/AA). Results: the mean age of patients with larynx cancer was 62 years and of control subjects 63 years. Of the total sample, over 95% were men, and over 90% were smokers. The presence of null genotypes for GTM1 was 50% in patients with larynx cancer (p = 0.042), while GSTT1 was 88.75% (p = 0.002). CYP1A1 rs4646903 T>C polymorphisms were detected in 100% of cases of larynx cancer and 17.39% of healthy subjects (p > 0.001). Conclusions: patients with larynx cancer present more gene GSTM1 and GSTT1 null polymorphisms, and CYP1A1 rs4646903 T>C polymorphisms.

Association of glutathione S-transferase M1 and T1 genotypes with asthma: A meta-analysis.

Background:We performed an updated meta-analysis to clarify the relationship between glutathione S-transferase Mu and theta (GSTM1 and GSTT1, respectively) null/positive genotypes and asthma.Methods:We performed a literature search using PubMed and Web of Science databases in August 2019. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the role of GSTM1 and GSTT1 genotypes in the risk of asthma.Results:Overall, we found a significant association with asthma risk in the general population for both the GSTM1 genotype (OR = 1.21; 95% CI: 1.07–1.35; P < .001; I2 = 69.5%) and the GSTT1 genotype (OR = 1.61; 95% CI: 1.30–2.00; P < .001; I2 = 83.6%). Moreover, significant associations between both genotypes and asthma risk were also found by age stratification. Furthermore, for GSTM1 we found significant associations in populations living in Asia, Europe, and Russia, but not in Africa. Conversely, for GSTT1, we found a significantly increased risk in populations living in Asia, Europe, Africa, and Russia. In addition, a significant association was found for both genotypes with a sample size <500, but not a sample size >2000.Conclusion:Our meta-analysis provides evidence that GSTM1 and GSTT1 genotypes could be used as asthma-associated biomarkers.

Lack of association between glutathione S-transferase M1 and T1 gene polymorphisms and susceptibility to preeclampsia: An updated systematic review and meta-analysis.

Insufficient response to oxidative stress in placenta is proposed as a contributing factor for preeclampsia (PE) development. Glutathione S-transferases (GST) have significant role in detoxification processes. Conflicting results were published by several research groups regarding GST T1 and GST M1 deletion polymorphism as risk factors for PE. The aim of the present meta-analysis was to get a better understanding of the impact of these polymorphisms in preeclampsia development. To identify relevant case-control studies, the author team searched Clarivate Analytics Web of Science, Scopus, PubMed, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, major subject journals, and gray literature. Pooled odds ratios and 95% confidence intervals for GST M1 and GST T1 deletion polymorphism and preeclampsia were derived from random effects models. This meta-analysis included 10 eligible studies. The pooled analyses showed no association between GST M1/GST T1 deletion polymorphisms and susceptibility to PE. Even though high heterogeneity was founded among results for GST M1 and double null genotypes, Egger's and Begg's tests (0.17 and 0.18, respectively) revealed no statistical evidence of publication bias among included studies. The present updated systematic review and meta-analysis found no association between GST M1 and GST T1 deletion polymorphism and PE risk.

Glutathione S-transferase activity and genetic polymorphisms associated with exposure to organochloride pesticides in Todos Santos, BCS, Mexico: a preliminary study.

The objective of this study was to identify and evaluate the impact of exposure to mixtures of organochloride pesticides (OCPs) in agricultural workers by detecting their effects on the activity of the enzyme glutathione S-transferase (GST) and the presence of polymorphisms of the GSTT1 and GSTM1 genes. The presence of OCPs was identified and quantified by gas chromatography, while spectrophotometry was used to measure enzymatic GST activity. The frequencies of the GSTM1 genotypes were analyzed by multiplex PCR. A total of 18 metabolites of OCPs were identified in the workers' blood, most of which are either prohibited (DDT and its metabolites p, p'DDD and p, p'DDE, dieldrin, endrin, aldrin) and/or restricted (δ hexachlorocyclohexane, cis chlordane, methoxychlor, and endosulfan). The results obtained indicate lower levels of GST activity at higher OCPs concentrations detected in blood from exposed workers, together with an increase in OCP levels in individuals who presented the GSTT1*0 and GSTM1*0 genotypes. These conditions place the detoxification process in agricultural workers with null polymorphisms in the GST genes and high concentrations of OCPs in the blood (especially DDT and its metabolites, DDD and DDE) at risk, and increase their susceptibility to develop serious diseases.

DNA damage analysis concerning GSTM1 and GSTT1 gene polymorphism in gold jewellery workers from Peshawar Pakistan

Purpose To evaluate the genotoxic effects of gold jewellery fumes and its association with GSTM1 and GSTT1 genetic polymorphisms. Materials and methods We examined 94 subjects including 54 gold jewellery workers and 40 controls. The DNA damage was evaluated by alkaline comet assay and genotyping by PCR. Results The mean total comet score (TCS) in gold jewellery workers was significantly higher as compared to the control subjects (128.0 ± 60.6 versus 47.7 ± 21.4; p = 0.0001). Duration of occupational exposure had positive correlation (r = 0.453, p < 0.01) with DNA damage. Age and tobacco use had significant effects on the TCS of the exposed group as compared to the control group (p < 0.05). The frequency of the GSTM1-null genotype in the exposed group was significant (p = 0.004) as compared to the control group. No significant association (p > 0.05) between the GSTM1 and GSTT1 genotypes and DNA damage was found. Conclusions Our results suggest that there is increased DNA damage in gold jewellery workers due to their occupational surroundings. Hence there is a strong need to educate the workers about the adverse health effects of potentially hazardous chemicals and highlight the importance of using protective measures.

Association of Genetic Polymorphisms in GSTP1, GSTM1, and GSTT1 Genes with Vesicoureteral Reflux Susceptibility in the Children of Southeast Iran.

Background:Vesicoureteral reflux (VUR) disease is the most common type of urinary tract anomalies in children. Genetic risk factors may be associated with the etiology of VUR. The role of the Glutathione S-transferases (GSTs) as multifunctional enzymes is cellular oxidative stress handling. This is the first study aimed at evaluating the relative risk of GSTP1, GSTM1, and GSTT1 polymorphisms in VUR susceptibility in children and provides new important insights into the genetics of affected children.Methods:The study was done in 2013 in Sistan and Baluchestan University, eastern Iran. Genotyping of three GSTP1, GSTM1, and GSTT1 genes were determined using the multiplex polymerase chain reaction assay in 216 reactions for 72 VUR children and 312 reactions for 104 healthy controls.Results:The presence of GSTT1 deletion was associated with high risk of VUR in children, whereas GSTP1 and GSTM1 genotypes did not show the same effect. Furthermore, the combination of GSTT1/GSTM1 and GSTT1/ GSTP1 genotypes showed a significant influence on lower risk of VUR in children.Conclusion:Deletion of GSTT1 functional gene is a genetic risk factor causing VUR in children. Interestingly, the combination of GSTM1 and GSTP1 null genotypes with GSTT1 has shown a protective role against risk of GSTT1 deletion.

Abstract A41: Assessing the effect of glucobrassicin-rich Brussels sprouts on the metabolism of deuterated phenanthrene: Developing food-based chemoprevention of tobacco-related lung cancer

Abstract Introduction: Indole-3-carbinol (I3C) and 3,3-´diindolylmethane (DIM), derived from the glucosinolate glucobrassicin, are found in cruciferous vegetables. I3C and DIM possess a potent chemopreventive effect against the development of tobacco carcinogen-induced lung tumors in mice. Polycyclic aromatic hydrocarbons (PAH) are potent lung carcinogens present in high levels in tobacco smoke. An individual’s ability to metabolically activate and/or detoxify PAH may be related to lung cancer risk from smoking. We hypothesize that I3C administered by eating a rational dose of Brussels sprouts, defined in terms of glucobrassicin concentration, can decrease the metabolic activation and/or increase detoxification of PAH, represented by the noncarcinogenic PAH [D10]Phenanthrene ([D10]Phe). Use of deuterated phenanthrene eliminates confounding by environmental phenanthrene. Metabolic activation of [D10]Phe is represented by [D10]Phenanthrene tetraol ([D10]PheT), and detoxification is represented by [D10]phenanthrol. We are conducting a clinical trial to determine whether glucobrassicin-rich Brussels sprouts can favorably modify the metabolism of the [D10]Phe. Study Design: This is a single-arm clinical trial. The primary objective is to determine the effect of a 7-day course of Brussels sprout consumption on [D10]PheT. Secondary objectives include analysis of [D10]phenanthrol and the [D10]PheT:[D10]phenanthrol ratio. Exploratory objectives include determining the correlation between 24 h urinary DIM with the reduction in [D10]PheT, and determining the effect of Brussels sprout consumption on circulating immune cell composition and activity. Forty-eight generally healthy, adult current smokers and former smokers will be enrolled. Subjects are given 1 microgram of [D10]phe, and all urine is collected for 6 hours (h) afterwards to quantify baseline levels of [D10]PheT and [D10]phenanthrol. Subjects then consume 200 micromol glucobrassicin in the form of raw Brussels sprouts (~200-300 g) once daily for 7 days. Urine is collected for 24 h after vegetable consumption on days 3 ± 1 and 6 of the feeding intervention for DIM quantification. On day 7 of the feeding intervention, a second dose of 1 microgram of [D10]phe is administered at the study center 60 minutes ± 10 minutes after vegetable consumption, followed by another 6 h urine collection. [D10]pheT and [D10]phenanthrol levels are quantified using a validated tandem mass spectrometry assay. Pre- and post-[D10]PheT levels are compared using a paired t-test after log transformation. The results will also be analyzed by GSTT1 and GSTM1 genotyping. Results: Twelve subjects have completed the study. Baseline [D10]PheT levels ranged from 48.34 to 331.05 pmol/6 h. Day 7 [D10]PheT levels ranged from 26.57 to 333.35 pmol/6 h. Percent change from baseline to Day 7 [D10]PheT ranged from a 33% decrease to an 86.5% increase (mean +/- SE of 12.8 +/- 11.6%). Conclusions: The study is ongoing and more subjects are necessary to make a definitive conclusion. Citation Format: Naomi Fujioka, Michelle To, Bruce R. Lindgren, Vincent A. Fritz, Charles Rohwer, Dorothy Hatsukami, Stephen S. Hecht. Assessing the effect of glucobrassicin-rich Brussels sprouts on the metabolism of deuterated phenanthrene: Developing food-based chemoprevention of tobacco-related lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A41.

Genetic Polymorphism of Glutathione S-transferase and Cervical Cancer Susceptibility in Northeastern Thailand

Background: Exposure to certain carcinogens together with host genetic predisposition likely has an influence on cervical carcinogenesis. Objective: Our aim was to evaluate synergistic effects of glutathione S-transferase (GST) polymorphisms and risk behaviors (i.e., smoking and contraceptive use) on squamous cell cervical cancer (SCCA) development in northeastern Thailand. Methods: Subjects were 198 (SCCA) patients and 198 age-matched healthy controls. Multiplex PCR and PCR-RFLP were used to determine GSTT1 and GSTA1 gene polymorphism, respectively. Results: Interaction between the four polymorphic loci of GSTs (GSTM1, GSTT1, GSTP1 and GSTA1) and increased risk for cervical cancer was not observed. The three genotypes of GSTM1 consistently showed significant risks of smoking with a lower OR for the Null individuals (1.741) at around one -fourth of wild type homozygous individuals (8.000). The effects of GST polymorphisms on cervical cancer risk under the use of hormonal contraceptives apparently did not occur. Conclusions: The predisposition of smoking risk is related to the GST genotype. It is suggested that knowing one’s own genotype data will contribute to the prevention of SCCA by controlling risk habits.

GSTs polymorphisms are associated with epigenetic silencing of CDKN2A gene in esophageal squamous cell carcinoma.

Esophageal cancer is the eighth most common cancer and the sixth most frequent cause of cancer mortality worldwide. Exposure to polycyclic aromatic hydrocarbons formed by incomplete combustion of organic matter is an important risk factor. Genetic polymorphisms in genes encoding PAH-metabolizing enzymes like glutathione S-transferases (GSTM1, GSTP1, GSTT1) which conjugate glutathione to PAHs for reduction of oxidative stress may affect an individual's response to PAH exposure. Genomic DNA from 50 esophageal squamous cell carcinoma patients extracted from peripheral blood. PCR-RFLP technique was employed to determine GSTM1, GSTT1, and GSTP1 polymorphisms. Aberrant promoter methylation of CDKN2A was applied by methylation-specific PCR technique. Concentration of urinary 1-hydroxypyrene was determined using a HPLC system. About 38.7% showed the null GSTM1 genotype (54% cases and 13% controls), 23.7% showed GSTT1 null genotype (30% cases and 13% controls), and 62.5% were GSTP1 A/A genotype (66% cases and 56% controls). Polymorphic variants of GSTM1 and GSTT1 were significantly associated with aberrant methylation of CDKN2A gene. The null state of GSTT1 was significantly associated with high concentrations of 1-OHP in urea (p < 0.01). There was significant association between methylated states of CDKN2A and high concentrations of 1-OHP in urine (p < 0.01). We identified significant association between polymorphism of GSTs genes and epigenetic silencing of tumor suppressor gene CDKN2A in esophageal squamous cell carcinoma.

P1577DOES VITAMIN E -COATED MEMBRANES INFLUENCE ON MARKERS OF OXIDATIVE STRESS IN HEMODIALZSIS PATIENTS WITH HOMOZYGOUS GST M1 GENE DELETION?

Abstract Background and Aims Increased free radicals production and down-regulated antioxidant enzymes activities contribute to protein, lipid and DNA oxidative damage particularly in HD patients lacking for GSTM1 enzyme activity. At the same time, those patients exhibit higher mortality rate than those with active GSTM1 genotype. It has been shown that vitamin E-coated membranes (VitEM) may decrease oxidative stress and inflammatory status in overall HD patients. Therefore, for the first time we analyzed VitEM dialyzers in patients who are homozygote for GSTM1 gene deletion and in whom anti-oxidative and anti-inflammatory benefit could be the greatest. Method GSTM1 genotypes were determined by PCR in 170 chronic HD patients. Those with GSTM1-null genotype were randomized and 80 were included in the study. Forty of them were dialyzed for three months with VitEM, while other forty were dialyzed with high-flux polysufone membranes of the same surface. Markers of protein and lipid oxidative damage, inflammation (thiol groups, malondialdehyde (MDA), Interleukin-6 (IL-6)), together with plasma antioxidant activity (glutathione peroxidase (GPX), superoxide dismutase (SOD)) were determined at the start and at the end of the study. Results Seventy-five patients’ finished the study. There were no significant differences in baseline characteristics between the two groups (age, sex, body weight, dialysis vintage, vascular access, presence of diabetes, dialyzers surface, Kt/V and CRP). Also, there were no significant differences at baseline markers of protein and lipid oxidative damage, inflammation and plasma antioxidant activity. After three months of therapy, GPX, MDA, thiol groups increased significantly in both groups, but without statistical significance between groups (Table 1). SOD did not change significantly during three month period. IL-6 increased in control group, at the same time decreased in VitEM group, but without statistical significance. Conclusion Vitamin E-coated membranes did not influence markers of oxidative stress in HD patients with GSTM1-null genotype. Further studies in the field are required.

Vitamin E-Bonded Membranes Do Not Influence Markers of Oxidative Stress in Hemodialysis Patients with Homozygous Glutathione Transferase M1 Gene Deletion.

Background: Increased oxidative stress is a hallmark of end-stage renal disease. Hemodialysis (HD) patients lacking glutathione transferase M1 (GSTM1) enzyme activity exhibit enhanced oxidative DNA damage and higher mortality rate than those with active GSTM1 enzyme. To our knowledge, this is the first study to use the vitamin E-bonded membranes (VEM) in patients with homozygous GSTM1 gene deletion, and we aimed to determine the effect of VEM on oxidative and inflammatory status in HD patients with homozygous GSTM1 gene deletion. Methods: GSTM1 genotypes were determined by polymerase chain reaction (PCR) in 170 chronic HD patients. Those with GSTM1-null genotype were randomized and 80 were included in the study. Forty of them were dialyzed for three months with VEM, while the other forty were dialyzed with high-flux same-surface polysulfone dialyzers. Markers of protein and lipid oxidative damage and inflammation (thiol groups, malondialdehyde (MDA), Interleukin-6 (IL-6)), together with plasma antioxidant activity (glutathione peroxidase (GPX), superoxide dismutase (SOD)) were determined. Results: Seventy-five patients finished the study. There were no differences at baseline in markers of protein and lipid oxidative damage, inflammation and plasma antioxidant activity. After three months of therapy, GPX, MDA, and thiol groups increased significantly in both groups, but without statistical significance between groups. SOD and C reactive protein (CRP) did not change significantly during the three-month period. IL-6 increased in the control group, and at the same time, decreased in the VEM group, but without statistical significance. Hemoglobin (Hb) value, red blood cells, erythropoiesis resistance index (ERI), serum ferritin and iron did not change significantly within or between groups. Regarding other laboratory parameters, proteins, albumins, triglycerides, serum phosphorus, serum bicarbonate and Kt/V showed significant improvements within groups but with no significant difference between groups. Conclusions: Our data shows that therapy with VEM over three months had no benefit over standard polysulfone membrane in decreasing by-products of oxidative stress and inflammation in dialysis patients lacking GSTM1 enzyme activity.

GSTM1 null and GSTT1 null: predictors of cisplatin-caused acute ototoxicity measured by DPOAEs

Preventing the ototoxicity caused by cisplatin is a major issue yet to be overcome. Useful preventive treatments will soon be available. Consequently, the next step is to filter out those patients who are more prone to develop ototoxicity. The aim of this study was to prospectively evaluate potential predictive markers of acute ototoxicity as determined by measures of distortion product otoacoustic emissions (DPOAEs). A total of 118 patients from our previous DPOAE analysis were put under evaluation. Ototoxic cases were divided according to unilateral (n = 45) or bilateral (n = 23) involvement. The clinicopathological characteristics, hearing test results, germline GSTT1, GSTM1, and GSTP1 polymorphisms, and common laboratory parameters were included in the new analysis. Univariate and multivariate statistical tests were applied. According to multivariate logistic regression, the only independent predictor of unilateral ototoxicity (vs. non-affected) was a GSTM1 null genotype (OR = 4.52; 95%CI = 1.3–16.3), while for bilateral damage, the GSTT1 null genotype (OR = 4.76; 1.4–16) was a predictor. The higher starting serum urea level was characteristic of bilateral ototoxicity; however, the only independent marker of bilateral (vs. unilateral) ototoxicity was the presence of GSTT1 null genotype (OR = 2.44; 1.23–4.85). Different processes, involving the GSTM1 and GSTT1 genotypes, respectively, govern the development of acute unilateral and bilateral ototoxicities. Further research is needed to clarify these processes. Based on the above findings, patients whom are at risk may be selected for otoprotective therapies.Key messagesThe acute ototoxicity was determined by DPOAE in 118 testicular cancer patients.GSTM1 null was the only marker of unilateral ototoxicity (vs. non-affected).The only marker of bilateral hearing loss (vs. non-affected) was the GSTT1 null.GSTT1 null was also the marker of bilateral vs. unilateral ototoxicity.A high-risk group may be selected for new, individualized otoprotective treatment.

Association of GSTP1, GSTT1 and GSTM1 Gene Variants with Coronary Artery Disease in Iranian Population: A Case-Control Study.

BackgroundCoronary artery disease (CAD) is a multifactorial disease that may be caused by the interaction between environmental and genetic risk factors. Glutathione S-transferases (GSTs) are known to participate in detoxification and metabolism of a wide range of xenobiotic compounds and oxidative stress products. Considering the interaction between environmental and genetic factors in CAD, we investigated the genetic polymorphisms of GSTM1, GSTT1, and GSTP1 in the Iranian population.Patients and MethodsTwo hundred and forty-four CAD cases and 281 healthy controls were studied. The genotype of GSTM1, GSTT1, and GSTP1 genes was determined by multiplex polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) techniques. Multivariable logistic regression analysis was used to calculate the odds ratios (ORs) and 95% confidence intervals (CI). Multifactor dimensionality reduction (MDR) analysis was also carried out to analyze the gene–gene and gene–environment interaction.ResultsThe genotype and allele distribution of the three variations were not significantly different between CAD patients and controls (p > 0.05). The subgroup analysis revealed no significant gene–gene interactions or gene–gene combination effects linked to CAD susceptibility. However, MDR analysis selected the GSTM, GSTT pairwise and three genes combination models associated with the susceptibility to CAD. In addition, its result revealed that smoking in combination with GSTM1 (two-way) and GSTT, GSTP (three-way) genes might increase the risk of CAD. Furthermore, a significant interaction between GSTT1-null polymorphism and dyslipidemia was found in multivariable logistic regression analyses in the gene–environmental interactions on CAD risk.ConclusionOur results suggest that the GSTM1, GSTT1 and GSTP1 genetic variations are not directly associated with the susceptibility to CAD in Iranian patients. Due to MDR results, there might be a non-linear association between interactions of two or three genes and smoking with CAD. There is also an association between CAD risk factors and GST variations, which requires supplementary confirmation with larger sample sizes.

Glutathione S-transferase M1 and T1 genes deletion polymorphisms and risk of developing essential hypertension: a case-control study in Burkina Faso population (West Africa)

BackgroundGlutathione S-transferases play a key role in the detoxification of persistent oxidative stress products which are one of several risks factors that may be associated with many types of disease processes such as cancer, diabetes, and hypertension. In the present study, we characterize the null genotypes of GSTM1 and GSTT1 in order to investigate the association between them and the risk of developing essential hypertension.MethodsWe conducted a case-control study in Burkina Faso, including 245 subjects with essential hypertension as case and 269 control subjects with normal blood pressure. Presence of the GSTT1 and GSTM1 was determined using conventional multiplex polymerase chain reaction followed by gel electrophoresis analysis. Biochemical parameters were measured using chemistry analyzer CYANExpert 130.ResultsChi-squared test shows that GSTT1-null (OR = 1.82; p = 0.001) and GSTM1-active/GSTT1-null genotypes (OR = 2.33; p < 0.001) were significantly higher in cases than controls; the differences were not significant for GSTM1-null, GSTM1-null/GSTT1-active and GSTM1-null/GSTT1-null (p > 0.05). Multinomial logistic regression revealed that age ≥ 50 years, central obesity, family history of hypertension, obesity, alcohol intake and GSTT1 deletion were in decreasing order independent risk factors for essential hypertension. Analysis by gender, BMI and alcohol showed that association of GSTT1-null with risk of essential hypertension seems to be significant when BMI < 30 Kg/m2, in non-smokers and in alcohol users (all OR ≥ 1.77; p ≤ 0.008). Concerning GSTT1, GSTM1 and cardiovascular risk markers levels in hypertensive group, we found that subjects with GSTT1-null genotype had higher waist circumference and higher HDL cholesterol level than those with GSTT1-active (all p < 0.005), subjects with GSTM1-null genotype had lower triglyceride than those with GSTM1-active (p = 0.02) and subjects with the double deletion GSTM1-null/GSTT1-null had higher body mass index, higher waist circumference and higher HDL cholesterol than those with GSTM1-active/GSTT1-active genotype (all p = 0.01).ConclusionOur results confirm that GSTT1-null genotype is significantly associated with risk of developing essential hypertension in Burkinabe, especially when BMI < 30 Kg/m2, in non-smokers and in alcohol users, and it showed that the double deletion GSTM1-null/GSTT1-null genotypes may influence body lipids repartition.

Glutathione S-transferase (T1 &amp; M1) Null Genotypes as Risk Determinants in Sudanese for Developing Type Two Diabetes Mellitus

Glutathione S-transferases (GSTT1 and GSTM1) are globular proteins responsible for the detoxification of xenobiotics and the prevention of oxidative damage. Functional polymorphisms of the antioxidant glutathione and enzymes have a role in the pathogenicity of T2DM and its complications. The present study is aimed to assess association between GSTM1 and GSTT1 genetic polymorphisms with T2DM in Sudanese people. This case-control study was done in Khartoum. A total of 181 Sudanese (115 T2DM patients and 66 controls) included in this study. Genomic DNA was extracted and processed by Multiplex PCR. The present genotype and null genotypes of GSTT1 and GSTM1 were identified. The biochemical parameters have been estimated in plasma samples. Glycated hemoglobin was also estimated in the whole blood samples. SPSS version 20 was used for the analysis of genotypes distribution, mean values, P-values and Odd Ratio with 95% confidence intervals. Sudanese patients with T2DM showed an increased frequency of the GSTT1 null genotype when compared to the non-diabetic controls (48.7% versus 28.8%). The diabetic patients showed a lower frequency of GSTT1 genotype compared to their controls (51.3% versus 71.2%). The study revealed a high frequency of the GSTM1 null genotype in diabetic Sudanese compared to their controls (40.9% versus 36.4%); while type-2 diabetes mellitus patients showed a lower frequency of GSTM1 present genotype compared to non-diabetic Sudanese (59.1% versus 63.6%). The GSTM1 and GSTTI genes polymorphism can be a good marker for early identification of Sudanese people at risk of T2DM and its complications.