GSTP1 A313G Research Articles

The GSTP1 rs1695 Polymorphism Is Associated with Mercury Levels and Neurodevelopmental Delay in Indigenous Munduruku Children from the Brazilian Amazon.

Genetic polymorphisms may influence mercury (Hg) toxicity. The aims of this study were to evaluate individual factors, such as the presence of the GSTP1 rs1695 polymorphism, associated with internal Hg dose and child neurodevelopment in indigenous people from the Brazilian Amazon chronically exposed to Hg. Eighty-two indigenous children were clinically evaluated, hair Hg was measured, and the GSTP1 rs1695 polymorphism was genotyped. The mean age was 4.8 years, the median Hg was 5.5 µg/g, and 93.8% of children exceeded the safe limit (2.0 µg/g). Fish consumption was associated with Hg levels (p = 0.03). The GSTP1 rs1695 A>G polymorphism was in the Hardy-Weinberg equilibrium and the highest prevalence of the GSTP1 AA genotype (80%) was found in Sawré Aboy, which had the highest Hg levels (10 µg/g) among the studied villages. The Hg levels tended to increase over the years in males and in carriers of the GSTP1 AA genotype (0.69 µg/g and 0.86 µg/g, respectively). Nine children failed the neurodevelopmental test, all of whom had Hg > 2.0 µg/g, and 88.9% carried the GSTP1 AA or AG genotypes, previously associated with the highest internal Hg doses and neurocognitive disorders. The genetic counseling of this population is important to identify the individuals at greater risk for neurodevelopmental disorders resulting from chronic Hg exposure.

Chromosomal Damage, Chromosome Instability, and Polymorphisms in GSTP1 and XRCC1 as Biomarkers of Effect and Susceptibility in Farmers Exposed to Pesticides.

In the department of Boyacá, Colombia, agriculture stands as one of the primary economic activities. However, the escalating utilization of pesticides within this sector has sparked concern regarding its potential correlation with elevated risks of genotoxicity, chromosomal alterations, and carcinogenesis. Furthermore, pesticides have been associated with a broad spectrum of genetic polymorphisms that impact pivotal genes involved in pesticide metabolism and DNA repair, among other processes. Nonetheless, our understanding of the genotoxic effects of pesticides on the chromosomes (as biomarkers of effect) in exposed farmers and the impact of genetic polymorphisms (as susceptibility biomarkers) on the increased risk of chromosomal damage is still limited. The aim of our study was to evaluate chromosomal alterations, chromosomal instability, and clonal heterogeneity, as well as the presence of polymorphic variants in the GSTP1 and XRCC1 genes, in peripheral blood samples of farmers occupationally exposed to pesticides in Aquitania, Colombia, and in an unexposed control group. Our results showed statistically significant differences in the frequency of numerical chromosomal alterations, chromosomal instability, and clonal heterogeneity levels between the exposed and unexposed groups. In addition, we also found a higher frequency of chromosomal instability and clonal heterogeneity in exposed individuals carrying the heterozygous GSTP1 AG and XRCC1 (exon 10) GA genotypes. The evaluation of chromosomal alterations and chromosomal instability resulting from pesticide exposure, combined with the identification of polymorphic variants in the GSTP1 and XRCC1 genes, and further research involving a larger group of individuals exposed to pesticides could enable the identification of effect and susceptibility biomarkers. Such markers could prove valuable for monitoring individuals occupationally exposed to pesticides.

Association between the oxidative stress gene polymorphism and chronic obstructive pulmonary disease risk: a meta-analysis

BackgroundThe association between the oxidative stress gene polymorphism and chronic obstructive pulmonary disease (COPD) risk has been extensively studied but the results have been controversial. This study aimed to investigate the overall association between the oxidative stress gene including glutathione S-transferase (GST), epoxide hydrolase exon (EPHX), superoxide dismutase (SOD), catalase (CAT), cytochrome P450 system (CYP) and heme oxygenase (HO-1) polymorphism and the risk of COPD.MethodsWe searched the PubMed and EMBASE database to identify studies that investigated the association between the oxidative stress gene polymorphism and risk of COPD. The relevant data were extracted and statistical analyses were performed using the Revman 5.4 and STATA 12 software. Dominant genetic model, recessive model, co-dominant model, heterozygote model, and allele model were analyzed. Venice criteria and publication bias were conducted to access the credibility and reliability.ResultsIn total, 63 publications including 14,733 patients and 50,570 controls were included in the meta-analysis.15 genetic variants of 6 genes were analyzed, and 7 SNPs in GSTP1, CAT, CYP, SOD were first analyses until now. In our study, EPHX T113C C allele, GSTM1 null, GSTT1 null, GSTP1 A313G G and C341T T allele, CYP1A1 MspI C allele, SOD3 A213G G allele and L type in Ho-1 showed increased COPD risk, especially in Asians. T allele in CAT C262T and C allele in SOD2 Val 9 Ala were associated with decreased COPD risk. To avoid high heterogeneity and publications bias, subgroups analysis was performed in accord with HWE and ethnicity. Publication bias was assessed by Begg’s funnel plots and Egger’s test, and no publication bias were found for recessive models. 4 variants were identified with strong levels of epidemiological evidence of associations with the COPD risk.ConclusionsOur results confirm that oxidative stress gene polymorphism was associated with COPD risk. These finding can improve human understanding of this disease gene molecular level and enable early intervention and prevention of COPD. Well-designed studies with large sample sizes are essential to clarify the association of these significant variants with the susceptibility to COPD.

Association of CYP1A2 and GST gene variants with asthma in cases presenting with allergic chronic rhinosinusitis

BackgroundInter-individual differences in regulation and activity of xenobiotic metabolizing enzymes (XMEs) CYP1A and GST might cause distinct susceptibility to chronic rhinosinusitis (CRS) phenotypes that need to be explored. Therefore, the present study aimed to evaluate the role and risk of CYP1A and GST gene variants in allergic CRS subjects with and without asthma. A total of 224 allergic CRS cases with asthma, 252 allergic CRS cases without asthma, and 350 healthy control subjects were subjected to genetic analysis. Gene variants of cytochrome P450 (CYP1A1 T3801 rs4646903, A2455G rs1048943, C2453A rs1799814 and CYP1A2 G3858A rs2069514, T739G rs2069526, C163A rs762551) and glutathione S-transferase P (GSTP1 A313G rs1605 & C341T rs1799811) were investigated by polymerase chain reaction-restriction fragment length polymorphism and GSTM1null, and GSTT1null by multiplex PCR methods.ResultsTG genotype of CYP1A2 rs2069526 (OR 1.73, 95% CI 1.20–2.50, p < 0.002), TC genotype of CYP1A1 rs4646903 (OR 1.43, 95% CI 1.03–1.98, p < 0.031) and GSTM1del (OR 1.87, 95% CI 1.24–2.81, p < 0.003) and were found to be significantly associated with only allergic CRS cases. CYP1A2 rs2069526 (OR 2.33, 95% CI 1.61–3.37, p < 0.001), GG genotype of GSTP1 rs1605 (OR 4.75, 95% CI 2.62–8.63, p < 0.001), GSTM1del (OR 1.82, 95% CI 1.19–2.78, p < 0.006), GSTM1/GSTT1 double null (OR 2.58, 95% CI 1.36–4.87, p < 0.004) and were found to be significantly associated with asthma in allergic CRS cases. Further, G-G-C haplotype of CYP1A2 rs2069514, rs2069526 and rs762551 gene variants was found to increase the risk for asthma by 5 folds in allergic CRS subjects (OR 5.53, 95% CI 1.76–17.31, p < 0.003) while T-G-C haplotype of CYP1A1 rs4646903, rs1048943, rs1799814 (OR 0.11, 95% CI (0.01–0.95, p < 0.045) and A-T haplotype of GSTP1 rs1605, rs1799811 (OR 0.27, 95% CI (0.08–0.89, p < 0.032) showed protective effect in allergic CRS group.ConclusionThe present study reports the significantly increased association of CYP1A2, GSTM, and GSTP gene variants with asthma in allergic CRS.

Gene polymorphisms and prognosis of head and neck squamous cell carcinoma: a systematic review.

Head and neck squamous cell carcinomas (HNSCCs) are associated with variable prognosis even with similar clinical characteristics and treatments. Gene polymorphisms have been suggested as prognostic factors for HNSCC which can justified this variable prognosis. So, the aim was to review literatures on gene polymorphisms and prognosis of HNSCCs. A systematic search was conducted using PubMed, Web of science, SCOPUS, Google Scholar and Cochrane library databases to find all related articles published up to December 2021 in the field of gene polymorphisms and HNSCC prognosis. Of 1029 initial searched articles, 71 articles were selected for inclusion in this systematic review. About 93 genes and 204 polymorphisms have been discussed in these articles. Among the most studied polymorphisms, the XRCC1 Arg399Gln and Arg194Trp polymorphisms were not associated with survival in most studies; the ERCC1 C19007T polymorphism had no significant association in any of the studies. Different gene polymorphisms of glutathione s-transferase family, including GSTM1 deletion, GSTT1 deletion and GSTP1 A313G, were not associated with survival in included studies. There are conflicting results regarding the association between polymorphisms such as ERCC2 A35931C, Asp312Asn, ERCC5 rs1047768 and rs17655 with HNSCC prognosis. Less studied polymorphisms, such as hOGG1 rs1052133 or the VEGF rs699947, were generally not associated with HNSCC prognosis. Reviewed articles reported varied and contradictory results regarding the association of gene polymorphisms and HNSCC prognosis, which necessitates further studies along with meta-analysis on the results of such studies.

PB2066: THE STUDY OF GSTP1 AND MDR1 GENES POLYMORPHISMS IN HODGKIN’S LYMPHOMA AND THEIR LINK WITH CHEMOTHERAPY RESPONSE.

Background: Glutathione-S-transferase P1 and ATP-dependent transporter P-glycoprotein are enzymes of the second phase of xenobiotic metabolism that participate in biotransformation of agents of standard protocol of Hodgkin’s Lymphoma chemotherapy. The polymorphism of the GSTP1 and MDR1 genes encoding these proteins causes changes in their activity, which can provide an individual patients’ response to chemotherapy. In this regard, the search for predictive genetic factors for the effectiveness of antitumor therapy is an important task. Aims: to demonstrate the association between polymorphic variants of GSTP1 (A313G, C341T) and MDR1 (C1236T, G2677T, C3435T) genes in patients with Hodgkin’s lymphoma. Methods: Overall, 77 Hodgkin’s lymphoma patients aged 18-74 years who were treated by BEACOPP and ABVD chemotherapy protocols in Oncohematological Departments of City Clinical Hospital №2 and Novosibisk State District clinical Hospital were enrolled in this study. The effectiveness of chemotherapy was evaluated after 4-6 cycles of chemotherapy in accordance with clinical guidelines. Depending on the achieved results of treatment, all patients were divided into two groups: patients with complete/partial remission and patients with progressive/refractory or relapsed lymphoma. Polymorphisms of GSTP1 (A313G, C341T) and MDR1 (C1236T, G2677T, C3435T) genes were defined by PCR method with real-time detection in the samples of peripheral blood in the Centre of Collective Usage «Proteomic analysis» FRC FTM. The odds ratio (OR) used to evaluate the link between genotypes with efficacy of chemotherapy. Results: We found the following frequencies of mutant alleles in Hodgkin’s Lymphoma patients: GSTP1313G – 31.17%, GSTP1 341T – 9.7%, MDR1 1236T – 50.00%, MDR1 2677T – 48.70%, MDR13435 ТОНН – 58.44%. Patient’s genotypes were similar to described genotypes of healthy Europeans. There was no significant difference in distribution of frequency alleles and GSTP1 A313G (χ2=0,89, p=0,34), GSTP1 C341T (χ2=0,11 R=0,74), MDR1 C1236T (χ2=0,01, p=0,93), MDR1 G2677T (χ2=0,37, p=0,54), MDR1 C3435T (χ2=0,01, р=0,97) genotypes between group of Hodgkin’s lymphoma patients with complete/partial remission and group with progressive/refractory or relapsed lymphoma. At the same time we found the significant correlation between GSTP1 A313G heterozygotes and formation of progressive/refractory and prolapsed course of disease (OR = 10.80; CI 95% = 1.23 – 496.52). There was no significant association between efficacy of chemotherapy and other studied genotypes, namely GSTP1 C341T, MDR1 C1236T, MDR1 G2677T, MDR1 C3435T genotypes. Summary/Conclusion: The observed correlation between GSTP1 A313G gene polymorphisms and formation progressive/refractory or prolapsed course of disease needs to be studied to provide safe and effective specific chemotherapy.

Glutathione S-transferase, catalase, and mitochondrial superoxide dismutase gene polymorphisms modulate redox potential in systemic lupus erythematosus patients from Manaus, Amazonas, Brazil.

To investigate the frequency of glutathione S-transferase (GST), catalase, and SOD2 genetic polymorphisms and their correlation with SLE. A total of 290 females (patients = 151; controls= 139) were recruited. Multiplex PCR was performed for genotyping GSTM1 and GSTT1 genes, whereas real-time qPCR was used for determination of SNPs: CAT C262T, SOD2 C47T, GSTP1 A313G and GSTP1 IVS6 -C16T. Thiol levels are decreased in SLE patients (p<0.001), while MDA levels were significantly higher (p<0.001) and those carrying the polymorphisms had higher rates of oxidative stress. Patients with double null deletion GSTT1null/GSTM1null had a frequency almost five times higher than the controls (p<0.001, OR 4.81, CI 1.98-12.11). SLE patients had a lower wild-type frequency of SOD2CC allele compared to controls (12.4% vs 27.3%). Statistical significances were observed on the association between the GSTT1null and GSTM1null with SOD2mut (p<0.001, OR 0.15, CI 0.05-0.47), with GSTP1 A303G (p=0.012, OR 0.19, CI 0.05-0.69), and with GSTP1 IVS6 (p=0.008, OR 0.14, CI 0.03-0.63). The same was observed between SOD2 C47T with GSTP1 A303G (p=0.09, OR 0.27, CI 0.09-0.74) and GSTP1 IVS6 (p=0.036, OR 0.41, CI 0.18-0.92). The deletion GSTT1null/GSTM1null may contribute to the increased of the oxidative stress in SLE patients. Isolated GSTP1 and CAT polymorphisms do not seem to influence the increased oxidative stress, neither SLE clinical manifestations. SOD2 47CT/TT allele may have greater oxidative stress due to structural change in the protein and decreased H2O2 production. The combination of polymorphic genes may be involved in the pathogenesis of the disease. Key points • Major question of our paper: Many studies have shown that the antioxidant status levels are decreased in patients with SLE, especially in severe stages of disease. We believe that this paper will be of interest to the readership of your journal had the involvement of polymorphisms and mutations in several genes that contribute to the genetic etiology of SLE, suggesting that these may influence the mechanisms of disease. • Our results. Thiol level was significantly (p<.001) lower and MDA level significantly increased (p<.001) among SLE patients. Those carrying the polymorphisms hadhigher rates of oxidative stress. SLE Patients had a frequency almost five times higher of double null deletion GSTT1null/GSTM1null than the controls.SLE Patients had a lower wild type frequency of SOD2CC allele compared to controls (12.4% vs 27.3%). We believed the deletion GSTT1null/GSTM1nullmay contribute to the increased of the oxidative stress in SLE patients while carriers of the mutant SOD2 47CT/TT allele may have greater oxidative stressdue to structural change in the protein and decreased H2O2 production. The combination of polymorphic genes may be involved in the pathogenesis of thedisease. • Implications of our results: Evidence for the involvement of genetic factors in severe clinical to lupus is compelling. This manuscript shows genetic insights in pathogenic pathways that may lead to severe clinical implications to LES. Therefore, it is necessary to understand their impact on overall disease pathogenesis and prognosis in these patients. We understand from general consensus about environmental factors can modify disease, however, maybe just in individuals who have a permissive genetic background. Even that no single gene predisposes some individuals to LES, we believe the genetic factors described in this manuscript are important elements in susceptibility to severe clinical to LES.

ROLE OF GENETIC PREDISPOSITION, GENE POLYMORPHISM OF GLUTATHIONE-S-TRANSFERASE (GSTT1, GSTM1, GSTP1) AND SOME ADVERSE FACTORS IN DEVELOPMENT OF BRONCHIAL ASTHMA IN CHILDREN - RESIDENTS OF RADIOACTIVELY CONTAMINATED AREAS.

to determine the influence of hereditary predisposition, polymorphism of GSTT1, GSTM1, GSTP1 genes andenvironmental factors on the development of bronchial asthma in children - residents of radioactively contaminat-ed areas. School-age children-residents of radioactively contaminated areas with bronchial asthma,and those without clinical signs of respiratory pathology were examined. Genetic, medical, biological and social riskfactors were determined based on the study of anamnestic data and medical records. Ventilation lung capacity wasassessed by the method of computer spirometry. Molecular genetic studies were carried out using polymerase chainreaction (PCR) and restriction fragment length polymorphism (RFLP) for further analysis. Molecular genetic studies of the distribution of genotypes and frequencies of polymorphic variants of thegenes GSTT1, GSTM1, GSTP1 were performed in children living under long-term intake of 137Cs by food chains. It wasfound that in children with BA the tendency to frequency of the deletion variant of the GSTT1 and GSTM1 genes incomparison with children without bronchial and pulmonary pathology was increased. The study of distributing theGSTP1 A313G gene polymorphic variants revealed in children with BA a significant increase in the frequency of AG-genotype, compared with the data of reference group. Adverse factors that increase the risk of developing bron-choobstructive disorders and the probability of their implementation in the form of bronchial asthma in children -residents of RCA have been identified. It is established that among them the leading role is played by hereditarypredisposition to this disease. On the part of the child, such negative factors were unfavorable conditions of fetaldevelopment, the presence of signs of exudative-catarrhal diathesis, manifestations of allergies and frequent respi-ratory diseases from the first months of life. It was found that the risk of developing BA was significantly increasedin children with the GSTT1 and GSTM1 gene deletion genotypes; an increased risk of developing BA in children witha combination of the GSTP1 A313G gene polymorphism with deletion polymorphism of the GSTT1 or GSTM1 gene wasdetermined. Сonclusion. Оne of the leading mechanisms, due to which there is a realization of hereditary predisposition tobronchial asthma in children living under constant intake of radionuclides with a long half-life, is the polymorphismof certain glutathione-S-transferase genes, namely, GSTT1, GSTM1 and A313G gene deletion polymorphism and GSTP1gene polymorphism.

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.

Impact of GSTM1, GSTT1 and GSTP1 genes polymorphisms on clinical toxicities and response to concomitant chemoradiotherapy in cervical cancer

ABSTRACTBackground: Certain forms of chemoradiotherapy generate toxic reactive oxygen species, which may be ameliorated by antioxidant enzymes such as glutathione S-transferase (GST). Genetic polymorphisms of GST may predict treatment outcomes and can be used as genetic marker to screen patients before treatment. We hypothesised an effect of GST polymorphisms on the response and toxicities produced by chemoradiation therapy.Materials and methods: GST polymorphisms were determined by multiplex polymerase chain reaction and PCR-restriction fragment length polymorphism (PCR-RFLP) in 227 women with cervical cancer receiving cisplatin based chemoradiotherapy. Treatment response and toxicities were evaluated by standard internationally recognised criteria (RECIST and RTOG).Results: Severe (grade 3–4) gastrointestinal and haematological toxicities were present in 22 (9.4%) and 16 (7.0%) patients, respectively. GSTM1 null, GSTT1 null and GSTP1 AG genotypes brought marginally better non-significant associations. In single locus analysis GSTP1 AG and GG was linked to greatest risk of severe (grade 3–4) gastrointestinal toxicity (OR = 3.12, P = 0.035 and OR = 6.99, P = 0.01, respectively). In gene–gene interaction analysis, GSTM1 null-GSTP1 GG showed 4.2-fold higher risk of severe gastrointestinal toxicity (P = 0.014). GSTT1 null-GSTP1 AG reached statistical significance with a 3.9-fold higher risk of high grade gastrointestinal toxicity (P = 0.038).Conclusions: Although no significant links were found between GST polymorphism and treatment response, null genotypes of GSTM1, GSTT1 and ‘G’ allele of GSTP1 bring a higher risk of severe gastrointestinal toxicity due to chemoradiation therapy in cervical cancer.

WITHDRAWN: GSTP1 A313G, GSTM1, and GSTT1 gene polymorphisms influence clinical outcome in advanced non-small cell lung cancer patients receiving first-line platinum-based chemotherapy: an updated metaanalysis with trial sequential analysis

// Qiang Xiao 1 , Quan Zhou 2 , Mu Mei 1 , Wenjun Pei 1 , Qiangye Zou 1 , Erdong Chen 1 , Susu Dong 1 , Yafen Tan 1 , Tianli Wang 1 and Wei Du 3 1 Department of Respiratory Medicine, The First People&rsquo;s Hospital of Changde City, Hunan Province, P.R. China 2 Department of Science and Education, The First People&rsquo;s Hospital of Changde City, Hunan Province, P.R. China 3 Department of Pathology, The First People&rsquo;s Hospital of Changde City, Hunan Province, P.R. China Correspondence to: Tianli Wang, email: wtl195@163.com Wei Du, email: dw417@sina.com Keywords : GSTP1; GSTM1; GSTT1; advanced non-small cell lung cancer; chemotherapy Received: April 07, 2017&nbsp;&nbsp;&nbsp;&nbsp; Accepted: December 27, 2017&nbsp;&nbsp;&nbsp;&nbsp; Epub: January 05, 2018&nbsp;&nbsp;&nbsp;&nbsp; Abstract The GSTP1 A313G , GSTM1 and GSTT1 gene polymorphisms reportedly correlate with prognosis in advanced non-small cell lung cancer (NSCLC) patients receiving first-line platinum-based chemotherapy, but the results are inconsistent. An updated meta-analysis and trial sequential analysis (TSA) were performed to further examine the correlation and determine whether currently available evidence is sufficient and conclusive. A total of 25 studies covering 4410 advanced NSCLC patients were included. For the GSTP1 A313G polymorphism, the G allele was associated with a better treatment response under four genetic models and better overall survival (OS) under the homozygote model (HR = 0.550, 95% CI = 0.337&ndash;0.898, P = 0.017). The GSTM1 null genotype was also correlated with a better response (OR = 1.654, 95%CI = 1.290&ndash;2.120, P = 0.000) but not better OS. However, the GSTT1 gene variant had no significant effect on clinical outcome. The TSA results indicated that the evidence of the effect was sufficient for GSTP1 A313G under three genetic models (dominant, heterozygote, and allele), for GSTM1 , and for GSTT1 , but the correlations were not confirmed for the homozygote and recessive models of GSTP1 A313G . Our study suggest the GSTP1 313G and GSTM1 null genotypes correlate with a better clinical outcome for advanced NSCLC patients receiving platinum-based chemotherapy.

Association of glutathione S-transferases M1, P1 and T1 variations and risk of late-onset Alzheimer’s disease

Objective: Late-onset Alzheimer’s disease (AD) is a genetically heterogeneous neurodegenerative disorder. Associations of the glutathione S-transferases (GSTs) polymorphisms with the risk factors for AD have not been definitely confirmed. We investigated the association of GSTM1 and GSTT1 null deletion and GSTP1 313 A/G polymorphisms and the risk of AD in an Iranian population.Methods: The case group consisted of 280 individuals with AD and the control group included 168 age-matched healthy individuals. The genotyping of the GSTP1 polymorphism was determined by PCR-RFLP and the GSTM1 and GSTT1 deletions were done by multiplex PCR method.Results: The GSTP1 AG genotype was significantly lower (p = 0.005; OR = 0.57, 95% CI: 0.38–0.84) in the patients (41.1%) than the control group (56.5%). The GSTM1 null genotype was significantly higher (p < 0.001) in the patients (40.5%) than the control group (15.8%). The GSTT1 null genotype was significantly higher (p < 0.038) in the patients (31.2%) than the control group (21.5%). The patients homozygous for the GSTM1 and GSTT1 null alleles showed a 3.5 and 1.5-fold increased risk of AD, respectively. There were interaction between GSTP1 AG genotype and absence of APOE e4 allele (p = 0.001), as well as presence of APOE ε4 and GSTM1 null genotype (p < 0.0001).Conclusion: These findings suggested that GSTM1 and GSTT1 null deletions may be associated with susceptibility to AD and people with APOE e4 and GSTM1 null deletion have a higher increased risk for Late-onset AD in Iranian population.

Glutathione S-Transferase Gene Polymorphisms and the Development of New-Onset Diabetes After Liver Transplant.

The association between the glutathione S-transferase polymorphisms and the development of new-onset diabetes mellitus after liver transplant was studied. Peripheral blood samples were collected from 106 liver transplant patients divided into 2 groups: 52 with new-onset diabetes mellitus and 54 without new-onset diabetes mellitus; 169 healthy individuals with no clinical evidence of diabetes mellitus were selected as a control group. The multiplex polymerase chain reaction technique was used for genotyping GSTM1 and GSTT1 genes, using the cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) gene as an internal control. The genotype of GSTP1 was determined using the restriction fragment length polymorphism-polymerase chain reaction technique. The frequency of both GSTM1 null and GSTT1 null genotypes was not significantly different in liver transplant patients with new-onset diabetes mellitus compared with the control group (P = .11 for GSTM1; P = .71 for GSTT1). Also, there was no statistically significant association between the frequency of the GSTP1 genotypes in the liver transplant patients with new-onset diabetes mellitus compared with controls. Neither GSTM1 nor GSTT1 null genotypes were associated with the risk of developing new-onset diabetes mellitus (P = .22 for GSTM1; P = .56 for GSTT1). However, the frequency of the heterozygous mutation (AG) in the A313G GSTP1 polymorphism in patients with new-onset diabetes mellitus was significantly higher than in patients without new-onset diabetes mellitus (55.8% vs 7.4%; P = .00). Thus, the risk of developing new-onset diabetes mellitus was significantly higher in patients presenting with heterozygous GSTP1 genotypes (odds ratio = 15.76; 95% confidence interval = 4.53-60.28; P = .00). The GSTP1 AG genotype was associated with an increased susceptibility to the development of new-onset diabetes mellitus after liver transplant.

Effect of GSTP1 and ABCC2 Polymorphisms on Treatment Response in Patients with Advanced Non-Small Cell Lung Cancer Undergoing Platinum-Based Chemotherapy: A Study in a Chinese Uygur Population.

BackgroundGene polymorphisms are associated with sensitivity to platinum drugs. This study aimed to investigate the polymorphisms of GSTP1 rs1695 locus and ABCC2 rs717620 locus, and the sensitivity of patients with advanced non-small cell lung cancer (NSCLC) to platinum drugs in a Xinjiang Uygur population.Material/MethodsThe gene polymorphisms of GSTP1 rs1695 and ABCC2 rs717620 of Uygur NSCLC patients were assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The relationship between the prognosis of advanced NSCLC Uygur patients and the gene polymorphisms of GSTP1 rs1695 and ABCC2 rs717620 was analyzed using progression-free survival (PFS) and overall survival (OS) as the major outcome indicators.ResultsThe median PFS of patients with advanced NSCLC was 6.9 months and the OS of Uygur patients with advanced NSCLC was 10.8 months. Kaplan-Meier survival analysis indicated that survival time of patients with GSTP1 AG + GG was significantly longer than in patients with AA gene (P<0.05), and survival time of patients with ABCC2 CT + TT was significantly longer than in patients with the CC gene (P<0.05).ConclusionsPolymorphisms of GSTP1 rs1695 and ABCC2 rs717620 can be used to predict the outcomes of Uygur patients with advanced NSCLC who have received platinum-based chemotherapy. Additionally, this information could be used to guide the individualized treatment of Uygur patients with advanced NSCLC.

Pharmacogenetic and ethnicity influence on oxaliplatin therapy for colorectal cancer: a meta-analysis.

Oxaliplatin-based chemotherapy for colorectal cancer demonstrates interindividual variability in response, and polymorphisms of ERCC1, ERCC2, XRCC1, GSTP1 and GSTM1 genes may be contributing factors. Additionally, the effect of these genotypes may differ between ethnic groups. Material& Methods: A meta-analysis of the association between these genotypes and response, progression-free survival and overall survival (OS) for patients with colorectal cancer treated with oxaliplatin-based therapy is reported.Results:ERCC1 C118T (TT vs CC OS [hazard ratio (HR): 2.59; p = 0.001]), ERCC2 A2251C (CC or AC vs AA OS [HR: 1.53; p = 0.04]) and GSTP1 A313G (GG vs AA OS, [HR: 0.47; p < 0.001]) polymorphisms were associated with survival. The effect size may be larger for ERCC1 C118T and XRCC1 G1196A in Asian compared with Caucasian populations. No association was apparent for the GSTM1 genotype. ERCC1 C118T, ERCC2 A2251C and GSTP1 A313G polymorphisms were associated with clinical outcomes.

The influence of glutathion S-transferase P-1 polymorphism A313G rs1695 on the susceptibility to cyclophosphamide hematologic toxicity in Indonesian patients

Background: Chemotherapy often causes side effects such as hematologic toxicity. The degree of toxicity is often associated with genetic polymorphism. This study aims to determine the influence of GSTP1 A313G polymorphism, an enzyme responsible for detoxifying cyclophosphamid, on incidence and severity of cyclophosphamid hematologic toxicity.Methods: 91 Indonesian females diagnosed with breast cancer at Haji Adam Malik Central General Hospital, Medan, receiving cyclophosphamide, doxorubicin/epirubicin and 5-FU were included in this retrospective cohort study. DNA was extracted from peripheral leukocytes and GSTP1 A313G genotyping was analyzed using polymerase chain reaction-restriction length fragment polymorphism (PCR-RFLP). Genotype deviation and allele frequencies were also determined by Hardy-Weinberg Equilibrium. The degrees of hematologic toxicity (leucopenia and neutropenia data after chemotherapy cycles 1 and 3) were collected from the patient medical records. The data were analyzed using chi-square test.Results: 60.4% of the patients had the wildtype (A/A), while 29.7% were heterozygous (A/G), and 9.9% were homozygous mutant (G/G). There was no significant deviation of allele and genotype frequency from Hardy-Weinberg Equilibrium. The G allele (A/G &amp; G/G) contributes to more severe degree of leukopenia compared to patients with wild type allele (A/A) (p&lt;0.05) after the 3rd chemotherapy cycles.Conclusion: There was association between GSTP1 polymorphism with the degree of hematologic toxicity in breast cancer patients receiving cyclophosphamide chemotherapy regimen.

Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy.

The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities. 93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded. GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity. These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.

Modification of the association between maternal smoke exposure and congenital heart defects by polymorphisms in glutathione S-transferase genes

Congenital heart defects (CHDs) arise through various combinations of genetic and environmental factors. Our study explores how polymorphisms in the glutathione S-transferase (GST) genes affect the association between cigarette smoke exposure and CHDs. We analysed 299 mothers of children with CHDs and 284 mothers of children without any abnormalities who were recruited from six hospitals. The hair nicotine concentration (HNC) was used to quantify maternal smoke exposure, and the maternal GSTT1, and GSTM1 and GSTP1 genes were sequenced. We found a trend of higher adjusted odds ratios with higher maternal HNC levels, suggesting a dose-response relationship between maternal smoke exposure and CHDs. The lowest HNC range associated with an increased risk of CHDs was 0.213–0.319 ng/mg among the mothers with functional deletions of GSTM1 or GSTT1and 0.319–0.573 ng/mg among the mothers with normal copies of GSTM1 and GSTT1. In addition, the adjusted odds ratio for an HNC of >0.573 ng/mg was 38.53 among the mothers with the GSTP1 AG or GG genotype, which was 7.76 (χ2 = 6.702, p = 0.010) times greater than the AOR in the mothers with GSTP1 AA genotype. Our study suggests that polymorphisms of maternal GST genes may modify the association of maternal smoke exposure with CHDs.

Meta-analysis of associations between MTHFR and GST polymorphisms and susceptibility to multiple sclerosis.

We examined whether methylenetetrahydrofolate reductase (MTHFR) and glutathione S-transferase (GST) polymorphisms are associated with susceptibility to multiple sclerosis (MS). We performed a meta-analysis on the association between MS and the following genotypes: MTHFR C677T, A1298C, and GSTP1 A313G polymorphisms, and GSTM1 and GSTT1 null alleles. Fifteen comparisons involving 2,486 patients and 2,861 controls were considered. Meta-analysis of all study subjects considered together showed no association between MS and the MTHFR 677 T allele (OR=1.014, 95% CI 0.803-1.280, p=0.909). Stratification by ethnicity showed no similar association in Caucasian and Arab populations. Likewise, no link was found between MS and the MTHFR 1298 C allele in the total data (OR=2.477, 95% CI 0.507-12.10, p=0.263), nor when it was stratified by ethnicity. No association with MS was observed in relation to the GSTM1 null genotype in Caucasian populations (OR=1.229, 95% CI 0.693-2.181, p=0.481), nor with the GSTP1 A313G polymorphism (OR for G allele=1.133, 95% CI 0.903-1.421, p=0.281). However, there was an association between MS and the GSTT1 null genotype in data obtained from Caucasian populations (OR=1.945, 95% CI 1.452-2.605, p=8.6×10(-7)). GSTT1 null genotype is associated with MS in Caucasian populations; however, no association was found between MS and polymorphisms of MTHFR, GSTM1, and GSTP1.

Germline TYMS genotype is highly predictive in patients with metastatic gastrointestinal malignancies receiving capecitabine-based chemotherapy.

This work was initiated to extend data on the effect of pharmacogenetics and chemotherapy pharmacokinetics (PK) on clinical outcome in patients with gastrointestinal malignancies. We assessed 44 gene polymorphisms in 16 genes (TYMS, MTHFR, GSTP1, GSTM1, GSTT1, DPYD, XRCC1, XRCC3, XPD, ERCC1, RECQ1, RAD54L, ABCB1, ABCC2, ABCG2 and UGT2B7) in 64 patients with metastatic colorectal cancer (CRC) receiving capecitabine/oxaliplatin and 76 patients with advanced gastroesophageal cancer (GEC) receiving epirubicin/cisplatin/capecitabine, respectively. Plasma concentrations of anticancer drugs were measured for up to 24h, and results were submitted to population PK analysis. We calculated the association between gene polymorphisms, chemotherapy exposure, tumor response, progression-free survival (PFS), overall survival (OS) and chemotherapy-related toxicity using appropriate statistical tests. Patients with a low clearance of 5FU were at increased risk of neutropenia (P<0.05) and hand-foot syndrome (P=0.002). DPYD T85C, T1896C and A2846T mutant variants were associated with diarrhea (P<0.05) and HFS (P<0.02), and IVS14+1G>A additionally with diarrhea (P<0.001). The TYMS 2R/3G, 3C/3G or 3G/3G promoter variants were associated with worse PFS in the CRC (HR=2.0, P<0.01) and GEC group (HR=5.4, P<0.001) and worse OS in the GEC group (HR=4.7, P<0.001). The GSTP1 A313G mutant variant was associated with a higher PFS (HR=0.55, P=0.001) and OS (HR=0.60, P=0.002) in the CRC group. Germline polymorphisms of DPYD, TYMS and GSTP1 have a significant effect on toxicity and clinical outcome in patients receiving capecitabine-based chemotherapy for advanced colorectal or gastroesophageal cancer. These data should further be validated in prospective clinical studies.