GSTP1 AG Genotypes Research Articles

GSTT1 null and rs156697 Polymorphism in GSTO2 Influence the Risk and Therapeutic Outcome of B-Acute Lymphoblastic Leukemia Patients.

IntroductionGlutathione S-transferase (GST) gene deletion or polymorphic sequence variations lead to decreased enzyme activity that influences susceptibility and response to chemotherapy in acute lymphoblastic leukemia (ALL). This case–control study investigated the association of GST gene polymorphisms with the etiology and therapeutic outcome of B-ALL among Kashmiri population.MethodsA total of 300 individuals including 150 newly diagnosed B-ALL patients and an equal number of age and gender matched controls were genotyped for five GST gene polymorphisms by polymerase chain reaction–restriction fragment length polymorphism technique (PCR-RFLP) and multiplex PCR techniques.ResultsHigher frequency of GSTT1 null, GSTO2-AG, and GSTO2-GG genotypes was observed in ALL cases compared to controls that associated significantly with ALL risk (GSTT1 null: OR = 2.93, p = 0.0001; GSTO2-AG: OR = 2.58, p = 0.01; GSTO2-GG: OR = 3.13, p = 0.01). GSTM1, GSTP1, and GSTO1 SNPs showed no significant association (p > 0.05). Combined genotype analysis revealed significant association of GSTT1 null/GSTM1 null (OR = 4.11, p = 0.011) and GSTT1 null/GSTP1-AG (OR = 4.93, p = 0.0003) with B-ALL susceptibility. Haplotype analysis of rs4925 and rs156697 revealed that carriers of CG haplotype had increased risk of B-ALL (p = 0.04). Kaplan–Meier plots revealed significantly inferior 3-year disease-free survival for GSTO2-GG carriers (p = 0.002). Multivariate analysis confirmed GSTO2-GG as an independent poor prognostic factor for DFS (HR = 4.5, p = 0.034). Among combined genotypes, only GSTT1 null/GSTP1-AG associated significantly with poorer DFS rates (p = 0.032).ConclusionThis study demonstrated that GSTT1 null individually or in combination with GSTM1null and GSTP1-AG genotypes associated with increased B-ALL risk. Also, rs156697 variant genotypes (AG and GG) associated with B-ALL, whereas the GG genotype of rs156697 influenced the treatment outcome.

Genetic polymorphism of drug metabolism enzymes (GSTM1, GSTT1 and GSTP1) in the healthy Malian population

Glutathione S-transferase genes, known to be highly polymorphic, are implicated in the process of phase II metabolism of many substrates, including xenobiotics, anticancer and anti-infective drugs. The detoxification activity is linked to individual genetic makeup. Therefore, the identification of alleles and genotypes in these genes within a population may help to better design genetic susceptibility and pharmacogenetic studies. We performed the present study to establish the frequencies of the GSTM1, GSTT1, and GSTP1 c. 313A > G (rs1695) polymorphisms in 206 individuals of the Malian healthy population. GSTM1 and GSTT1 were genotyped by using multiplex polymerase chain reaction, whereas genotypes of GSTP1 were identified by polymerase chain reaction followed by restriction fragment length polymorphism. The frequencies of GSTM1-null and GSTT1-null genotypes were respectively 24.3 and 41.3%. The observed genotype frequencies for GSTP1 were 25.73% homozygous wild-type AA, 49.03% heterozygous AG and 25.24% homozygous mutant GG. The frequency of GSTP1-A allele was 50.24% versus 49.76% for the GSTP1-G allele. The distribution of these three genes was homogeneous between men and women (p > 0.05). We found no statistical association between the presence of a particular profile of GSTM1 or GSTT1 with the genotypes of GSTP1 (p > 0.05). Nevertheless, we noticed that the majority of the individuals harboring the GSTM1-present or the GSTT1-present harbor also the GSTP1-AG genotype. In addition, the triple genotype GSTM1-present/GSTT1-present/AG was the most frequent with 25.2%. Our findings will facilitate future studies regarding genetic associations of multifactorial diseases and pharmacogenetic, thus opening the way to personalized medicine in our population.

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.

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.

High order interactions of xenobiotic metabolizing genes and P53 codon 72 polymorphisms in acute leukemia

Polymorphisms in xenobiotic metabolizing genes are associated with altered metabolism of carcinogens in acute leukemia (AL). This study applied two data mining approaches to explore potential interactions among P53 and xenobiotic metabolizing genes in 230 AL patients [131 acute myeloid leukemia (AML) and 99 acute lymphoblastic leukemia (ALL)] and 199 controls. Individually, none of the genotypes showed significant associations with AML risk. However, in ALL the CYP1A12A TC genotype was associated with increased risk (OR = 2.02; 95% CI = 1.14-3.58; P = 0.01), whereas the GSTM1 null genotype imparted reduced risk (OR = 0.55; 95% CI = 0.31-0.96; P = 0.03). In classification and regression tree analysis, combinations of GSTM1 present, CYP1A12C AA or GG, EPHX1 exon3 TC, and EPHX1 exon4 AA or GG genotype strongly enhanced the risk of AML (OR = 5.89; 95% CI = 1.40-26.62; P = 0.01). In ALL, combinations of CYP1A12A TT, P53 GG or CC and GSTP1 AG genotypes conferred the highest risk (OR = 4.19; 95% CI = 1.45-12.25; P = 0.004). In multifactor dimensionality reduction analysis, a four locus model (GSTP1, P53, EPHX1 exon3, and CYP1A12A) was the best predictor model for ALL risk. The association between this model and ALL risk remained true even at low prior probabilities of 0.01% (false positive report probability = 0.05). Interaction entropy interpretations of the best model of ALL revealed that two-way interactions were mostly synergistic. These results suggest that high order gene-gene interactions play an important role in AL risk.

Functional glutathione S-transferase genotypes among testicular germ cell tumor survivors: associations with primary and post-chemotherapy tumor histology

The pathogenesis of testicular germ cell tumor (TGCT) remains unknown. The aim of this study was to evaluate the pathogenic role of functional polymorphisms in detoxification enzymes among TGCT patients, through association studies of constitutive genotypes and medical parameters before and after chemotherapy. Germline deletion polymorphisms in the glutathione S-transferase mu 1 (GSTM1) and the GST theta 1 (GSTT1), and a functional single nucleotide polymorphism in GST pi 1 (GSTP1, Ile105Val), were analyzed in TGCT survivors (TCSs) (n = 675) and controls (n = 189). Statistical analyses were performed for the genotype distributions between the TCSs and control populations, and between the genotypes and clinicopathological parameters of the TCSs. The GST genotypes showed comparable distributions among the TCSs and the control population. However, the genotype combination GSTT1positive/GSTP1-GG or GSTP1-AG/GSTM1positive was more frequent among the TCSs [P = 0.050, odds ratio (OR): 1.47, 95% confidence interval (CI): 0.998-2.165]. The combined genotype GSTT1positive/GSTP1AA/GSTM1positive was associated with decreased risk of development of pure embryonal carcinoma (P = 0.009, OR: 0.309, 95% CI: 0.122-0.784) and the GSTP1-A-allele (i.e. genotypes GSTP-AA or GSTP-AG) was also associated with decreased risk for development of pure teratoma (P = 0.032, OR: 0.326, 95% CI: 0.122-0.873). Furthermore, the GSTP1-A-allele was overrepresented within the 'good prognosis group' (P = 0.032, OR: 2.407, 95% CI: 1.060-5.469), whereas the GSTM1nulltype was associated with the extent of TC qualifying as 'poor prognosis group' (P = 0.025, OR: 2.839, 95% CI: 1.104-7.301). The GSTP1-AG genotype was associated with necrosis in the tumor's post-chemotherapy histology (P = 0.001, OR: 16.087, 95% CI: 1.930-134.087). Failure, after platinum-based chemotherapy, was associated with the GSTT1positive/GSTP-AA or GSTP-GG/GSTM1-positive genotype (P = 0.019, OR: 2.168, 95% CI: 1.130-4.160). This study confirms an association between the GSTP1-G-allele and TGCT. Combinations of GST genotypes were associated with primary and post-chemotherapy tumor histology, and prognostic group presentation.