Disease relevance of GSTT1

• No influence of GSTM1, GSTT1, or GSTM3 polymorphisms was evidenced on docetaxel toxicity [1].
• For lung cancer overall, and especially among SCC patients, the GSTT1 null genotype was underrepresented (SCC 11.2% v. control subjects 19%, P = 0.026, OR 0.57, CI 0.30-1.06) [2].
• The overall risk of KRAS2 mutation for patients with distal colorectal cancer and GSTT1 null genotype was 0.3 (95% CI 0.1-0.9) compared to patients with distal colorectal cancer and non-null GSTT1 genotype [3].
• The GSTT1-null genotype was significantly over-represented in adenocarcinomas (OR = 1.41; 95%CI 1.06-1.90; P = 0.02) but not in squamous cell carcinomas (OR = 1.03; 95%CI 0.76-1.41; P = 0.84) [4].
• Glutathione S-transferase GSTM1 B and GSTT1 null, and cytochrome P450 CYP2D6 EM have been associated with cutaneous basal cell carcinoma (BCC) numbers, although their quantitative effects show that predisposition to many BCC is determined by an unknown number of further loci [5].

Psychiatry related information on GSTT1

• To determine if breast cancer risk is associated with GSTM1 and GSTT1 genetic polymorphisms, and to evaluate the effect modification between GST genotypes and alcohol consumption in the risk of breast cancer, we conducted a case-control study in the state of Connecticut in the period 1998 and 2001 [6].
• To examine potential causes for this overlap, we evaluated the effect of GSTM1, GSTP1, and GSTT1 genotypes, together with various life-style and blood parameters, on the DEB induction of sister chromatid exchanges and cells with chromosomal aberrations (aberrant cells) in lymphocyte cultures of 115 and 62 human donors, respectively [7].
• 1. Correlations between deletions in two glutathione S-transferase (GST) genes, GSTM1 and GSTT1 and susceptibility to Alzheimer's disease (AD), motor neuron disease (MND) and Parkinson's disease (PD) have been investigated by PCR, using primers specific for both genes [8].
• Although our data suggest some individual differences according to the GSTT1 genotype in the outcome of the Comet assay, a large number of individuals should be studied in further investigations to obtain reliable conclusions [9].

High impact information on GSTT1

• MAIN OUTCOME MEASURE: Birth weight, gestation, fetal growth by smoking status and CYP1A1 MspI (AA vs Aa and aa, where Aa and aa were combined because of small numbers of aa and similar results), and GSTT1 (present vs absent) genotypes [10].
• When GSTT1 genotype was considered, the estimated reduction in birth weight was 285 g (SE, 99 g) (OR, 1.7; 95% CI, 0.9-3.2) and 642 g (SE, 154 g) (OR, 3.5; 95% CI, 1.5-8.3) for the present and absent genotype groups, respectively [10].
• OBJECTIVE: To investigate whether the association between maternal cigarette smoking and infant birth weight differs by polymorphisms of 2 maternal metabolic genes: CYP1A1 and GSTT1 [10].
• ORs for pancreatic cancer among heavy smokers with both GSTT1-null and GSTM1-null genotypes were similar in magnitude to those among heavy smokers with the GSTT1-null genotype alone [11].
• In a retrospective study, we investigated associations between common polymorphisms in genes for several GST subclasses (GSTP1, GSTT1, GSTM1) and survival of patients with metastatic colorectal cancer receiving 5-fluorouracil (5-FU)/oxaliplatin chemotherapy [12].

Chemical compound and disease context of GSTT1

• We therefore performed a systematic review of 10 studies on association of endometriosis and various genes involved in dioxin detoxification process excluding GSTM1/GSTT1 [13].
• No evidence was found of associations between GSTT1 deficiency or the CYP1A1 valine variant and lung cancer risk due to ETS exposure [14].
• GSTT1 was not associated with lung cancer risk and GSTP1 val was non-significantly associated with a modest reduction in risk, particularly among heavy smokers [15].
• The GSTT1+ phenotype can catalyse the glutathione conjugation of dichloromethane, a metabolic pathway which has been shown to be mutagenic in Salmonella typhimurium mutagenicity tester strains and is believed to be responsible for carcinogenicity of dichloromethane in the mouse [16].
• Cellular sensitivity to 1,2:3,4 diepoxybutane was significantly increased in GSTT1 deleted compared with GSTT1 positive cases (median chromosomal breaks 11.1 vs. 8.3, P < 0.01) but there was no effect on clinical manifestations of FA [17].

Biological context of GSTT1

• Four polymorphisms showed significant association with PD: slow acetylator genotypes of NAT2 (PD:control OR = 1.36), allele >188bp of the MAOB (GT)n polymorphism (OR = 2.58), the deletion allele of GSTT1 (OR = 1.34), and A4336G of tRNAGlu (OR = 3.0) [18].
• We also report a positive correlation between the null homozygote of GSTT1 with the risk of bladder cancer (OR 2.54, 95% CI 1.32-4.98, P = 0.003) [19].
• The protective effect of vegetables was only seen in those with deficient or intermediate GSTT1 predicted phenotype [OR 0.3, 95% confidence interval (0.1, 0.6), and OR 0.6 (0.4, 0.96), OR 1.4 (0.3, 2.4) for those with fast phenotype], and a similar result was observed for cruciferous vegetables [20].
• Glutathione transferase genetic polymorphisms (GSTM1, GSTT1) showed no association with cases compared with their siblings or unrelated controls [21].
• We postulate that inherited gene deletion of GSTT1 and M1 may produce increased genotoxic susceptibility for erythroid and lymphoid cell respectively, following exposure to xenobiotics that are substrates for these enzymes [22].

Anatomical context of GSTT1

• A higher proportion of the patients with positive lymph node status at the time of diagnosis had a combined GSTM1 null/GSTT1 null genotype (P = 0.05) [23].
• Thus, GSTT1 null was associated with T3/T4 lesions in the oral cavity/pharyngeal (P = 0.029), but not laryngeal, SCC cases [24].
• Enzymes including glutathione S-transferase mu (GSTM1) and theta (GSTT1) are involved in the metabolism of tobacco smoke chemicals and are expressed in human vessels and smooth muscle cells [25].
• METHODS: We estimated the effect of interaction of smoking with the deletion polymorphisms of GSTM1 and GSTT1 on the risk of carotid artery atherosclerosis [25].
• This implies a greater cytoprotective role for GSTT1 and GSTA1 in erythroid cells and GSTM1 in lymphoid cells [22].

Associations of GSTT1 with chemical compounds

• The carotenoid-bladder cancer association was not affected by the GSTM1, GSTT1 and GSTP1 genotypes [26].
• The field survey confirms that styrene exposure is associated with increased DNA damage and indicates a modulating role for GSTM1 and GSTT1 genotypes [27].
• The study also confirmed the impact of GSTT1 polymorphism on background N-(hydroxyethyl)-valine adduct levels in haemoglobin which are caused by endogenous ethylene oxide [28].
• A cohort of 211 French vinyl chloride workers was genotyped for common polymorphisms in GSTM1, GSTT1 and GSTP1 [29].
• The best-known example is probably the diepoxybutane sensitivity of GSTT1 null donors [30].
• We observed significant interaction on the multiplicative scale between GSTT1 wildtype and secondary methylation ratio [dimethylarsinic acid/MMA; likelihood ratio test (LRT), p = 0.01] [31].

Enzymatic interactions of GSTT1

• Individuals were genotyped for the Ile105Val variant of GSTP1 and the deleted variants of GSTT1 and GSTM1 [32].

Regulatory relationships of GSTT1

• No differences were found in the prevalences of the GSTM1 and GSTT1 null genotypes between alcoholics and the controls and no association was found between the rare CYP2E1 c2 allele and liver cirrhosis and pancreatitis [33].
• In this meta-analysis involving 14 GSTM1 studies with 1539 cases and 1805 controls and nine GSTT1 studies with 746 cases and 834 controls, respectively, substantial heterogeneities among studies were found [34].
• METHODS: Polymorphisms of the GSTM1 and GSTT1 genes in 106 Japanese patients with primary SS and in 143 healthy controls were analyzed by polymerase chain reaction [35].

Other interactions of GSTT1

• Allelic variation in genes encoding enzymes such as NADP(H) quinone oxidoreductase (NQO1) and glutathione S-transferase T1 (GSTT1) that metabolize environmental toxicants predispose to subtypes of AML, including therapy-related AML [36].
• Here, we present the results of a case-control study that investigated the effects that the genetic variants of the cytochrome (CYP)1A1, CYP1B1, glutathione-S-transferase (GST)M1, GSTT1, and GSTP1 genes have on modifying the risk of smoking-related HNSCC [37].
• We found no statistically significant associations between the null genotypes of GSTM1 and GSTT1, and CYP1A1 and risk of gliomas [38].
• Thus, we conducted a pilot case-control study to examine the association between CYP2E1, GSTM1, GSTT1, and GSTP1 genetic polymorphisms and esophageal cancer susceptibility [39].
• The data demonstrate site-dependent associations between GSTT1 null, CCND1 GG, and CYP2D6 PM and tumor extension, differentiation, and nodes [24].

Analytical, diagnostic and therapeutic context of GSTT1

• The null genotype of GSTT1 might be associated with increased toxicity after chemotherapy [40].
• Odds ratios (OR) after stratification by age, gender and smoking were slightly higher in the cancer group as a whole for GSTM1-null (*0/*0), GSTT1-null (*0/*0) and GSTM3 *A/*B or *B/*B when compared with the control group, but the differences did not reach statistical significance [41].
• Multivariate analysis revealed that GSTT1(-) was an independent prognostic factor for overall survival (relative risk: 1.53; P = 0.026) but not for disease-free survival of 140 patients who achieved complete remission (CR) [40].
• Deletion of the GSTM1 and GSTT1 genes was detected by multiplex PCR [42].
• However, results of epidemiologic studies do not confirm associations between GSTM1, GSTT1, and GSTP1 and epithelial ovarian cancer [43].

References