Formaldehyde in Hospitals Induces Oxidative Stress: The Role of GSTT1 and GSTM1 Polymorphisms.
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ABSTRACT:
SUBMITTER: Ghelli F
PROVIDER: S-EPMC8402352 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Radiotherapy exerts part of its antineoplastic effect by generating oxidative stress, therefore genetic variation in oxidative stress-related enzymes may influence survival of rectal cancer patients. We hypothesized that genetic polymorphisms associated with higher amounts of reactive oxygen species (ROS) that exaggerate cytotoxic activity could improve survival after radiotherapy. We followed 114 rectal cancer patients who received radiotherapy for an average of 42.5 months. Associations between genotypes (GSTP1, GSTM1, GSTT1, CAT, MnSOD, MPO and eNOS) and overall survival were assessed using Kaplan-Meier curves and Cox proportional hazards regression. As hypothesized, patients carrying low ROS producing eNOS Glu298Asp asparagine allele showed an increased hazard of death compared to homozygous carriers of the glutamine allele (hazard ratio (HR): 2.10, 95% confidence interval (CI): 1.01-4.38). However, carriers of low ROS producing MPO G463A A allele had a decreased hazard of death compared to patients homozygous for the G allele (HR: 0.44, 95% CI: 0.21-0.93) although patients homozygous for the A allele had a slightly increased hazard (HR: 1.12, 95% CI: 0.25-5.08). This explorative study provides first results and highlights the need for further, larger studies to investigate association between genetic variation in oxidative stress genes and survival of rectal cancer patients who received radiotherapy.
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Project description:Environmental, lifestyle, and occupational exposures on semen quality have been investigated in epidemiological studies with inconsistent results. Genetic factors involved in toxicant activation and detoxification have been examined in relation to the risk of outcomes such as cancer, cardiovascular, and neurologic disorders. However, the effect of common genetic variants in the metabolism of toxicants on semen quality parameters has rarely been evaluated. In this analysis, we evaluated functional SNPs of three genes of the glutathione-S-transferase (GSTM1, GSTT1, GSTZ1) enzyme family.Participants were 228 presumed fertile men recruited as part of a community-based study. Semen outcome data from this study included total sperm count and concentration, sperm morphology, and sperm DNA integrity and chromatin maturity. DNA was obtained from 162 men from a mouth-rinse sample and genotyped for the presence of GSTT1-1 and GSTM1-1 null genotypes and the GSTZ1 SNPs at positions 94 (rs3177427) and 124 (rs3177429). We used multivariable linear regression to assess the relationship between each genotype and sperm outcomes.Overall, our results did not reveal a consistent pattern between GSTM1 and GSTZ genotypes and increased occurrence of adverse sperm outcomes. However, the GSTT1 non-null genotype yielded the coefficients with the largest magnitude for sperm count and sperm concentration (beta=-0.528, 95% CI -1.238 to 0.199 and beta=-0.353, 95% CI -0.708 to 0.001, respectively), suggesting that it might be adverse.These results indicate that common polymorphisms in GST genes do not negatively impact sperm parameters in healthy men with good semen quality. Contrary to expectations, the GSTT1 non-null genotype was associated with reduced sperm concentration and count in semen. Further study with a larger study size and inclusion of gene-exposure interactions is warranted.
| S-EPMC3321349 | biostudies-other
Project description:PurposeGenetic predisposition to disease has become one of the most investigated risk factors in recent years, and breast cancer (BC) is no exception. In this study, we investigated specific genetic variants of three candidate genes belonging to the glutathione-S-transferase superfamily that have been implicated in increased risk of cancers.Materials and methodsThis case-control study comprised 241 Jordanian women who were diagnosed with BC in addition to 219 matched controls. Gel electrophoresis of PCR products was used to visualize and genotype both the GSTM1 and GSTT1 genes, while PCR-RFLP was employed to genotype the rs1695 of the GSTP1 gene.ResultsOur findings did not reveal any correlation between the investigated polymorphisms of GST genes and BC risk among Jordanian women. Otherwise, the combination of GSTM1 entire gene deletion and (GG) genotype of GSTP1 polymorphism (rs1695) was significantly associated with BC with p-value <0.05 (i.e. p-value was not significant after correcting for multiple comparison).ConclusionWe suggest that the interaction between GSTM1 polymorphism and rs1695 of GSTP1 may influence BC development and progression among Jordanian women. More epidemiological studies are needed to provide a baseline for the underlying role of GSTs polymorphisms in tumorigenesis.
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Project description:Emerging evidences suggest that GSTM1 and GSTT1 are involved in the detoxification of carcinogens, and polymorphisms in this gene that result in a loss of enzyme activity may increase the risk of renal cell carcinoma (RCC). Thus, to evaluate the association of GSTM1 and GSTT1 polymorphisms and RCC, we performed an updated meta-analysis of 10 case-control studies by RevMan 5.2, and the publication bias was tested using STATA 11.0. The meta-analysis showed that the single locus GSTM1 and GSTT1 polymorphisms were not significantly associated with a risk of RCC in a recessive model. However, that wild-type genotype versus the dual null genotype of GSTM1-GSTT1 showed a positive association with RCC risk (OR = 0.70; 95% CI = 0.51-0.98; P = 0.04). In another analysis of subjects exposed to pesticides, we found that the GSTM1 wild-type genotype was associated with increased RCC risk in Europeans (OR = 2.72; 95% CI = 1.54-4.82; P = 0.0006). We also identified an association between the GSTT1 wild-type and lower RCC TNM staging (I + II versus III + IV: OR = 1.88; 95% CI = 1.09-3.26; P = 0.02). This meta-analysis suggests that there may be a relationship between the GSTM1 and GSTT1 wild-type genotype and RCC.
| S-EPMC4677290 | biostudies-other
Project description:BackgroundA number of case-control studies were conducted to investigate the association of glutathione S-transferase (GST) genetic polymorphisms and hepatocellular carcinoma (HCC) risk. However, these studies have yielded contradictory results. We therefore performed a meta-analysis to derive a more precise estimation of the association between polymorphisms on GSTM1, GSTT1 and HCC.Methodology/prinicpal findingsPubMed, EMBASE, ISI web of science and the CNKI databases were systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess the strength of association. Potential sources of heterogeneity were also assessed by subgroup analysis and meta-regression. Funnel plots and Egger's linear regression were used to test publication bias among the articles. A total of 34 studies including 4,463 cases and 6,857 controls were included in this meta-analysis. In a combined analysis, significantly increased HCC risks were found for null genotype of GSTM1 (OR = 1.29, 95% CI: 1.06-1.58; P = 0.01) and GSTT1 (OR = 1.43, 95% CI: 1.22-1.68; P<10(-5)). Potential sources of heterogeneity were explored by subgroup analysis and meta-regression. Significant results were found in East Asians and Indians when stratified by ethnicity; whereas no significant associations were found among Caucasians and African populations. By pooling data from 12 studies that considered combinations of GSTT1 and GSTM1 null genotypes, a statistically significant increased risk for HCC (OR = 1.88, 95% CI: 1.41-2.50; P<10(-4)) was detected for individuals with combined deletion mutations in both genes compared with positive genotypes.Conclusions/significanceThis meta-analysis suggests that the GSTM1 and GSTT1 null genotype may slightly increase the risk of HCC and that interaction between unfavourable GSTs genotypes may exist.
| S-EPMC3502401 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a global health issue and develops into a broad range of illnesses from asymptomatic to fatal respiratory diseases. SARS-CoV-2 infection is associated with oxidative stress that triggers cytokine production, inflammation, and other pathophysiological processes. Glutathione-S-transferase (GST) is an important enzyme that catalyzes the conjugation of glutathione (GSH) with electrophiles to protect the cell from oxidative damage and participates in the antioxidant defense mechanism in the lungs. Thus, in this study, we investigated the role of GSTM1 and GSTT1 gene polymorphism with COVID-19 susceptibility, as well as its outcome. The study included 269 RT-PCR confirmed COVID-19 patients with mild (n = 149) and severe (n = 120) conditions. All subjects were genotyped for GSTM1 and GSTT1 by multiplex polymerase chain reaction (mPCR) followed by statistical analysis. The frequency of GSTM1-/- , GSTT1-/- and GSTM1-/- /GSTT1-/- was higher in severe COVID-19 patients as compared to mild patients but we did not observe a significant association. In the Cox hazard model, death was significantly 2.28-fold higher in patients with the GSTT1-/- genotype (p = 0.047). In combination, patients having GSTM1+/+ and GSTT1-/- genotypes showed a poor survival rate (p = 0.02). Our results suggested that COVID-19 patients with the GSTT1-/- genotype showed higher mortality.
| S-EPMC8242761 | biostudies-literature
Project description:BackgroundProgression of systemic lupus erythematosus (SLE) could be due to oxidative stress especially through reactive oxygen species (ROS). Detoxification of ROS is largely performed by Glutathione S-transferases (GSTs), therefore polymorphisms of GSTM1, GSTT1 and GSTP1 genes which decrease enzymes activity could affect SLE susceptibility. The aim of this study was to determine the effects of GSTM1 (deletion), GSTT1 (deletion) and GSTP1 (Ile105Val) polymorphisms on SLE susceptibility.MethodsGenomic DNA was extracted from blood samples of 163 SLE patients and 180 age, sex and ethnically matched controls. GSTs genotypes were determined by polymerase chain reaction (PCR)-multiplex procedure or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.ResultsGSTT1 null genotype frequency was higher in SLE patients than controls. NO association observed between GSTM1 null genotype or GSTP1 Ile105Val polymorphism with SLE. Nevertheless combination of GSTT1 null/ GSTM1 null genotypes showed 2.8-fold increase in risk of SLE. Moreover the combination of GSTT1 null/ GSTM1 null/GSTP1 Ile/Val and Val/Val genotypes increased the SLE risk about 8 fold.ConclusionPresent data suggest that GSTT1 null/ GSTM1 null/GSTP1 Ile/Val and Val/Val genotypes might largely contribute to the pathogenesis of SLE.
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Project description:BACKGROUND: Genetic susceptibility to tobacco smoke might modify the effect of smoking on pregnancy outcomes. METHODS: We conducted a case-control study of 543 women who delivered singleton live births in Kaunas (Lithuania), examining the association between low-level tobacco smoke exposure (mean: 4.8 cigarettes/day) during pregnancy, GSTT1 and GSTM1 polymorphisms and birthweight of the infant. Multiple linear-regression analysis was performed adjusting for gestational age, maternal education, family status, body mass index, blood pressure, and parity. Subsequently, we tested for the interaction effect of maternal smoking, GSTT1 and GSTM1 genes polymorphisms with birthweight by adding all the product terms in the regression models. RESULTS: The findings suggested a birthweight reduction among light-smoking with the GSTT1-null genotype (-162.9 g, P = 0.041) and those with the GSTM1-null genotype (-118.7 g, P = 0.069). When a combination of these genotypes was considered, birthweight was significantly lower for infants of smoking women the carriers of the double-null genotypes (-311.2 g, P = 0.008). The interaction effect of maternal smoking, GSTM1 and GSTT1 genotypes was marginally significant on birthweight (-234.5 g, P = 0.078). Among non-smokers, genotype did not independently confer an adverse effect on infant birthweight. CONCLUSIONS: The study shows the GSTT1-null genotype, either presents only one or both with GSTM1-null genotype in a single subject, have a modifying effect on birthweight among smoking women even though their smoking is low level. Our data also indicate that identification of the group of susceptible subjects should be based on both environmental exposure and gene polymorphism. Findings of this study add additional evidence on the interplay among two key GST genes and maternal smoking on birth weight of newborns.
| S-EPMC3562502 | biostudies-literature
Project description:Glutathione S-transferases (GSTs; EC: 2.5.1.18) are ubiquitous multifunctional enzymes, which play a key role in cellular detoxification. Functional genetic polymorphisms in genes encoding GSTM1 (a member of GST class mu; OMIM: 138350), and GSTT1 (a member of GST class theta; OMIM: 600436) have been well defined. The functional null alleles of GSTM1 and GSTT1 represent deletions of GSTM1 and GSTT1 genes, respectively. The aim of the present study is to investigate the association between GSTM1 and GSTT1 polymorphisms and methamphetamine dependence. The present population-based case-control study was performed in Shiraz (southern Iran). In total, 52 methamphetamine dependence (11 females, 41 males) and 635 healthy controls (110 females, 525 males) were included in this study. The genotypes of GSTM1 and GSTT1 polymorphisms were determined by PCR. Neither GSTM1 (OR=0.92, 95% CI: 0.52-1.61, P=0.771) nor GSTT1 (OR=0.71, 95% CI: 0.33-1.54, P=0.381) null genotypes were significantly associated with risk of methamphetamine dependence. It should be noted that although there was no association between the GSTM1 null genotype and risk of methamphetamine dependence, in both genders, there was significant interaction between gender and GSTM1 polymorphism (P=0.029). The combination genotypes of the GSTM1 and GSTT1 polymorphisms revealed that the genotypes of these two polymorphisms had no additive effect in relation to the susceptibility to methamphetamine dependence. The present study revealed that genetic polymorphisms of GSTT1 and GSTM1 are not risk factors for methamphetamine dependence.
| S-EPMC5019295 | biostudies-literature
Project description:Oxidative stress and systemic inflammation are closely linked with increased risk of cancer development. Tumor necrosis factor alpha (TNF-?) is one of the pro-inflammatory cytokines. Glutathione S-transferases (GSTs) are enzymes involved in oxidative stress handling. Polymorphisms of genes encoding mentioned molecules may potentially influence the risk and the outcome in neoplastic diseases. Multiple myeloma (MM) is a hematological malignancy characterized by clonal, atypical plasma cell proliferation. In the present study we investigated the association of deletion polymorphisms in GSTT1/GSTM1 genes and single nucleotide polymorphisms (SNPs) in the TNF-? gene at positions -308/-238 with the risk and outcome in MM and sensitivity to bortezomib under in vitro conditions. One hundred newly diagnosed MM patients and 100 healthy blood donors were genotyped by means of multiplex PCR (for GSTs) and PCR-RFLP (for TNF-?). In a subgroup of 50 MM patients, bone marrow cells were treated with bortezomib in vitro. Patients with -238GA+AA or GSTT1-null genotypes had 2.0 (p = 0.002) or 2.29 (p = 0.013) fold increased risk of MM. The interaction effects and risk of MM were observed in GSTT1/GSTM1-null (OR = 2.82, p = 0.018), -308/-238GA+AA (OR = 5.63, p < 0.001), as well as in all combinations of -308 with GSTs. The -308/-238GA+AA genotypes in comparison to GG were associated with earlier MM onset-61.14 vs. 66.86 years (p = 0.009) and 61.72 vs. 66.52 years (p = 0.035), respectively. Patients with GSTM1-present had shorter progression-free-survival (15.17 vs. 26.81 months, p = 0.003) and overall-survival (22.79 vs. 34.81 months, p = 0.039) compared with GSTM1-null. We did not observe relationship between response rate and studied polymorphisms. The in vitro study revealed significantly higher number of apoptotic cells at 12 nM of bortezomib in GSTT1-present, GSTM1-null/present, -308GG and -238GG/GA+AA genotypes. Our findings comprise large analysis of studied polymorphisms in MM.
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