Glutathione S-transferase M1 Gene Research Articles

Glutathione S-Transferase Gene Polymorphisms as Predictors of Methotrexate Efficacy in Juvenile Idiopathic Arthritis.

Because of the unpredictable efficacy of methotrexate (MTX) in the treatment of juvenile idiopathic arthritis (JIA), the possibility of a favourable outcome is reduced in more than 30% of patients. To investigate the possible influence of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) gene deletion polymorphisms on MTX efficacy in patients with JIA, we determined these polymorphisms in 63 patients with JIA who did not achieve remission and 46 patients with JIA who achieved remission during MTX therapy. No significant differences were observed in the distribution of single GSTM1 or GSTT1 deletion polymorphisms or their combination between the two groups: 58.7% to 63.5%; p = 0.567, 17.4% to 22.2%; p = 0.502, and 13% to 12.7%; p = 0.966, respectively. Our results suggest that GSTM1 and GSTT1 deletion polymorphisms do not influence the efficacy of MTX in patients with JIA. Additional studies are required to determine the possible influence of GST deletion polymorphisms on MTX efficacy in patients with JIA.

GST polymorphism as a predictive biomarker for modulating the susceptibility to chronic obstructive pulmonary disease: A North Indian study.

Chronic obstructive pulmonary disease (COPD) is commonly characterized by shortness of breath, coughing or expectoration. Smoking is the leading cause of COPD development, but only a small percentage of smokers develop symptoms, implying a genetic component. Glutathione S-transferase enzymes are responsible for detoxifying cigarette smoke components. The role of glutathione S-transferase T1 (GSTT1) and glutathione S-transferase M1 (GSTM1) gene polymorphism was assessed with COPD susceptibility and associated clinical parameters in the North Indian population. This was a cross-sectional study involving 200 COPD patients and 200 healthy individuals, with peripheral blood sampling and adequate questionnaires. Multiplex PCR was used for genotyping GSTT1 and GSTM1 gene polymorphism. Logistic regression was used to calculate the odds ratio and 95% confidence intervals to assess the COPD risk and GST polymorphisms. The GSTT1 gene deletion rate was higher in COPD cases (34.5%) than in healthy individuals (20.5%). A statistical relationship between the GSTT1(-) null genotype and COPD risk was observed (odds ratio=2.04, 95% CI=1.30-3.20, P=0.0019). After adjusting for covariates like age, sex and smoking status, a significant association was found for GSTT1(-) null genotype and COPD risk (adjusted odds ratio=2.90, 95% CI=1.43-5.87, P=0.003). The GSTT1(-) genotype was also significantly correlated with clinical parameters for COPD risk. Another primary observation was that females with the GSTT1(-) null genotype were more vulnerable to COPD than males with the same gene deletion. The GSTT1(-) null genotype strongly correlates with COPD development, while no association was observed in the GSTM1(-) null genotype in the North Indian population.

Potential role of glutathione S‑transferase M1 gene polymorphism in kidney calcium oxalate stone formation.

The purpose of this study was to look into the effects of glutathione S-transferase M1 (GSTM1) gene polymorphism on the formation of kidney calcium oxalate stones. A total of 159 patients with kidney calcium oxalate stones were included in this study as a case group. One hundred and three healthy individuals were included in the control group. The age, gender, and levels of calcium (Ca), uric acid (UA), creatinine (Cr), and urinary creatinine (Ucr) are tracked. Peripheral blood samples are used to perform a polymerase chain reaction to identify the glutathione S-transferase (GST) gene polymorphism (PCR). A commercial kit was used in this study to measure the levels of malondialdehyde (MDA), nitric oxide (NO), total antioxidant capacity (T-AOC), and 8-hydroxydeoxyguanosine (8-OHdG) in peripheral blood. There was no difference in age or gender distribution between the case and control groups (P > 0.05). The Cr, Ucr, Ca, UA, 8-OHdG, MDA, NO, and T-AOC in the case group were significantly higher than those in the control group (P < 0.001). The Hardy-Weinberg genetic equilibrium test showed no difference between the case group (P = 0.23) and the control group (P = 0.09). In the case group, the 8-OHdG and NO in GSTM1 null genotype were significantly higher than those in GSTM1 genotype(P < 0.05), but there was no significant difference in MDA and T-AOC (P > 0.05). Multivariate regression analysis showed that the GSTM1 null genotype was positively correlated with 8-OHdG (P < 0.001) and NO (P < 0.001). GSTM1 gene polymorphism might be a detecting risk factor for kidney calcium oxalate stone formation. ChiCTR2100051300.

Copy Number Variation in the GSTM1 and GSTT1 Genes and the Risk of Liver Cirrhosis in Eastern Ethiopia.

Polymorphisms in glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) can cause an entire gene deletion. The current methodology can accurately identify GSTM1 and GSTT1 copy number variants (CNVs), which may shed light on the true contribution of each gene copy to the cellular detoxification process and disease risk. Because liver cirrhosis is becoming a critical worldwide health issue, this study determined the CNVs of GSTM1 and GSTT1 and their relationship to the risk of liver cirrhosis. In this study, we compared 106 patients with liver cirrhosis to 104 healthycontrols. Real-time PCR was used to identify the CNVs of GSTM1 and GSTT1. Logistic and linear regression models were used to estimate the relationship between liver cirrhosis and clinical chemistry variables with the CNVs, respectively. In 3.3% of the study participants, >2 copies of the GSTM1 or GSTT1 genes were detected. GSTT1 carriers had a significantly lower risk of liver cirrhosis (p<0.05) compared with individuals who had homozygous deletion (adjusted odds ratio (AOR) = 0.47; 95% CI: 0.25, 0.86). This risk reduction was significant (p<0.05) in patients with a single copy of the GSTT1 gene (AOR = 0.48; 95% CI: 0.25, 0.91). Those with ≥2 copies of combined GSTM1 and GSTT1 also had a significantly (p<0.05) lower risk of developing liver cirrhosis compared with double null genotypes (AOR = 0.38; 95% CI: 0.16, 0.91, p trend <0.001). Moreover, ≥2 copies of combined GSTM1 and GSTT1 genes were associated with a substantial decrease in alanine amino transferase (ALT) and aspartate aminotransferase (AST) levels, respectively. A single copy number of GSTT1, and ≥2 copies of combined GSTM1 and GSTT1 genes were associated with a reduced risk of liver cirrhosis in Ethiopians. These findings underscore the importance of gene-environment interactions in the multifactorial development of liver cirrhosis.

Glutathione S-transferase M1 and T1 gene polymorphisms in psoriasis patients: a pilot case-control study

Background The exact etiology of psoriasis remains unknown; nevertheless, it has been found that oxidative stress plays a vital role. Among the multiple antioxidant enzymes, genetic polymorphisms in the Glutathione S-Transferases (GSTs) led to an imbalance in the antioxidant system, resulting in increased levels of reactive oxygen species. Accordingly, the polymorphism in these genes could increase the susceptibility to psoriasis. Objectives To assess the association between Glutathione S-Transferase M1 (GSTM1) and Glutathione S Transferase Theta-1 (GSTT1) gene polymorphisms in psoriasis patients compared to healthy controls. Methods A total of 200 participants, 100 psoriasis cases who were assessed by the Psoriasis Area and Severity Index (PASI), and 100 healthy controls were included. DNA extraction was done followed by multiplex PCR to detect genetic polymorphism in the GSTM1 and GSTT1 genes, Finally, the relation between the presence of polymorphism and the severity of psoriasis was estimated. Results The null genotype frequency of GSTM1 and GSTT1 was 76.0% and 58.0%, respectively among psoriasis patients, while it was 58.0% and 55.0%, respectively among healthy controls. There was a significantly higher risk for psoriasis in patients with the null genotype GSTM1 (OR=2.293) as compared to controls. On the other hand, there was no statistically significant relation between their polymorphisms and family history, psoriasis severity, and PASI score. Conclusion The null genotype GSTM1 could increase the risk of psoriasis susceptibility especially among males.

Relationship between glutathione S-transferase M1 gene polymorphism and gastric cancer

This experiment was designed to investigate the relationship between glutathione S-transferase M1 (GSTM1) gene polymorphism and gastric cancer (GC). For this purpose, from January 2013 to December 2014, 116 patients with GC diagnosed in the Department of Gastroenterology of our hospital and 120 healthy people in the physical examination center were selected as the research objects. 116 patients with GC served as the observation group and 120 healthy people in the physical examination center served as the control group. Collect and isolate the peripheral blood nucleated cells of the subjects, obtain the GSTM1 gene polymorphism by sequencing, analyze the differences of GSTM1 genotype between the two groups, compare the differences of clinicopathological characteristics of patients with different genotypes in the observation group, look for the survival relative risk factors of patients with GC, and analyze the risk factors of death risk of GC by multivariate Cox risk proportional regression. Results showed that the proportion of GSTM1 (-) in the observation group (62.07%) was raised compared with the control group (48.33%) (p<0.05). There was a correlation between GSTM1 gene polymorphism and smoking, TNM stage differentiation and GSTM1 gene polymorphism in the observation group. The specific analysis found that the proportion of non-smoking, stage I-III and low differentiation in the GSTM1 (-) group was raised compared with that in the GSTM1 (+) group (p<0.05). TNM stage, differentiation degree and GSTM1 gene polymorphism were correlated with the median survival time of patients with GC (p<0.05). Further multivariate Cox risk proportional regression analysis showed that TNM stage IV, low differentiation and GSTM1 (-) the relative risk coefficients of death in patients with GC were stage Ⅰ - Ⅲ, high/medium differentiation and GSTM1, respectively (+) patients were 1.75, 1.46, and 2.14 times higher. In conclusion, GSTM1 gene polymorphism is associated with susceptibility to GC, and the GSTM1 deletion genotype is an unfavourable factor for poor prognosis in patients with GC.

Association of Polymorphisms in Antioxidant Enzyme-Encoding Genes with Diabetic Nephropathy in a Group of Saudi Arabian Patients with Type II Diabetes Mellitus.

IntroductionAn imbalance between reactive oxygen species (ROS) generation and the defence mechanisms underlying the activity of antioxidant enzymes has been demonstrated as the leading pathology in diabetes mellitus (DM)-related microvascular complications.PurposeThis study aims to evaluate the association between polymorphisms in antioxidant enzyme-encoding genes: catalase (CAT); manganese superoxide dismutase (Mn-SOD); glutathione S transferase M1 (GSTM1); and GSTT1 glutathione S transferase T1 (GSTT1), and the risk of type II diabetic nephropathy (DN) in the Saudi population.Patients and MethodsThe present study involved 64 type II DM patients with nephropathy and 64 type II diabetes patients without nephropathy from the King Abdulaziz University (KAU) Hospital. They underwent real-time PCR genotyping for the Mn-SOD and CAT genes. Multiplex PCR was used to detect GSTM1- and GSTT1-null polymorphisms.ResultsA statistically significant difference was observed between the case and control groups with regard to polymorphisms in the CAT gene (P = 0.037), but not for polymorphisms in the Mn-SOD (P = 0.64) gene. In addition, a statistically significant association was observed between null polymorphisms of the GSTT1 and GSTM1 genes and DN in the case and control groups (P = 0.046 and P = 0.035, respectively).ConclusionOur results showed that the genetic ability to combat oxidative stress may play a major role in DN pathogenesis in Saudi type II DM patients. These polymorphisms in antioxidant enzyme-encoding genes could be used as independent genetic markers for the construction of risk prediction models for kidney-related complications in type II DM patients.

Metabolic enzyme gene polymorphisms predict the effects of antioxidant treatment on idiopathic male infertility.

To explore the relationship between genetic polymorphisms of metabolic enzymes such as CYP1A1, CYP2D6, GSTM1, GSTT1, and GSTP1 and idiopathic male infertility. By observing the efficacy of antioxidants in the treatment of idiopathic male infertility, the effect of metabolic enzyme gene polymorphisms on antioxidant therapy in patients with idiopathic male infertility was prospectively studied. This case–control study included 310 men with idiopathic infertility and 170 healthy controls. The cytochrome P450 1A1 (CYP1A1), cytochrome P450 2D6 (CYP2D6), glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), and glutathione S-transferase P1 (GSTP1) genotypes in peripheral blood samples were analyzed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). The idiopathic male infertility group was treated with vitamin C, vitamin E, and coenzyme Q10 for 3 months and followed up for 6 months. GSTM1(−), GSTT1(−), and GSTM1/T1(−/−) in the idiopathic male infertility groups were more common than those in the control group. The sperm concentration, motility, viability, mitochondrial membrane potential (MMP), and seminal plasma total antioxidant capacity (T-AOC) level in patients with GSTM1(−), GSTT1(−), and GSTM1/T1(−/−) were lower than those in wild-type carriers, and the sperm DNA fragmentation index (DFI), 8-hydroxy-2’-deoxyguanosine (8-OH-dG), and malondialdehyde (MDA) and nitric oxide (NO) levels were higher. Therefore, oxidative damage may play an important role in the occurrence and development of idiopathic male infertility, but antioxidant therapy is not effective in male infertility patients with GSTM1 and GSTT1 gene deletions.

Role of Glutathione S-Transferase M1 and Glutathione S Transferase Theta 1 Gene Polymorphism, Histopathological, and Immunohistochemistry in Carcinoma Breast

Background:Breast cancer is the most common invasive cancer in females in developing countries such as India. It is the most common malignancy in females in the Punjab state.Objectives:(1) The purpose of this study was to calculate the prevalence of the four subtypes of breast cancer based on molecular classification and (2) to determine the association of polymorphisms in Glutathione S-Transferase M1 (GSTM1) and Glutathione S transferase theta 1 (GSTT1) gene in carcinoma of the breast with histopathological grading.Materials and Methods:This study analyzed histologically confirmed 100 cases of carcinoma breast; immunohistochemistry and reverse transcription polymerase chain reaction molecular tests were performed for further grading, molecular typing, and gene polymorphism.Results:Out of 24 Grade I tumors, 18 (75.00%) expressed the GSTM1 gene and 6 (25.00%) were negative. Out of 48 Grade II tumors, 30 (62.50%) expressed the GSTM1 gene and 18 (37.50%) were negative. Out of 28 Grade III tumors, 8 (28.57%) expressed the GSTM1 gene and 20 (71.43%) were negative. Out of 24 Grade I tumors, 17 (70.83%) expressed the GSTT1 gene and 7 (29.17%) were negative. Out of 48 Grade 2 tumors, 28 (58.33%) expressed the GSTT1 gene and 20 (41.67%) were negative. Out of 28 Grade III tumors, 8 (28.57%) expressed the GSTT1 gene and 20 (71.43%) were negative.Conclusion:Our study shows that polymorphism of both GSTM1 and GSTT1, either individually or in combination, influences the risk of developing carcinoma due to DNA damage caused by many factors including environmental and genetic.

Detoxification Genomics in Children with β-Thalassemia Major: Pilot Study of Glutathione S Transferase M1, Pi &amp; Methyltetrahydrofolate Reductase Gene Polymorphisms Combinations in β- Thalassemia Major

Background: Children with β-thalassemia major differ regarding age at presentation, transfusion requirements and unpredictable timing, rate and severity of hemolytic crisis. The blood transfusions are associated with iron overload. Glutathione S transferase M1 (GSTM1) null mutation was reported to be associated with myocardial iron overload with low body iron. Aim of the Work: To investigate if children with β-thalassemia major have more than a detoxification enzyme defect. Materials and Methods: GSTM1, glutathione S transferase Pi (GSTPi) and methyltetrahydrofolate reductase (MTHFR) polymorphism were studied among 97 children with β-thalassemia major in a cross-sectional study. Results: The studied cohort comprised 24 (24.7%) girls and 73 (75.3%) boys. Mean hemoglobin was 5.9+/- 0.7gm%, serum iron was 145.69 +/- 58.6 mcg% and total iron binding capacity was 222.58 +/-50.66 mcg%. Of them, 68 (70.1%) demonstrated single or multiple polymorphisms (43 had GSTM1, 20 GSTPi and 32 with MTHFR polymorphisms respectively), while 29 (29.2%) did not demonstrate any polymorphism. There was no correlation between type, number of polymorphisms and clinical phenotype. Sample size and cross- sectional nature of our study did not allow genotype-phenotype correlation. Most of studied children express GSTM1, GSTPi and MTHFR gene polymorphism which was not consistent among them. Conclusion: Children with β-thalassemia major may have one or more than a detoxification/ regeneration potential enzyme gene GSTM1, GSTPi and MTHFR polymorphism. Every child with β-thalassemia major has unique genetic detoxification and regeneration abilities. The detected detoxification defects might explain the lack of predictability of occurrence of hemolytic attacks and their severity. More studies are needed to highlight impact of detoxification and regeneration genomics in β-thalassemia.

A prospective observational study to evaluate Glutathione S-transferase gene polymorphism and its association with Antitubercular drugs induced liver injury in tertiary hospital

BackgroundAnti-TB drugs are most common cause of idiosyncratic hepatotoxicity worldwide. Reactive metabolite formed during drug metabolism has been involved in a clinical toxicity are described as ‘idiosyncratic’ drug induce liver injury (DILI). We have observed the distribution of glutathione S -transferase (GST) gene polymorphism & its association with drug-induced liver injury in patients taking anti-tubercular treatment. MethodsA prospective observational study including 96 patients receiving anti-tubercular treatment. Blood sample was collected for LFT and gene extraction after ruling out other cause of liver injury. DNA extraction for GST gene was done follow by polymerase chain reaction to identify homozygous null mutation at GSTM1 and GSTT1 loci. Association of GSTM1 and GSTT1 gene with DILI was seen. ResultsOut of 96 tubercular patients under treatment, drug induced liver injury was found in 21 (21.9%) patients and 75 does not develop DILI, GST M1 gene null mutation was observed in 14 (66.7%), GST T1 gene null mutation was observed in 9 (42.9%), Both GST gene null mutation was observed in 8 (38.1%) in DILI group. ConclusionThe GSTM1 gene null mutation and both GSTM1 and T1 gene null mutation were a risk factor for the development of DILI. But there is no significant association between GSTT1 gene null mutation and DILI in TB patients.

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

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

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.

Individual and combined effects of GSTM1 and GSTT1 polymorphisms on colorectal cancer risk: an updated meta-analysis.

Background. The presence or absence of glutathione S-transferase M1 gene (GSTM1) and glutathione S-transferase T1 gene (GSTT1) polymorphisms, and their combined effects have been suggested as a risk factor for colorectal cancer (CRC). However, the results are inconsistent.Objectives. An updated meta-analysis was performed to solve the controversy.Methods. Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines were used.Results. Overall, the GSTM1 null genotype was associated with an increased CRC risk in Caucasians (odds ratio (OR) = 1.14, 95% confidence interval (CI): 1.05–1.23), Asians (OR = 1.19, 95% CI: 1.08–1.32), high-quality studies (OR = 1.12, 95% CI: 1.06–1.18). Moreover, the GSTM1 null genotype was also associated with an increased colon cancer risk (OR = 1.32, 95% CI: 1.16–1.51). The GSTT1 null genotype was also associated with an increased CRC risk in Asians (OR = 1.08, 95% CI: 1.02–1.15) and Caucasians (OR = 1.24, 95% CI: 1.09–1.41). Moreover, The GSTT1 null genotype was associated with an increased rectal cancer risk (OR = 1.13, 95% CI: 1.01–1.27, I2 = 8.3%) in subgroup analysis by tumor location. Last, the GSTM1 null/GSTT1 null genotype was associated with an increased CRC risk in Asians.Conclusion. This meta-analysis indicates that the GSTM1 and GSTT1 null genotypes are associated with increased CRC risk in Asians and Caucasians, and the GSTM1 null/GSTT1 null genotype was associated with increased CRC risk in Asians.

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 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.

Use of echocardiography and glutathione S-transferase to detect heart complications in β-thalassemic patients

Background and objective β-Thalassemia major (TM) is an inherited disorder of hemoglobin synthesis and characterized by defective hemoglobin synthesis, resulting in ineffective erythropoiesis, severe anemia, increased erythrocyte turnover, and excessive iron absorption. Accordingly, iron overload develops and may accumulate in the liver, heart, and endocrine organs. Several gene polymorphisms have been studied as protective or predisposing factors for cardiac dysfunction in patients with TM. Moreover, echocardiographic left ventricular (LV) diastolic evaluation is used to detect early myocardial dysfunction secondary to iron overload. This study aimed at determining some diastolic and tissue Doppler echo indices to predict iron load. Materials and methods This study included 42 β-thalassemic patients, among whom, 16 proved to have cardiac complications after clinical evaluation. Their age ranged from 3 to 25 years. Participants were subjected to clinical evaluation, molecular analysis to detect glutathione S-transferase M1 (GSTM1) gene polymorphism, and transthoracic color Doppler echocardiography to detect early myocardial dysfunction. Results Seven (43.7%) patients had the functional wild-type allele (GSTM1 non-null genotypes), whereas nine (56.2%) patients were homozygous for the GSTM1 null allele. There was a statistically significant increase regarding both right and LV E/A in GSTM1 null genotype when compared with GSTM1 non-null genotype in β-thalassemic patients with cardiac complications. Moreover, LV and right ventricular diastolic function has been significantly affected in participants with GSTM1 null genotype in β-thalassemic patients with cardiac complications, and particularly, LV diastolic function has been significantly impaired in cases experiencing frequent blood transfusion in β-thalassemic patients with cardiac complications. Conclusion Follow-up of patients with β-thalassemia and evaluating echocardiographic changes may permit better assessment of patients and early recognition of cardiac affection before disease progression.

GSTM1 and Liver Iron Content in Children with Sickle Cell Anemia and Iron Overload.

Chronic blood transfusions in patients with sickle cell anemia (SCA) cause iron overload, which occurs with a degree of interpatient variability in serum ferritin and liver iron content (LIC). Reasons for this variability are unclear and may be influenced by genes that regulate iron metabolism. We evaluated the association of the copy number of the glutathione S-transferase M1 (GSTM1) gene and degree of iron overload among patients with SCA. We compared LIC in 38 children with SCA and ≥12 lifetime erythrocyte transfusions stratified by GSTM1 genotype. Baseline LIC was measured using magnetic resonance imaging (MRI), R2*MRI within 3 months prior to, and again after, starting iron unloading therapy. After controlling for weight-corrected transfusion burden (mL/kg) and splenectomy, mean pre-chelation LIC (mg/g dry liver dry weight) was similar in all groups: GSTM1 wild-type (WT) (11.45, SD±6.8), heterozygous (8.2, SD±4.52), and homozygous GSTM1 deletion (GSTM1-null; 7.8, SD±6.9, p = 0.09). However, after >12 months of chelation, GSTM1-null genotype subjects had the least decrease in LIC compared to non-null genotype subjects (mean LIC change for GSTM1-null = 0.1 (SD±3.3); versus −0.3 (SD±3.0) and −1.9 (SD±4.9) mg/g liver dry weight for heterozygous and WT, respectively, p = 0.047). GSTM1 homozygous deletion may prevent effective chelation in children with SCA and iron overload.

Acetylcholinesterase, Butyrylcholinesterase and Glutathione S-Transferase Enzyme Activities and Their Correlation with Genotypic Variations Based on GST M1 and GST T1 Loci in Long Term-Pesticide-Exposed Tea Garden Workers of Sub-Himalayan West Bengal

Organophosphates (OPs) and carbamates (CBs) are known to reduce acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and increase Glutathione S-Transferase (GST) activities in the exposed individuals. We have evaluated AChE, BChE and GST activities in long-term pesticide exposed tea garden workers of sub-Himalayan West Bengal and tried to relate enzyme activities with polymorphisms in GST M1 and GST T1 genes. Enzyme activities were measured spectro-photometrically in blood samples of sprayers and pluckers in relation to age-matched control individuals. Allele-specific multiplex-PCR was employed to score the presence of GST M1 and GST T1 alleles. Significantly lower (p < 0.01) level of AChE and BChE activities were found in the worker group (3.15 ± 0.69 µmol/min/mL of lysate and 1.2 ± 0.54 µmol/min/mL of plasma respectively) compared to the control group (3.74±0.26 µmol/min/mL of lysate and 2.21 ±0.27 µmol/min/mL of plasma respectively). Whereas, significantly higher (p < 0.01) level of GST activity was detected in the worker group (3.83 ±0.97 lU/gm of Hb) comprising of 61 individuals compared to control group (2.47 ±0.29 lU/gm of Hb) comprising of equal number of individuals. Out of total 122 individuals, 34.43% had both GST M1 and GST T1, 23.77% had single-null genotype for GST T1, 27.05% had the single-null genotype for GST M1 and 14.75% individuals had double-null genotypes. We found no significant difference in enzyme activities among the four genotypes when test and control groups were compared. This study for the first time explored changes in AChE, BChE and GST activities in tea garden workers exposed chronically to OPs and CBs in the studied region. Our study indicated that exposure to OP and CB pesticides leads to changes in AChE, BChE and GST activities and the presence or absence of GST M1 and GST T1 alleles are possibly not related to the changes in AChE, BChE and GST activities.

Glutathione S-transferase T1, M1 and P1 gene polymorphisms and susceptibility to colorectal cancer, a Syrian population study

Colorectal cancer (CRC) is considered to be the third most common cancer worldwide, and it is the fourth most common cause of cancer deaths. CRC is described as multifactorial disease. Among others, Glutathione S-transferases are known to act pro-carcinogenic in CRCs, however, they are needed for the conjugation between chemotherapeutics and a wide spectrum of xenobiotics. In this study, 70 patients with CRC and 85 healthy volunteers without any cancer history were genotyped. Polymorphism genotypes for the genes GSTP1, GSTT1 and GSTM1 were studied by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and/or multiplex polymerase chain reaction. Our finding showed a significant risk for CRC associated with GSTP1 heterozygous Ile/Val (OR = 1.8; 95% CI: 0.93–3.44; p = 0.009), while GSTP1 Val/Val homozygous was observed only in the CRC patients. Significant differences in the frequency of GSTM1- and GSTT1-null genotypes were found. The GSTT1-null genotype was higher in CRC group (34.3%) than in control group (12.9%) (OR = 3.5; 95% CI: 1.57–7.83; p = 0.001). The GSTM1-null was higher in CRC cases (42.8%) compared with control group (21.1%) (OR = 2.79; 95% CI: 1.38–5.64; p = 0.003).Individuals carrying combined, both GSTM1/GSTT1-null genotype, were associated with an estimated 7.56-fold higher risk to form CRC than those having GSTM1/GSTT1-present genotype. Individuals carrying combined three genotypes of GSTM1-null/GSTT1-null/ heterozygous Ile/Val genotype for GSTP1 were associated with an estimated 21.63-fold higher risk to be CRC than those carrying GSTM1-present/GSTT1-present/ Ile/Ile genotype of the GSTP1 (OR = 21.63; 95% CI: 2.39–195.82; p = 0.001). Also, individuals with combined three genotypes of GSTM1-null/GSTT1-present/ heterozygous Ile/Val genotype for GSTP1 were associated with an estimated 13.9-fold higher risk to be CRC than those carrying GSTM1-present/GSTT1-present/ Ile/Ile genotype of the GSTP1 (OR = 13.9; 95% CI: 2.60–74.35; p = 0.0007). Overall, the results of this pilot study in 70 patients revealed that the GSTM1-null genotype, alone or in combination with GSTT1-null genotype, GSTP1-heterozygous is associated with enhanced risk for CRC in Syrian population.