Vesna Coric

Glutathione S-transferase A1, M1, P1 and T1 null or low-activity genotypes are associated with enhanced oxidative damage among haemodialysis patients

BACKGROUND Increased oxidative stress is a hallmark of end-stage renal disease (ESRD). Glutathione S-transferases (GST) are involved in the detoxification of xenobiotics and protection of oxidative damage. We hypothesized that genetic polymorphism in antioxidant enzymes GSTA1, GSTM1, GSTP1 and GSTT1 is more frequent in ESRD and modulates the degree of oxidative stress in these patients. METHODS GSTA1, GSTM1, GSTP1 and GSTT1 genotypes were determined in 199 ESRD patients and 199 age- and gender-matched controls. Markers of protein and lipid oxidative damage [thiol groups, carbonyl groups, advanced oxidative protein products, nitrotyrosine, malondialdehyde (MDA) and MDA adducts], together with total oxidant status and pro-oxidant-antioxidant balance were determined. RESULTS Individual GST polymorphisms influence vulnerability to both protein and lipid oxidation, with GSTM1-null gene variant having the most pronounced effect. Furthermore, a strong combined effect of null/low-activity GSTM1, GSTT1, GSTA1 and GSTP1 genotypes in terms of susceptibility towards oxidative and carbonyl stress was found in ESRD patients. When patients were stratified according to GSTM1 and GSTT1, the highest oxidant damage was noted in those with the GSTM1-null/GSTT1-null genotype. The observed effect was even stronger in patients with the third low-activity GSTP1 or GSTA1 genotype. Finally, the level of oxidative and carbonyl stress was most pronounced in the subgroup of patients with all four null or low-activity GSTM1, GSTT1, GSTP1 and GSTA1 genotypes. CONCLUSIONS According to the GST genotype, ESRD patients may be stratified in terms of the level of oxidative and carbonyl stress that might influence cardiovascular prognosis, but could also improve efforts towards individualization of antioxidant treatment.

GSTA1, GSTM1, GSTP1, and GSTT1 polymorphisms and susceptibility to smoking-related bladder cancer: A case-control study

OBJECTIVES Glutathione S-transferases (GSTs) are a family of enzymes involved in detoxification. Genes encoding for GSTA1, GSTM1, GSTP1, and GSTT1 proteins are polymorphic, which can result in complete or partial loss of enzyme activity. Previous studies have associated polymorphisms of GSTA1, GSTM1, and GSTP1 genes with a higher risk of bladder cancer, but this is still controversial. Potential role of GSTA1 polymorphism in susceptibility to bladder cancer in Whites is lacking. We examined association between GSTA1, GSTM1, GSTP1, and GSTT1 gene variants and bladder cancer risk and evaluated whether they were modified by smoking. MATERIALS AND METHODS A hospital-based case-control study recruited 201 incidence cases and 122 age-matched controls. Deletion polymorphism of GSTM1 and GSTT1 was identified by polymerase chain reaction method. Single nucleotide polymorphism of GSTA1 and GSTP1 was identified by restriction fragment length polymorphism method. Uniconditional multivariate logistic regression was applied to model association between genetic polymorphisms and bladder cancer risk, as well as effect modification by smoking. RESULTS No significant difference was observed in the distributions of GSTM1, GSTT1, GSTA1, and GSTP1 gene variants between patients and controls. None of the examined polymorphisms was significantly associated with bladder cancer risk independently. The results of gene-smoking interaction analyses indicated a significant combined effect of smoking and all common GST polymorphisms tested (P for trend = 0.001). However, the most significant effect on bladder cancer risk was observed in smokers carrying lower activity GSTA1-AB/BB and GSTM-null genotype (OR = 3.5, P < 0.05) compared with GSTA1-AA and GSTM1-active non-smokers. Overall, the risk observed did not significantly differ with respect to quantity of cigarettes smoked. However, heavy smokers with GSTM1-null genotype had 2 times higher risk of bladder cancer than GSTM1-null light smokers (OR = 4.8 vs. OR = 2.0) when GSTM1-active non-smokers served as reference group. Smokers carrying both GSTM1-null and GSTA1-AB + BB genotypes exhibited the highest risk of bladder cancer (OR = 2.00, P = 0.123). CONCLUSIONS Null or low-activity genotypes of the GSTA1, GSTM1, GSTT1, and GSTP1 did not contribute independently towards the risk of bladder cancer in our patients. However, in association with smoking, both low activity GSTA1 and GSTM1-null genotype increase individual susceptibility to bladder cancer.

Effect of hyperglycemia and hyperinsulinemia on glutathione peroxidase activity in non-obese women with polycystic ovary syndrome

OBJECTIVE: In order to gain deeper insight into molecular mechanisms underlying oxidative stress (OS) and its relation to insulin resistance and hyperandrogenemia, plasma markers of OS and antioxidant glutathione-peroxidase (GPX) activity were studied in non-obese polycystic ovary syndrome (PCOS) women via the oral glucose tolerance test (OGTT) and hyperinsulinemic euglycemic clamp. DESIGN: In 36 PCOS women, plasma nitrotyrosine, thiol groups, uric acid (UA) and GPX activity were studied during OGTT and clamp. Insulin resistance was assessed by the homeostasis model (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Matsuda insulin sensitivity index (ISI) and M/I ratio. RESULTS: In PCOS patients, significant positive correlations were obtained for UA with testosterone (r=0.385, p=0.039) as well as indices of insulin resistance. Acute hyperglycemia during OGTT induced alteration in both OS markers and GPX. The change in nitrotyrosine and GPX during OGTT correlated with testosterone (r=0.543, p=0.036 and r=−0.457, p=0.025, respectively). The most significant association was found between OS markers and ISI. CONCLUSIONS: Our results indicate that non-obese PCOS women are prone to oxidative stress induced by hyperglycemia, but this seems not to be related to the direct effect of hyperinsulinemia during clamp. Oxidative stress markers correlated with indices of insulin resistance and circulating testosterone.

Glutathione S-Transferase T1, O1 and O2 Polymorphisms Are Associated with Survival in Muscle Invasive Bladder Cancer Patients

Objective To examine the association of six glutathione transferase (GST) gene polymorphisms (GSTT1, GSTP1/rs1695, GSTO1/rs4925, GSTO2/rs156697, GSTM1, GSTA1/rs3957357) with the survival of patients with muscle invasive bladder cancer and the genotype modifying effect on chemotherapy. Patients and Methods A total of 105 patients with muscle invasive bladder cancer were included in the study. The follow-up lasted 5 years. The effect of GSTs polymorphisms on predicting mortality was analyzed by the Cox proportional hazard models, while Kaplan-Meier analysis was performed to assess differences in survival. Results GSTT1 active, GSTO1 Asp140Asp or GSTO2 Asp142Asp genotypes were independent predictors of a higher risk of death among bladder cancer patients (HR = 2.5, P = 0.028; HR = 2.9, P = 0.022; HR = 3.9, P = 0.001; respectively) and significantly influenced the overall survival. There was no association between GSTP1, GSTM1 and GSTA1 gene variants with overall mortality. Only GSTO2 polymorphism showed a significant effect on the survival in the subgroup of patients who received chemotherapy (P = 0.006). Conclusion GSTT1 active genotype and GSTO1 Asp140Asp and GSTO2 Asp142Asp genotypes may have a prognostic/pharmacogenomic role in patients with muscle invasive bladder cancer.

Glutathione S‐transferase omega‐2 polymorphism Asn142Asp modifies the risk of age‐related cataract in smokers and subjects exposed to ultraviolet irradiation

Glutathione S‐transferase omega‐1 and 2 have a unique range of enzymatic activities, including the regeneration of ascorbate by their dehydroascorbate reductase activities. Because these enzymes could have a protective role from oxidative damage in the lens, the question of whether the two coding glutathione S‐transferase omega polymorphisms confer the risk of age‐related cataract was addressed.

The Role of GSTM1 and GSTT1 Polymorphism in Patients with Renal Cell Carcinoma

The Role of GSTM1 and GSTT1 Polymorphism in Patients with Renal Cell Carcinoma Members of the glutathione S-transferase (GST) superfamily exhibit polymorphic expression. GSTs are investigated as biomarkers of risk for various cancers, including renal cell carcinoma (RCC). The aim of this study was to test the association between GSTM1 and GSTT1 polymorphism and susceptibility to RCC, independently or in conjunction with known risk factors. Genomic DNA was isolated from 182 controls and 76 patients with RCC. GSTM1 and GSTT1 genotypes were determined by multiplex PCR. Data obtained were analyzed with respect to RCC risk factors including smoking and occupational exposure. The frequency of GSTM1-null genotype was higher in patients with RCC (60.5%) compared to controls (47.2%). GSTT1-null genotype was found in 28.6% controls and 27.6% of cases. GSTM1-null individuals exhibit 1.9-fold increased risk of RCC (95% CI: 1.06-3.33). The presence of GSTT1 active genotype was associated with increased risk of RCC in occupationally exposed subjects when unexposed GSTT1-null subjects were used as a comparison group (OR: 2.48; 95% CI: 1.05-5.86). No association was found between the inactive form of GSTM1 and GSTT1 and smoking in RCC patients. In a Serbian cohort of patients, the presence of a GSTM1 active genotype is protective against RCC, whereas a GSTT1 active genotype increases RCC risk in occupationally exposed subjects. Uloga Polimorfizma Glutation S-Transferaza M1 i T1 kod Pacijenata sa Karcinomom Bubrežnog Parenhima Genetski polimorfizam je prisutan kod mnogih članova superfamilije glutation-S transferaza. U toku su istraživanja koja ispituju ulogu GST kao biomarkera za nastanak različitih karcinoma, uključujući karcinom bubrežnog parenhima (KBP). U ovoj studiji je ispitivana uloga GSTM1 i GSTT1 polimorfizma u nastanku KBP, nezavisno ili udruženo sa poznatim faktorima rizika za ovaj karcinom. DNK je izolovana iz krvi 182 kontrolna subjekta i 76 bolesnika sa KBP. Polimorfizam GSTM1 i GSTT1 je određivan metodom PCR-a. Dobijeni rezultati su analizirani u odnosu na faktore rizika za KBP, uključujući pušenje i profesionalnu izloženost. Učestalost GSTM1-nultog genotipa je bila viša kod bolesnika sa KBP (60,5%) nego kod kontrola (47,2%). Prisustvo GSTT1-nultog genotipa je utvrđeno kod 28,6% kontrola i 27,6% bolesnika sa KBP. Nosioci GSTM1-nultog genotipa imaju 1.9-puta veći rizik za KBP (95% CI: 1,06-3,33). Prisustvo GSTT1 aktivnog genotipa je udruženo sa povećanim rizikom za KBP kod profesionalno izloženih subjekata kada su kao referentna grupa uzeti neizloženi nosici GSTT1-nultog genotipa (OR: 2,48; 95% CI: 1,05-5,86). Nije otkrivena povezanost između nedostatka aktivne forme GSTM1 i GSTT1 i pušenja kod obolelih od KBP. Studija izvedena u Srbiji je pokazala da prisustvo GSTM1 aktivnog genotipa štiti od nastanka KBP, dok prisustvo GSTT1 aktivnog genotipa povećava rizik kod profesionalno izloženih osoba.

GSTA1, GSTM1, GSTP1 and GSTT1 polymorphisms in progressive myoclonus epilepsy: A Serbian case–control study

PURPOSE Oxidative stress is recognized as an important factor in progressive myoclonus epilepsy (PME). Genetic polymorphism of glutathione S-transferases (GSTs), which are involved in both protection from oxidative damage and detoxification, might alter the capacity for protecting tissues from exogenous and endogenous oxidants. We aimed to assess a possible association between GST polymorphism and PME, as well as, correlation between GST genotypes and oxidative phenotype in PME patients. METHODS GSTA1, GSTM1, GSTP1 and GSTT1 genotypes were determined in 26 patients with PME and 66 controls. Byproducts of protein oxidative damage (thiol groups (P-SH) and nitrotyrosine), superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities were determined. RESULTS The frequency of GSTA1, GSTM1 and GSTP1 genotypes was not significantly different between PME patients and controls, while individuals with GSTT1-null genotype were at 5.44-fold higher risk of PME than carriers of GSTT1-active genotype. Moreover, significant risk of PME was obtained in carriers of both GSTT1-null and GSTM1-null genotypes. Carriers of combined GSTA1- active and GSTT1-null genotype were at highest, 7.55-fold increased risk of PME. Byproducts of protein damage did not reach statistical significance, while SOD and GPX activities were significantly higher in PME patients then in controls. When stratified according to GST genotype, P-SH groups were significantly lower only in patients with GSTT1-null genotype in comparison to carriers of active genotype. Only SOD activity was increased in GSTT1-null when compared to corresponding active genotype. CONCLUSIONS GSTT1-null genotype might be associated with the increased risk and enhanced susceptibility to oxidative stress in PME patients.

Does Occupational Exposure to Solvents and Pesticides in Association with Glutathione S-Transferase A1, M1, P1, and T1 Polymorphisms Increase the Risk of Bladder Cancer? The Belgrade Case-Control Study

Objective We investigated the role of the glutathione S-transferase A1, M1, P1 and T1 gene polymorphisms and potential effect modification by occupational exposure to different chemicals in Serbian bladder cancer male patients. Patients and Methods A hospital-based case-control study of bladder cancer in men comprised 143 histologically confirmed cases and 114 age-matched male controls. Deletion polymorphism of glutathione S-transferase M1 and T1 was identified by polymerase chain reaction method. Single nucleotide polymorphism of glutathione S-transferase A1 and P1 was identified by restriction fragment length polymorphism method. As a measure of effect size, odds ratio (OR) with corresponding 95% confidence interval (95%CI) was calculated. Results The glutathione S-transferase A1, T1 and P1 genotypes did not contribute independently toward the risk of bladder cancer, while the glutathione S-transferase M1-null genotype was overrepresented among cases (OR = 2.1, 95% CI = 1.1–4.2, p = 0.032). The most pronounced effect regarding occupational exposure to solvents and glutathione S-transferase genotype on bladder cancer risk was observed for the low activity glutathione S-transferase A1 genotype (OR = 9.2, 95% CI = 2.4–34.7, p = 0.001). The glutathione S-transferase M1-null genotype also enhanced the risk of bladder cancer among subjects exposed to solvents (OR = 6,5, 95% CI = 2.1–19.7, p = 0.001). The risk of bladder cancer development was 5.3–fold elevated among glutathione S-transferase T1-active patients exposed to solvents in comparison with glutathione S-transferase T1-active unexposed patients (95% CI = 1.9–15.1, p = 0.002). Moreover, men with glutathione S-transferase T1-active genotype exposed to pesticides exhibited 4.5 times higher risk in comparison with unexposed glutathione S-transferase T1-active subjects (95% CI = 0.9–22.5, p = 0.067). Conclusion Null or low-activity genotypes of the glutathione S-transferase A1, T1, and P1 did not contribute independently towards the risk of bladder cancer in males. However, in association with occupational exposure, low activity glutathione S-transferase A1 and glutathione S-transferase M1-null as well as glutathione S-transferase T1-active genotypes increase individual susceptibility to bladder cancer.

Combined GSTM1-Null, GSTT1-Active, GSTA1 Low-Activity and GSTP1-Variant Genotype Is Associated with Increased Risk of Clear Cell Renal Cell Carcinoma

The aim of this study was to evaluate specific glutathione S-transferase (GST) gene variants as determinants of risk in patients with clear cell renal cell carcinoma (cRCC), independently or simultaneously with established RCC risk factors, as well as to discern whether phenotype changes reflect genotype-associated risk. GSTA1, GSTM1, GSTP1 and GSTT1 genotypes were determined in 199 cRCC patients and 274 matched controls. Benzo(a)pyrene diolepoxide (BPDE)-DNA adducts were determined in DNA samples obtained from cRCC patients by ELISA method. Significant association between GST genotype and risk of cRCC development was found for the GSTM1-null and GSTP1-variant genotype (p = 0.02 and p<0.001, respectively). Furthermore, 22% of all recruited cRCC patients were carriers of combined GSTM1-null, GSTT1-active, GSTA1-low activity and GSTP1-variant genotype, exhibiting 9.32-fold elevated cRCC risk compared to the reference genotype combination (p = 0.04). Significant association between GST genotype and cRCC risk in smokers was found only for the GSTP1 genotype, while GSTM1-null/GSTP1-variant/GSTA1 low-activity genotype combination was present in 94% of smokers with cRCC, increasing the risk of cRCC up to 7.57 (p = 0.02). Furthermore, cRCC smokers with GSTM1-null genotype had significantly higher concentration of BPDE-DNA adducts in comparison with GSTM1-active cRCC smokers (p = 0.05). GSTM1, GSTT1, GSTA1 and GSTP1 polymorphisms might be associated with the risk of cRCC, with special emphasis on GSTM1-null and GSTP1-variant genotypes. Combined GSTM1-null, GSTT1-active, GSTA1 low activity and GSTP1-variant genotypes might be considered as “risk-carrying genotype combination” in cRCC.

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

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