GSTP1 Polymorphisms Research Articles

The Relation between Polymorphisms in Exon 5 and Exon 6 of GSTP1 Gene and the Risk of Lung Cancer in Iranian People

Objective:The GSTP1 gene, which is located on chromosome 11q13, consists of 7 exons and 6 introns. There are two polymorphisms in GSTP1 that have been exposed to a transposition for codon 105 (Ile/Val) and 114 (Ala/Val) in exons 5 and 6, which have been studied previously in relation to lung cancer. Since the level of GSTP1 expression in lung tissues and other human epithelial tissues is high, GSTP1Val-105 polymorphism is recognized as a sensitive factor for tobacco-related cancers, especially lung cancer.Methods:One hundred and twenty tissue block samples of patients with lung cancers and 120 peripheral blood samples of the control group were obtained from two referral cancer centers in Tehran, Iran, from 2011 to 2016. Genomic DNA was extracted from tissue blocks and buffy coat of study cases to detect SNP of GSTP1 gene using Tetra-primer ARMS-PCR.Results:There was a notable correlation between the incidence of lung cancer and variant Val105 (P-value=0.001; OR=2/6; 95% CI=1.49-4.53) and Ile105 (P-value=0.003; OR=0.41; 95% CI=0.23-0.73). The odds ratio for lung cancer in the homozygous Ile105/Ile105 genotype was 3.56 times higher than that of individual with heterozygous Ile105/Val105 (P-value<0.001; OR=3/56; 95% CI=1.826-6.934) genotype, that was statistically significant. Furthermore, the results showed that there was no significant correlation between Ala114/Val114 genotypes and lung cancer. The BC (P-value=0.007; OR=0.16; 95% CI=0.04-0.61) and AA (P=0.001) genotypes were statistically significant (P-value <0.05); and for those who had AA genotype, the odds ratio was almost six times higher than those with BC genotype.Conclusions:The study of GSTP1 polymorphisms indicated that unlike the polymorphism in exon 5, the GSTP1 exon 6 polymorphism correlated with the lung cancer risk in the select group of Iranian people. Likewise, the potential use of this genetic polymorphism as a lung cancer predictor is confirmed.

Association of GSTP1 and ERCC1 polymorphisms with toxicity in locally advanced head and neck cancer platinum-based chemoradiotherapy treatment.

Platinum-based chemoradiotherapy (CRT) is the standard treatment for locally advanced head and neck squamous-cell carcinomas (HNSCC), and most patients experience serious toxicities. The aim of this study was to investigate the association between candidate genes involved in radiation/platinum pathways and acute toxicity of CRT to determine the predictive value of these polymorphisms for toxicity. Thirty-six selected single nucleotide polymorphisms (SNPs) in 29 genes were genotyped in 110 patients treated with cisplatin-based CRT. DNA was obtained from blood samples, and SNP analysis was performed using a MassARRAY iPLEX Gold (Sequenom) method. Patients with ERCC1 rs11615-C allele (P = .0066), ERCC1 rs735482-C allele (P = .0204), and ERCC4 rs1799801-C allele (P = .0286) had lower risk of grade 2-3 hematologic toxicity. In addition, the presence of G allele of GSTP1 was associated with a significantly lower risk of severe dysphagia (P = .0004). Polymorphisms in ERCC1 and GSTP1 may act as prognostic factors of acute toxicity during treatment with CRT in HNSCC patients.

Cytology and molecular study for GSTP1 effect on asthma Iraqi patients

BackgroundGST belongs to a super family of phase II detoxification enzyme and it plays an important role in preventing the damage that may occur due to reactive water-soluble compounds generated by the association of reactive intermediates with glutathione.MethodIn the present study, we analyzed the frequencies of GSTP1 polymorphism among the Iraqi population using PCR–RFLP technique. Fifty samples from bronchial asthma patients and fifty samples from control cases were subjected to conventional PCR and Restriction Fragment Length Polymorphism (RFLP) to detect GSTP1 genotype and measured different parameters together such as IgE, eosinophilic count, WBC, and so forth. Some of the cases were made to undergo sequence analysis and enrolled in NCBI GenBank with accession number (MG657249–MG657258). The GSTP1 polymorphism was determined using PCR and the resultant 176-bp fragment was subjected to RFLP and digested with BsamA1 to recognize the A–G transition at nucleotide.ResultsHomozygotes for Ile105 encoding allele resulted in 176-bp fragment found in 62% andVal105 encoding allele had two fragments of 91 and 85 bp in PCR was found in 4% of asthmatic patients. On the other hand, heterozygotes resulted in three fragments of 176, 91 and 85 bp seen in 34% of patients.ConclusionTo the best of the researcher’s knowledge, this is the first-of-its-kind report with regards to the role played by GSTP1 polymorphism in bronchial asthma among the Iraqi patients. Though the study outcomes do not support the large role played by GSTP1 gene polymorphism in the evolution of bronchial asthma disorder, future researchers are suggested to investigate more features for many promising results.

Association of GSTM1, GSTT1, GSTM3, and GSTP1 Genes Polymorphisms with Susceptibility to Osteosarcoma: a Case- Control Study and Meta-Analysis

Background:Some studies have investigated the association of GSTM1, GSTT1, GSTM3, and GSTP1 polymorphisms with susceptibility to osteosarcoma; however, these studies results are inconsistent and inconclusive. In order to drive a more precise estimation, the present case-control study and meta-analysis was performed to investigate association of GSTM1, GSTT1, GSTM3, and GSTP1 polymorphisms with osteosarcoma.Methods:Eligible articles were identified by a search of several electronic databases for the period up to May 5, 2018. Odds ratios were pooled using either fixed-effects or random effects models.Results:Finally, a total of 24 case-control studies with 2,405 osteosarcoma cases and 3,293 controls were included in the present meta-analysis. Overall, significantly increased osteosarcoma risk was found when all studies were pooled into the meta-analysis of GSTT1 (Null vs. Present: OR= 1.247 95% CI 1.020-1.524, P= 0.031) and GSTP1 polymorphism (B vs. A: OR= 8.899 95% CI 2.722-29.094, P≤0.001). In the stratified, significantly increased osteosarcoma risk was observed for GSTT1 polymorphism among Asians (Null vs. Present: OR= 1.300 95% CI 1.034-1.635, P= 0.025), but not among Caucasians.Conclusions:This meta-analysis demonstrated that GSTP1 and GSTT1 null genotype are associated with the risk of osteosarcoma. Future large well-designed epidemiological studies are warranted to validate our results.

Are genetic polymorphisms of glutathione S-Transferase P1 gene associated with urothelial carcinoma of the urinary bladder?

Background: Polymorphisms in genes encoding glutathione S-transferase (GST) may affect susceptibility to develop urothelial carcinomas (UCs). One of the extensively studied genes in this group is GST P1 (GSTP1), but studies of the relationship of polymorphisms of GSTP1 and UC of the bladder have been equivocal. Hence, we assessed the association between genetic polymorphism of GSTP1 gene and the development of UC of the urinary bladder. Materials and Methods: This prospective, case–control study was conducted in the departments of urology and clinical genetics at a tertiary care teaching hospital in South India, which included 52 patients with histopathologically confirmed UC bladder and matched with 46 controls from August 2012 to July 2013. The study participants provided a single venous blood sample for extraction of genomic DNA. Laboratory personnel was blinded to sample groups. The primary outcome of the study was to detect association of genetic polymorphism of GSTP1 gene with UC of the bladder. The secondary outcome was to assess if the risk of urothelial bladder cancer is increased in smokers with polymorphism of GSTP1 gene. Statistical Analysis Used: We used the Chi-square or Fisher's (F) exact test to compare discrete variables. Unconditional logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals. Results: Although the heterozygous polymorphic genotype ile/val (AG) was seen more frequently in cancer group (34.6% vs. 23.9%), the difference was not statistically significant (P = 0.202). None of the smokers had homozygous polymorphic valine allele and GSTP1 did not add to the susceptibility of UC bladder even among smokers. Conclusions: A lack of association between GSTP1 313 G/G polymorphism and urothelial cancer of bladder was observed.

Telomere Length in Workers Was Effected by Omethoate Exposure, GSTM1 Deletion, Interaction Between Smoking and GSTP1 Polymorphisms.

The aim of this study was to explore the association between telomere length and metabolizing enzyme gene polymorphisms and environmental factors in omethoate-exposed workers. The gene-environment interactions were analyzed with generalized linear model method. The relative telomere lengths in the individuals with GSTM1-deletion were longer than that in non-deletion genotype in the control group (P = 0.011); the relative telomere lengths with GG+AG genotypes in GSTP1 rs1695 were longer than that of AA genotype in the exposure group (P = 0.039). The interaction between the GG+AG genotypes in GSTP1 rs1695 and smoking exposure had significant effect on telomere length (P < 0.05). The prolongation of relative telomere length in omethoate-exposed workers was associated with GSTM1-deletion, GG+AG genotypes, and interactions of GG+AG genotypes and smoking factor.

Promoter methylation and Ile105val polymorphism of GSTP1 gene in the modulation of colorectal cancer risk in ethnic Kashmiri population.

Glutathione-S-transferases (GSTs) are the most important phase II enzymes of the xenobiotic pathway responsible for the detoxification of carcinogens. GSTP1 gene polymorphisms are mostly associated with a lack or an alteration of enzymatic activity toward several substrates thus resulting in increased cancer susceptibility. GSTP1 promoter methylation is also frequently associated with tumor development or poor prognosis in a wide range of tumors. In this study, we examined the role of genetic polymorphism and promoter methylation of GSTP1 gene in the context of modulation of risk of colorectal cancer (CRC) in Kashmiri population. This study used tissue tumor samples (114) and blood samples from (160) patients with CRC and 200 blood samples from healthy donors. GSTP1 polymorphism was studied using polymerase chain reaction (PCR)-restriction fragment length polymorphism and methylation using methylation-specific PCR. There was no significant association between GSTP1 I105V genotypes and the CRC (P>0.05). However, we found a significant association of the Val/Val variant genotype with the dwelling and smoking status (P-value < 0.05). Overall, the homozygous variant Val/Val genotype was associated with a modestly elevated risk for CRC (OR = 1.57; 95% CI = 0.67-3.57). Methyl-specific-PCR analysis revealed 25.4% methylation of the GSTP1 promoter in CRC cases and was not found to be statistically significantly associated with clinicopathological parameters of the CRC cases (P>0.05). Also, no significant associations of any of the three genotypes with promoter hypermethylation were observed. We conclude that promoter hypermethylation in homozygous GSTP1 mutants did not elevate the risk of CRC in Kashmiri population.

Effects of GST variants on the risk odds of hematological malignancy: A meta-analysis.

Whether glutathione S-transferases (GST) polymorphisms influence the risk odds of hematological malignancy remains controversial. Therefore, we performed this meta-analysis to better analyze correlations between GST polymorphisms and hematological malignancy. Literature retrieve was conducted in PubMed, MEDLINE, and Embase. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Sixty-two studies were enrolled for analyses. Significant associations with hematological malignancy were observed for GSTM1 (P < 0.0001, OR = 1.25, 95% CI, 1.14-1.38), GSTP1 (P = 0.002, OR = 1.20, 95% CI, 1.07-1.34), and GSTT1 (P < 0.0001, OR = 1.57, 95% CI, 1.39-1.76) polymorphisms in overall analyses. Further subgroup analyses by ethnicity revealed that GSTM1 and GSTT1 polymorphisms were both significantly correlated with hematological malignancy in Caucasians, East Asians, and West Asians, whereas GSTP1 polymorphism was only significantly correlated with hematological malignancy in Caucasians and West Asians. When we stratified data according to type of disease, positive results were found for all investigated polymorphisms in patients with certain types of acute leukemia. Moreover, GSTP1 polymorphism was also found to be significantly associated with chronic leukemia and lymphoma. Our findings indicated that GSTM1, GSTT1, and GSTP1 polymorphisms may serve as potential genetic biomarkers of hematological malignancy in certain ethnicities.

Genotoxicity of inhalational anesthetics and its relationship with the polymorphisms of GSTT1, GSTM1, and GSTP1 genes.

Due to their wide applications, concern exists regarding possible genotoxic effects of inhalational anesthetics (IAs) among operating room personnel. This study was undertaken to examine genotoxic properties of co-exposure to nitrous oxide, sevoflurane, and isoflurane on induction of micronucleus (MN) and chromosomal aberrations (CAs) and to determine whether any associations exist between polymorphisms of GST genes and the level of genomic damage measured by MN and CAs assays. Sixty operating room personnel and 60 unexposed referent nurses were studied. The workers' exposure to the IAs was determined. DNA damage was evaluated by MN and CAs assays. Additionally, the GSTM1, GSTT1, and GSTP1 polymorphisms were detected. The mean concentrations of nitrous oxide, isoflurane, and sevoflurane were found to be 850.92 ± 919.78, 2.40 ± 0.86, and 0.18 ± 0.14ppm, respectively. The frequency of MN and CAs in the exposed group was significantly higher than that of the non-exposed group. The frequency of MN was significantly higher in referent nurses with null GSTT1, compared to referent nurses with positive GSTT1. The frequency of MN was significantly higher in exposed individuals carrying the combined genotype of GSTT1 (-), GSTM1 (-), and GSTP1 AG as compared with subjects carrying a combination of GSTT1 (+), GSTM1 (+), and GSTP1 AA. Statistically significant associations were noted between exposure to the IAs, gender, and the combination of the three GSTs genotypes with MN frequency. These findings indicate that inhalation exposure to IAs induces genotoxic response and the polymorphisms of GSTs genes might modulate the effect of exposure to IAs on MN.

Glutathione S-Transferase Gene Polymorphisms are Associated with an Improved Treatment Response to Cisplatin-Based Chemotherapy in Patients with Non-Small Cell Lung Cancer (NSCLC): A Meta-Analysis.

BackgroundPrevious studies have shown an association with glutathione S-transferase (GST) gene polymorphisms in patients with non-small cell lung cancer (NSCLC) and treatment response. This study aimed to undertake a literature review and meta-analysis of GST gene polymorphisms, including GSTT1, GSTM1, and GSTP1 IIe105Val, and the treatment response to cisplatin-based chemotherapy in patients with NSCLC.Material/MethodsA literature search was undertaken of the main medical publication databases for publications, up to March 2017, on the association between GSTT1, GSTM1, and GSTP1 IIe105Val polymorphisms and the clinical outcome in patients with NSCLC treated with cisplatin-based chemotherapy. A random fixed-effects model was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) to evaluate the associations, considering multiple genetic models. A subgroup analysis according to ethnicity was performed.ResultsTwenty-three published studies were identified that showed that both the null GSTM1 and the GG genotype of GSTP1 IIe105Val were associated with improved treatment response to cisplatin-based chemotherapy (GSTT1 present/null: OR=1.328; 95% CI, 1.074–1.643) (GSTP1 GG + AG vs. AA: OR=0.596; 95% CI, 0.468–0.759). In subgroup analysis, the GSTP1 polymorphism was significantly associated with treatment response in East-Asian patients, but not in Caucasian patients.ConclusionsMeta-analysis showed that the GG genotype of GSTP1 IIe105Val and the null GSTM1 genotype were associated with an improved treatment response to cisplatin-based chemotherapy in patients with NSCLC, especially in East-Asian patients.

AA Homozygous Genotype of GSTP1 I105V Polymorphism in Oral Cancer: In Silico Screening, Molecular Dynamics Simulation and Activity Studies of Wild and Mutant GSTP1

Background: Highest incidence of oral squamous cell carcinoma (OSCC) has been reported in north-eastern India and causal association between cancer and raw areca-nut (RAN) consumption are well evident. Earlier studies revealed that monitoring the occurrence of precocious anaphase and expression of securin in blood lymphocytes can be a good biomarkers for cancer risk in RAN+lime chewers. Glutathione S-transferases (GSTs) are considered an important cellular detoxification system that provide protection against the effects of toxins and determine individual's cancer susceptibility. Aim: Although GST gene family has been extensively studied, its role as susceptibility factor in oral cancer risk in the RAN chewing population in Meghalaya state, India has not been explored. The association of polymorphisms in GSTP1 (Ile105Val) gene with OSCC risk in Meghalaya, India, was evaluated. Earlier both AA reference and the GG/AG mutant genotype of GSTP1 gene showed an association with different types of cancers. Methods: Genetic polymorphism was evaluated by genotyping 129 cases and 156 controls using PCR-RFLP method and validated by Sanger sequencing in a hospital-based case-control study. GSTP1's interaction status with c-Jun Kinase (JNK) was evaluated through protein-protein docking analysis and this was also validated experimentally by immunohistochemistry and qRT-PCR. Results: Individuals with AA allele of GSTP1 showed significant association with the risk of OSCC compared with individuals with AG/GG mutant genotypes in habit-matched “RAN-only” and “RAN+Tobacco” group. The binding geometry between JNK and GSTP1 was disrupted in mutant combinations. It was demonstrated that AA homozygous genotype of oral epithelial cells showed reduced c-Jun-phosphorylation and proapoptotic genes expression than AG/GG genotypes. In silico docking revealed that homodimeric GSTP1 with AA genotype showed weak catalytic activity in detoxification of RAN and tobacco toxins compared with the AG/GG mutant proteins. Interestingly, the quantitation of 8-Oxo-2´-deoxyguanosine in DNA digests by ELISA-kit showed no differences in these genotypes, however the frequency of sister-chromatid exchanges was significantly higher in individuals with GSTP1 AA genotype than GG genotype. Conclusion: Thus in this population, specific traditional habit along with GSTP1 AA genotype play a significant role in predisposition to oral cancer risk by showing higher DNA-lesions, might be caused by some specific RAN/tobacco metabolites, and lower c-Jun phosphorylation which may inhibit apoptosis.

In Vitro Studies on Ameliorative Effects of Limonene on Cadmium-Induced Genotoxicity in Cultured Human Peripheral Blood Lymphocytes.

Cadmium (Cd) is a non-redox metal that can indirectly cause oxidative stress by depleting cellular levels of glutathione. It is well-known for the generating reactive oxygen species (ROS) such as hydroxyl radicals, superoxide anions, nitric oxide, and hydrogen peroxide. The latter inactivates antioxidant enzymes and induces lipid peroxidation and DNA damage in cells. In our study, we have investigated the ameliorative effect of limonene against Cd-induced genotoxicity using various biomarkers such as sister chromatid exchange (SCE), comet, and lipid peroxidation (LPA) assays in cultured human peripheral blood lymphocytes (PBL) from healthy individuals. It is a naturally occurring flavonoid, found in essential oil of citrus fruits. Limonene at 20-μM and 100-μM concentrations had significantly (P < 0.05 and P < 0.01) reduced the SCE frequency, tail moment, and peroxidation of lipids. Ameliorative effect of limonene was also determined by measuring the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT). We found a significant increase (P < 0.05) in the enzyme activity after limonene treatment. We also studied the effect of GSTP1 gene polymorphism on Cd-induced genotoxicity and antigenotoxic potential of limonene. We found a significant decrease (P < 0.05) in SCE frequency, tail moment, and lipid peroxidation after limonene treatment compared to Cd. However, we did not observe any significant relationship (P > 0.05) between GSTP1 polymorphism and Cd, limonene genotoxicity and antigenotoxicity, respectively.

Interaction between manganese and GSTP1 in relation to autism spectrum disorder while controlling for exposure to mixture of lead, mercury, arsenic, and cadmium

BackgroundWe previously reported a significant interactive association between polymorphisms of GSTP1 and blood manganese concentrations (BMC) with autism spectrum disorder (ASD) in Jamaican children. In this paper, we investigate the same interactive association with ASD while adjusting for the mixture of four metals (lead, mercury, cadmium, and arsenic). MethodWe used data from 163 case-control pairs of children 2–8 years of age from our autism project in Jamaica, in which we collected blood for heavy metals analysis at enrollment. To minimize potential multicollinearity between concentrations of the four metals, we generated a mixture index using generalized weighted quantile sum regression, which was used in conditional logistic regression models to control for the four metals while assessing the interactive association between GSTP1 and BMC with ASD. ResultsSimilar to the findings we reported previously, we found that in co-dominant and dominant models for GSTP1, among children with the Ile/Ile genotype, those with BMC ≥ 12 μg/L had 4.6 and 4.27 times higher odds of ASD compared to those with BMC < 12 μg/L (adjusted Matched Odds Ratio (MOR) = 4.6, 95% CI: 1.21–17.42 and adjusted MOR = 4.27, 95% CI: 1.15–15.85, respectively). In the co-dominant model, for children with the Ile/Val and Val/Val genotypes, the adjusted MORs were 1.26 (95% CI: 0.32, 5.01) and 0.26 (95% CI: 0.05, 1.42), respectively. ConclusionsAfter adjusting for the mixture of four metals, the interactive association of BMC and GSTP1 with ASD remained significant with similar magnitude of associations. Results should be interpreted cautiously.

Association of the Polymorphism of GSTP1 with the Susceptibility to the Development of Schizophrenia

Schizophrenia is a complex mental illness characterized by the presence of symptoms such as hallucinations, delusions, catatonic behavior, cognitive impairment among others. Although the studies exceed 100 years, it is one of the mental illnesses less understood. Oxidative stress has been investigated as one of the potential stimulant factors in the development of schizophrenia. For the study of these relationships, the research focuses on polymorphisms of antioxidant enzymes, such as glutathione S-transferase (GST), an important phase II detoxification enzyme. In this context, the aim of the study is to associate the GSTP1 gene polymorphism with the susceptibility to the development of schizophrenia through a case-control study. The knowledge of the genetic predisposition comes as a support for the understanding of schizophrenia, allowing later the establishment of markers of susceptibility to the disease, which when identified will allow the taking of preventive measures and better targeting of the treatment. Methods: For the analysis of the polymorphisms using the PCR-RFLP technique, the samples collected at the Brain Institute Clinic were divided into two groups, case and control, for later study of the heterozygous genotypes (Ile / Val), wild homozygote (Ile / Ile) and mutant homozygote (Val / Val). Results: There was no statistically significant correlation between GSTP1 polymorphism and the risk of developing schizophrenia. Conclusions: In this sense, more studies should be carried out in search of more consistent results, thus allowing a more accurate correlation regarding the role of this polymorphism with the susceptibility to schizophrenia.

Molecular Analysis of the Glutathione S-Transferase System in Patients with Depression

Depression is defined as a mood disorder in which changes in temperament occur making the patient sad, lacking energy and, at a severe stage, with suicidal thoughts. Depression is a multifactorial tantrum that may be associated with changes in neurotransmitters, social or genetic factors. It is suggested that oxidative stress may be associated with worsening of depression in patients not treated with antidepressants. In addition, it is known that oxidative stress is favored in situations where the individual presents a compromise in the function of antioxidant enzymes, such as GSTP1. The objective of the present study was to verify if the GSTP1 gene polymorphism confers genetic susceptibility to depression. Methods: PCR-RFLP technique was used to analyze polymorphisms. The samples were collected at the Brain Institute Clinic were divided into two groups, case and control, for later study of the heterozygous genotypes (Ile / Val), wild homozygote (Ile / Ile) and mutant homozygote (Val / Val). The results suggest that there was no statistically significant correlation between GSTP1 polymorphism and the risk of developing depression (p = 0.1835). Conclusions: In this sense, more studies should be carried out in search of more consistent results, thus allowing more accurate correlation regarding the role of this polymorphism with the susceptibility to depression.

GSTM1, GSTT1, and GSTP1 polymorphisms and colorectal cancer risk in Polish nonsmokers.

Glutathione S-transferase (GST) enzymes are responsible for cellular detoxification of many carcinogens and are important anticancer elements. This study assessed potential relationships between GSTM1, GSTT1, and GSTP1 polymorphisms and colorectal cancer (CRC) risk in Polish nonsmokers. We also analyzed the influence of GST gene polymorphisms on CRC clinical and histopathological features. Our study included 197 CRC patients and 104 healthy controls. GSTM1, GSTT1, and GSTP1 polymorphisms were evaluated using qPCR. Polymorphism frequencies observed in our control group corresponded to those in other European populations. The GSTM1 null and GSTT1 null genotypes were observed with similar frequencies in both CRC patients and controls (GSTM1 null: 46.7% vs. 45.2%; GSTT1 null: 15.7% vs. 20.2%). GSTP1 Ile/Ile, Ile/Val, and Val/Val genotype frequencies were respectively 42.1%, 48.2%, and 9.6% in patients and 48.1%, 42.3%, and 9.6% in controls. GSTT1 polymorphism correlated with higher tumor grade in CRC patients, and the GSTM1 null/null genotype was associated with more frequent metastasis to lymph nodes (pN classification). Our results suggest that GST gene polymorphisms may influence CRC tumor grade and stage.

Maternal polymorphisms in glutathione-related genes are associated with maternal mercury concentrations and early child neurodevelopment in a population with a fish-rich diet

IntroductionGlutathione (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. MethodsThe 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. ResultsGCLC 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 (β = −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. ConclusionsMaternal 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.

Association of N-acetyltransferase-2 and glutathione S-transferase polymorphisms with idiopathic male infertility in Vietnam male subjects

N-acetyltransferase-2 (NAT2) and Glutathione S-transferases (GSTs) are phase-II xenobiotic metabolizing enzymes participating in detoxification of toxic arylamines, aromatic amines, hydrazines and reactive oxygen species (ROS), which are produced under oxidative and electrophile stresses. The purpose of this research was to investigate whether two common single-nucleotide polymorphisms (SNP) of NAT2 (rs1799929, rs1799930) and GSTP1 (rs1138272, rs1695) associated with susceptibility to idiopathic male infertility. A total 300 DNA samples (150 infertile patients and 150 healthy control) were genotyped for the polymorphisms by ARMS - PCR. We revealed a significant association between the NAT2 variant genotypes (CT + TT (rs1799929), (OR: 3.74; p < 0.001)) and (GA + AA (rs1799930), (OR: 3.75; p < 0.001)) or GSTP1 variant genotypes (GA + AA (rs1695), (OR: 5.11; p < 0,001)) and (CT + TT (rs1138272), (OR: 7.42; p < 0,001) with idiopathic infertility risk. Our findings rate the effect of single-nucleotide polymorphisms of GSTP1 and/or NAT2 in modulation of the risk of male infertility in subjects from Vietnam. This pilot study is the first (as far as we know) to reveal that polymorphisms of NAT2 (rs1799929, rs1799930) and GSTP1 (rs1138272, rs1695) are some novel genetic markers for susceptibility to idiopathic male infertility.

Glutathione s-transferase m1, t1, and p1 gene polymorphism in exudative age-related macular degeneration: a preliminary report.

To elucidate whether the gene polymorphisms of glutathione S-transferase (GST) M1, T1, and P1 are associated with the development of exudative age-related macular degeneration. The authors genotyped 35 white patients with exudative age-related macular degeneration and 159 healthy controls. Genomic DNA from peripheral blood was examined using polymerase chain reaction and defined for the genetic polymorphisms of GST. No association was observed between GSTM1, GSTT1, and GSTP1 polymorphisms and age-related macular degeneration risk (p>0.05). The frequencies of the combination of the GSTM1 (null) and GSTP1 (mutant), GSTM1 (null), and GSTT1 (null) genotype polymorphisms in patients with exudative age-related macular degeneration differed greatly from those of the control group (p=0.001 OR [95% CI]: 7.70 [2.28-25.98] and p=0.007 OR [95% CI]: 3.88 [1.51-10.02], respectively). The present study suggests that the GSTM1 (null) and GSTT1 (null), GSTM1 (null), and GSTP1 (mutant) combinations may be a genetic risk factor for the development of exudative age-related macular degeneration. However, the potential role of GST polymorphisms as a marker of susceptibility to age-related macular degeneration needs further studies in a larger number of patients. (Eur J Ophthalmol 2006; 16: 105-10).

Correlation analysis between polymorphism of GSTP1, XPD and XRCC1 gene in esophageal carcinoma patients and treatment efficiency of cisplatin chemo-therapy

Objective: As a common malignant tumor, esophageal carcinoma lacked specific clinical symptoms, leading to distal metastasis at terminal stage. Cisplatin is the first-line chemotherapy drug for the treatment of esophageal cancer. Identification of sensitive molecular marker is thus of critical importance for individualized treatment of cancer. This study analysed polymorphism of GSTP1, XPD and XRCC1 genes, aiming to illustrate its correlation with treatment efficacy of cisplatin on esophageal cancer, in order to provide evidences for individualized treatment effect. Methods: A total of 104 esophageal carcinoma patients were recruited for follow-ups. Using Response Evaluation Criteria in Solid Tumor (RECIST), treatment efficacy was evaluated. PCR-RFLP was employed for detecting gene polymorphism. Results: Frequency distribution of XRCC1 Arg399Gln, XPD Lys751Gln and GSTP1 Ile105Val all fitted Hardy-Weinberg equilibrium (p>0.05). Both one-factor and multi-factor analysis showed higher effective rate and survival time of patients with XRCC1 Arg399Gln GA+AA genotype after receiving cisplatin treatment compared to those patients with GG genotype (p 0.05). Conclusions: Esophageal carcinoma patients with XRCC1 Arg399Gln GA+AA genotype and GSTP1 Il3105Val AG+GG genotype are more sensitive to cisplatin treatment.