Glutathione Transferase P1 Polymorphism Might Be a Risk Determinant in Heart Failure.
ABSTRACT: Disturbed redox balance in heart failure (HF) might contribute to impairment of cardiac function, by oxidative damage, or by regulation of cell signaling. The role of polymorphism in glutathione transferases (GSTs), involved both in antioxidant defense and in regulation of apoptotic signaling pathways in HF, has been proposed. We aimed to determine whether GST genotypes exhibit differential risk effects between coronary artery disease (CAD) and idiopathic dilated cardiomyopathy (IDC) in HF patients. GSTA1, GSTM1, GSTP1, and GSTT1 genotypes were determined in 194 HF patients (109 CAD, 85 IDC) and 274 age- and gender-matched controls. No significant association was found for GSTA1, GSTM1, and GSTT1 genotypes with HF occurrence due to either CAD or IDC. However, carriers of at least one variant GSTP1?Val (rs1695) allele were at 1.7-fold increased HF risk than GSTP1?Ile/Ile carriers (p = 0.031), which was higher when combined with the variant GSTA1?B allele (OR = 2.2, p = 0.034). In HF patients stratified based on the underlying cause of disease, an even stronger association was observed in HF patients due to CAD, who were carriers of a combined GSTP1(rs1695)/GSTA1 "risk-associated" genotype (OR = 2.8, p = 0.033) or a combined GSTP1?Ile/Val+Val/Val (rs1695)/GSTP1?AlaVal+?ValVal (rs1138272) genotype (OR = 2.1, p = 0.056). Moreover, these patients exhibited significantly decreased left ventricular end-systolic diameter compared to GSTA1?AA/GSTP1?IleIle carriers (p = 0.021). Higher values of ICAM-1 were found in carriers of the GSTP1?IleVal+?ValVal (rs1695) (p = 0.041) genotype, whereas higher TNF? was determined in carriers of the GSTP1?AlaVal+?ValVal genotype (rs1138272) (p = 0.041). In conclusion, GSTP1 polymorphic variants may determine individual susceptibility to oxidative stress, inflammation, and endothelial dysfunction in HF.
Project description:Background and Objectives: One of the most frequent genetic alterations reported to date in prostate cancer (PC) is aberrant methylation of glutathione transferase P1 (GSTP1). Taking into consideration the involvement of oxidative stress in PC pathogenesis and recent advances in scientific understanding of the role of GSTP1*Ala114Val rs1138272 polymorphism in carcinogenesis, we hypothesized that this single-nucleotide polymorphism (SNP) influences the risk of PC independently of, or in combination with, other GST polymorphisms, including GSTP1*IIe105Val rs1695 or GSTM1 and GSTT1 deletion polymorphisms. Materials and Methods: Genotyping was performed in 237 PC cases and in 236 age-matched controls by multiplex polymerase chain reaction (PCR) for deletion of GST polymorphisms and by quantitative PCR for SNPs. Results: We found that carriers of either GSTP1*Val (rs1138272) or GSTP1*Val (rs1695) variant alleles had a PC risk compared to individuals with both referent alleles (OR = 4.93, 95%CI: 2.89-8.40, p < 0.001 and OR = 1.8, 95%CI: 1.19-2.73, p = 0.006, respectively). Additionally, in a haplotype analysis we found that individuals with GSTP1*C haplotype, represented by both variant alleles (GSTP1*Val rs1695 + GSTP1*Val rs1138272), had a 5.46 times higher risk of PC development compared to individuals with the most frequent haplotype (95%CI = 2.56-11.65, p < 0.001), suggesting a potential role of those variants in PC susceptibility. A regression analysis on the number of risk-associated alleles per individual (GSTM1*active, GSTT1*null, GSTP1*Val rs1695 and GSTP1*Val rs1138272) showed a significant increase in the risk of developing PC, from 3.65-fold in carriers of two risk alleles (95%CI = 1.55-8.61, p = 0.003) to an approximately 12-fold increase in carriers of all four risk alleles (95%CI = 3.05-44.93, p < 0.001). Conclusion: Prostate cancer may be influenced by multiple glutathione transferase (GST) polymorphic genes, especially GSTP1, highlighting the role of gene-gene interactions in human susceptibility to this cancer.
Project description:Age-related cataract (ARC) is one of the most common eye diseases in the elderly worldwide, especially in China. The genetic polymorphisms of many glutathione S-transferases coding genes are likely to be closely related to the development of ARC, especially the GSTT1, the GSTM1 and the GSTP1. This investigation is aimed to determine the possible associations of GSTT1, GSTM1 and GSTP1 polymorphisms with the susceptibility of ARC in Chinese Han Population.A case-control study including ARC cases (n = 312) and controls (n = 256) in Chinese Han Population was performed. GSTT1 and GSTM1 polymorphisms were detected by duplex polymerase chain reaction (PCR), and two SNPs (rs1695, A/G and rs1138272, C/T) in GSTP1 gene were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, all the results were verified by sequencing method.The GSTT1 null genotype carriers had a much higher risk of ARC compared with non-null genotype (χ(2) = 14.091, P<0.001), and the allele G carriers also had a increased risk over the allele A carriers in the SNP (rs1695, A/G) in GSTP1 gene (χ(2) = 7.696, P = 0.006), while the GSTM1 polymorphism and the SNP (rs1138272, C/T) in GSTP1 gene seem had no association with the susceptibility of ARC in Chinese Han Population.These preliminary results indicated carriage of null GSTT1 and GSTP1 Val/Val genotypes may contribute to genetic susceptibility to ARC in Chinese Han Population, and these genetic polymorphisms might be used as molecular markers for detecting ARC susceptibility.
Project description:BACKGROUND: Genetics may partially explain observed heterogeneity in associations between traffic-related air pollution and incident asthma. OBJECTIVE: Our aim was to investigate the impact of gene variants associated with oxidative stress and inflammation on associations between air pollution and incident childhood asthma. METHODS: Traffic-related air pollution, asthma, wheeze, gene variant, and potential confounder data were pooled across six birth cohorts. Parents reported physician-diagnosed asthma and wheeze from birth to 7-8 years of age (confirmed by pediatric allergist in two cohorts). Individual estimates of annual average air pollution [nitrogen dioxide (NO2), particulate matter ? 2.5 ?m (PM2.5), PM2.5 absorbance, ozone] were assigned to each child's birth address using land use regression, atmospheric modeling, and ambient monitoring data. Effect modification by variants in GSTP1 (rs1138272/Ala114Val and rs1695/IIe105Val) and TNF (rs1800629/G-308A) was investigated. RESULTS: Data on asthma, wheeze, potential confounders, at least one SNP of interest, and NO2 were available for 5,115 children. GSTP1 rs1138272 and TNF rs1800629 SNPs were associated with asthma and wheeze, respectively. In relation to air pollution exposure, children with one or more GSTP1 rs1138272 minor allele were at increased risk of current asthma [odds ratio (OR) = 2.59; 95% CI: 1.43, 4.68 per 10 ?g/m3 NO2] and ever asthma (OR = 1.64; 95% CI: 1.06, 2.53) compared with homozygous major allele carriers (OR = 0.95; 95% CI: 0.68, 1.32 for current and OR = 1.20; 95% CI: 0.98, 1.48 for ever asthma; Bonferroni-corrected interaction p = 0.04 and 0.01, respectively). Similarly, for GSTP1 rs1695, associations between NO2 and current and ever asthma had ORs of 1.43 (95% CI: 1.03, 1.98) and 1.36 (95% CI: 1.08, 1.70), respectively, for minor allele carriers compared with ORs of 0.82 (95% CI: 0.52, 1.32) and 1.12 (95% CI: 0.84, 1.49) for homozygous major allele carriers (Bonferroni-corrected interaction p-values 0.48 and 0.09). There were no clear differences by TNF genotype. CONCLUSIONS: Children carrying GSTP1 rs1138272 or rs1695 minor alleles may constitute a susceptible population at increased risk of asthma associated with air pollution.
Project description:Background Response to glucocorticoid (GC) monotherapy in the initial phase of remission induction treatment in childhood acute lymphoblastic leukemia (ALL) represents important biomarker of prognosis and outcome. We aimed to study variants in several pharmacogenes (NR3C1, GSTs and ABCB1) that could contribute to improvement of GC response through personalization of GC therapy. Methods Retrospective study enrolling 122 ALL patients was carried out to analyze variants of NR3C1 (rs33389, rs33388 and rs6198), GSTT1 (null genotype), GSTM1 (null genotype), GSTP1 (rs1695 and rs1138272) and ABCB1 (rs1128503, rs2032582 and rs1045642) genes using PCR-based methodology. The marker of GC response was blast count per microliter of peripheral blood on treatment day 8. We carried out analysis in which cut-off value for GC response was 1000 (according to Berlin-Frankfurt-Munster [BFM] protocol), as well as 100 or 0 blasts per microliter. Results Carriers of rare NR3C1 rs6198 GG genotype were more likely to have blast count over 1000, than the non-carriers (p = 0.030). NR3C1 CAA (rs33389-rs33388-rs6198) haplotype was associated with blast number below 1000 (p = 0.030). GSTP1 GC haplotype carriers were more likely to have blast number below 1000 (p = 0.036), below 100 (p = 0.028) and to be blast negative (p = 0.054), while GSTP1 GT haplotype and rs1138272 T allele carriers were more likely to be blasts positive (p = 0.034 and p = 0.024, respectively). ABCB1 CGT (rs1128503-rs2032582-rs1045642) haplotype carriers were more likely to be blast positive (p = 0.018). Conclusions Our results have shown that NR3C1 rs6198 variant and GSTP1 rs1695-rs1138272 haplotype are the most promising pharmacogenomic markers of GC response in ALL patients.
Project description:BACKGROUND:The glutathione S transferases P1 (GSTP1) is one of the common type of the GSTs family. This gene has several genetic polymorphisms that the rs1695 and rs1138272 are the most common variations in this gene. This study aimed to examine the association of these genetic variations with breast cancer risk which was followed by bioinformatics analysis. MATERIAL AND METHODS:In a case-control study, 200 participants including 100 women with breast cancer and 100 healthy women were enrolled. After blood sample collection and DNA extraction, the total genomic DNA was extracted from this sample. The SNPeffects online software was employed to evaluate the effects of rs1695 genetic variation on the GSTP1 protein structure. RESULTS:Our data revealed that there is a significant association between rs1695 genetic variation and the risk of breast cancer in homozygote (OR= 3.1532, 95%CI= 1.1072 to 8.9798, p= 0.0315) and allelic (OR= 1.6098, 95%CI= 1.0577 to 2.4500, p= 0.0263) genetic comparisons. This despite the fact that the rs1138272 polymorphism was not associated with breast cancer risk. Our bioinformatics analysis based on WALTZ output showed that the rs1695 polymorphism reduces the amyloid propensity of the GSTP1 enzyme (dWALTZ= -228.00). CONCLUSIONS:Based on our findings, the rs1695 genetic variation is a genetic risk factor for breast cancer and it could be considered as a biomarker for screening of susceptible women.
Project description:BACKGROUND: The presence of glutathione transferase (GST) M1 null genotype (GSTM1-null) in end-stage renal disease (ESRD) patients is associated with lower overall survival rate in comparison to those with GSTM1-active variants. We examined association between GSTM1 and GSTT1 deletion polymorphisms as well as SNPs in GSTA1/rs3957357 and GSTP1/rs1695 genes with overall and cause-specific cardiovascular mortality in ESRD patients. METHODS: Total of 199 patients undergoing hemodialysis were included in the study. Median value of time elapsed from dialysis initiation until the death, or the end of follow-up was 8?±?5 years. The effect of GSTM1, GSTT1, GSTP1 and GSTA1 gene polymorphisms on predicting overall and specific cardiovascular outcomes (myocardial infarction, MI or stroke) was analyzed using Cox regression model, and differences in survival were determined by Kaplan-Meier. RESULTS: GSTM1-null genotype in ESRD patients was found to be independent predictor of overall and cardiovascular mortality. However, after false discovery rate and Bonferroni corrections this effect was lost. The borderline effect modification by wild-type GSTA1*A/*A genotype on associations between GSTM1-null and analyzed outcomes was found only for death from stroke. Homozygous carriers of combined GSTM1*0/GSTA1*A genotype exhibited significantly shorter time to death of stroke or MI in comparison with carriers of either GSTM1-active or at least one GSTA1*B gene variant. The best survival rate regarding cardiovascular outcome was found for ESRD patients with combined GSTM1-active and mutant GSTA1*B/*B genotype. CONCLUSIONS: Combined GSTM1*0/GSTA1*A genotypes might be considered as genetic markers for cardiovascular death risk in ESRD patients, which may permit targeting of preventive and early intervention.
Project description:BACKGROUND:Exposure to numerous chemicals, including industrial ones, may result in liver damage. The body susceptibility to the environmental hazards largely depends on the activity of the enzymes in the xenobiotic detoxification system. Function abnormalities of such enzymes due to genetic variations would increase the risk of developing various diseases. OBJECTIVE:To elucidate the relationship between polymorphism in glutathione S-transferase genes (GSTM1, GSTT1 and GSTP1) and the risk of toxic liver damage in a group of petrochemical workers. METHODS:This study was conducted on 72 workers with toxic liver injury, 156 healthy workers, and 322 healthy individuals without history of occupational exposure to chemicals. Genotyping of the GSTP1 rs1695 gene polymorphism was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Polymerase chain reaction (PCR) was used to perform genotyping of the GSTM1 and GSTT1 genes polymorphism. RESULTS:There was a significant difference in genotype frequencies of the GSTP1 rs1695 gene polymorphism among the groups studied. The distribution of Val/Val genotype of the GSTP1 rs1695 gene polymorphism had a higher incidence in healthy workers compared with patients with toxic liver damage (p=0.036). No significant association was found between the GSTM1 and GSTT1 polymorphisms and toxic liver damage. CONCLUSION:The GSTP1 rs1695 gene polymorphism can play a protective role in the development of toxic liver damage in petrochemical workers.
Project description:INTRODUCTION:Glutathione (GSH) pathways play a key role the metabolism and elimination of the neurotoxicant methylmercury (MeHg). We hypothesized that maternal genetic variation linked to GSH pathways could influence MeHg concentrations in pregnant mothers and children and thereby also affect early life development. METHODS:The GCLM (rs41303970, C/T), GCLC (rs761142, T/G) and GSTP1 (rs1695, A/G) polymorphisms were genotyped in 1449 mothers in a prospective study of the Seychellois population with a diet rich in fish. Genotypes were analyzed in association with maternal hair and blood Hg, fetal blood Hg (cord blood Hg), as well as children's mental (MDI) and motor development (PDI; MDI and PDI assessed by Bayley Scales of Infant Development at 20?months). We also examined whether genotypes modified the association between Hg exposure and developmental outcomes. RESULTS:GCLC rs761142 TT homozygotes showed statistically higher mean maternal hair Hg (4.12?ppm) than G carriers (AG 3.73 and GG 3.52?ppm) (p?=?0.037). For the combination of GCLC rs761142 and GCLM rs41303970, double homozygotes TT?+?CC showed higher hair Hg (4.40?ppm) than G?+?T carriers (3.44?ppm; p?=?0.018). No associations were observed between GSTP1 rs1695 and maternal hair Hg or between any genotypes and maternal blood Hg or cord blood Hg. The maternal GSTP1 rs1695 rare allele (G) was associated with a lower MDI among children (??=?-1.48, p?=?0.048). We also observed some interactions: increasing Hg in maternal and cord blood was associated with lower PDI among GCLC rs761142 TT carriers; and increasing Hg in hair was associated with lower MDI among GSTP1 rs1695 GG carriers. CONCLUSIONS:Maternal genetic variation in genes involved in GSH synthesis is statistically associated with Hg concentrations in maternal hair, but not in maternal or fetal blood. We observed interactions that suggest maternal GSH genetics may modify associations between MeHg exposure and neurodevelopmental outcomes.
Project description: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.
Project description: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.