Glutathione S-Transferase: An Overview on Distribution of GSTM1 and GSTT1 Polymorphisms in Malaysian and Other Populations

@#Glutathione s-transferases (GSTs) are the vital enzymes involved in Phase II metabolism to detoxify a wide range of carcinogenic metabolites in the body. GST class mu-1 (GSTM1) and GST class theta-1 (GSTT1) are the genes encoding for the GST isoenzymes. Nevertheless, both genes were frequently reported absent (null) in most of the populations at different frequencies. Null polymorphism will affect the production of GSTs and impair the ability to eliminate carcinogenic compounds which had been shown to expose null individuals to high risk of several cancers such as gastric and lung cancer. Thus, this review will briefly summarize on the GSTM1 and GSTT1 polymorphisms, frequencies of null variants in populations worldwide, including Malaysian, and their relevancy to the underlying basis of toxicological response to xenobiotics. Additionally, the genotyping assays used in GST studies will also be discussed.

GSTT1 and GSTM1 null variants in Mestizo and Amerindian populations from northwestern Mexico and a literature review

Abstract The GSTT1 and GSTM1 genes are key molecules in cellular detoxification. Null variants in these genes are associated with increase susceptibility to developing different types of cancers. The aim of this study was to determine the prevalence of GSTT1 and GSTM1 null genotypes in Mestizo and Amerindian individuals from the Northwestern region of Mexico, and to compare them with those reported worldwide. GSTT1 and GSTM1 null variants were genotyped by multiplex PCR in 211 Mestizos and 211 Amerindian individuals. Studies reporting on frequency of GSTT1 and GSTM1 null variants worldwide were identified by a PubMed search and their geographic distribution were analyzed. We found no significant differences in the frequency of the null genotype for GSTT1 and GSM1 genes between Mestizo and Amerindian individuals. Worldwide frequencies of the GSTT1 and GSTM1 null genotypes ranges from 0.10 to 0.51, and from 0.11 to 0.67, respectively. Interestingly, in most countries the frequency of the GSTT1 null genotype is common or frequent (76%), whereas the frequency of the GSMT1 null genotype is very frequent or extremely frequent (86%). Thus, ethnic-dependent differences in the prevalence of GSTT1 and GSTM1 null variants may influence the effect of environmental carcinogens in cancer risk.

No Association Between GSTT1/M1 Polymorphism in Glutathione S-Transferase (GST) Gene with Cataract in Hypertensive Patients from North India.

Age-related cataract has globally emerged as the leading cause visual impairment leading to blindness. Glutathione S-Transferases and their genetic variantsplay an important role in pathogenesis of cataract. This case-control study was carried out to investigate possible association of GSTT1/M1 polymorphism with Cataract risk in North Indians. Our study included 221 individuals, 132 as Cataract cases (70 with and 62 without hypertension) and 89 age and ethnicity matched controls. Genetic polymorphism in GST gene (GSTT1/M1 polymorphism) wasevaluated by multiplexPolymerase Chain Reaction (PCR) technique.The frequencies of the GSTM1-positive and GSTT1-positive in hypertensive cataract cases were 55.71%, 92.86%; while they were 61.29% and 95.16% in cataract cases without hypertension and; 46.07% and 97.75% in healthy controls respectively. The frequencies of GSTM1-null and GSTT1-null in hypertensive cataract cases were 44.29% and 7.14% %; while they were 38.71% and 4.84% in cataract cases without hypertension and; 53.93% and 2.25% in healthy controls respectively. The frequency of GSTT1/M1 positive wild type genotype was 48.57% in hypertensive and 56.45% in normotensive cataract cases while it was 43.82% in control subjects. Our study found no association between GSTT1/M1 polymorphism with cataract but a nearly significant relationship was observed in GSTM1 positive and GSTM1 null genotypes (p=0.065) with cataract in subjects without hypertension. The study needs furtherinvestigation due to limited sample size.

Copy number polymorphism of glutathione-S-transferase genes (GSTM1 & GSTT1) in susceptibility to lung cancer in a high-risk population from north-east India.

Background & objectives: Genetic polymorphisms in glutathione-S-transferase genes (GSTM1 and GSTT1) have been studied intensively for their potential role in lung cancer susceptibility. However, most of the studies on association between the polymorphisms and lung cancer do not distinguish between genotypes with one or two copies of the genes. The present study investigates the gene dosage effects of GSTT1 and GSTM1 copy number and their environmental interactions to examine the association of lung cancer risk with trimodular genotypes of the GSTs in a high-risk population from north-east India. Methods: A total of 154 lung cancer cases and 154 age and sex matched controls from the high risk region of north-east India were analyzed by multiplex real-time PCR to determine the trimodal genotypes (+/+, +/- and -/-) in both the genes (GSTM1 and GSTT1). Results: No significant association and gene dosage effect of GSTM1 gene copy number with lung cancer risk (Ptrend=0.13) were found. However, absence of GSTT1 conferred 68 per cent (OR=0.32;95%CI=0.15-0.71;P=0.005) reduced risk compared to the two copy number of the gene. tThere was evidence of gene dosage effect of GSTT1 gene (Ptrend=0.006). Tobacco smoking was a major environmental risk factor to lung cancer (OR=3.03;95%CI=1.73-5.31;P<0.001). However, its interaction with null genotype of GSTT1 conferred significant reduced risk to lung cancer (OR=0.30;95%CI=0.10-0.91;P=0.03). Further in only tobacco smokers, null genotype was associated with increased reduced risk [0.03(0.001-0.78)0.03; Ptrend=0.006]. No effect modification of GSTM1 was observed with lung cancer risk by environmental risk factors. Interpretation & conclusions: The results suggest that absence of GSTT1 null genotype may be associated with a reduced risk of lung cancer and the effect remains unchanged after interaction with smoking.

Method for detection of GSTM1, GSTT1 deletion variants using Taq 2x Dual master mix / Монголын Анагаах Ухаан

IntroductionGSTs are a family of antioxidant enzymes that responsible for the detoxification of many carcinogens.Glutathione S-transferases are polymorphic in humans and the null genotypes are results in lack ofenzyme activity. In many studies the polymorphisms of GSTM1, GSTT1 have been associated withcancers of the lung, bladder, breast and colon.GoalIn this research we aimed to establish PCR condition for obtaining “long” PCR product for detection ofdeletions in GSTT1, GSTM1 genes using various master mixes, which would help us further to detectheterozygous variants for these two genes in Mongolian population.Materials and MethodsThree kinds of commercial master mixes as Go Taq PCR master mix (USA), Taq 2x Dual master mix(Mongolia), and DyNAzyme EXT buffer were tested at various PCR conditions on 117 DNA samples,isolated in three ways such as phenol chloroform extraction method, guanidine hydrochloride methodand using Promega Wizard Genomic Fragment DNA Extraction Kit from fresh blood lymphocytes, buccalswabs and dried blood spots.Results:Three types of samples were used for DNA extraction such as buccal swabs, dried onto soft tissue bloodspots and fresh peripheral blood lymphocytes, using three kind extraction methods from which DNAtemplate obtained from fresh blood isolated by guanidine chloride method had best quality. Combinationas template DNA from fresh blood, guanidine chloride DNA extraction method and Taq 2x Dual mastermix (Mongolia) resulted in all four band, whereas other combination did not display desired results.Conclusions:Out of three kinds commercial master mixes tested in this study for various PCR template DNApreparation and PCR conditions we observed that:1. PCR with Taq 2x Dual master mix (Mongolia) resulted in all four initially desired PCR productsas 625bp for GSTM1, 969bp for GSTT1 genes and 4748bp for GSTM1, 3106bp for GSTT1 genedeletions correspondingly;2. Template genome DNA prepared from fresh peripheral blood lymphocytes by guanidine hydrochlorideextraction methods suited best for “long” PCR reaction;3. Using Taq 2x Dual master mix produced in Mongolia saved us time and was cheaper.4. Multplex primer mix is excellent tool in research of GST gene polymorphism.

Method for detection of GSTM1, GSTT1 deletion variantsusing Taq 2x Dual master mix / Монголын Анагаах Ухаан

INTRODUCTION:GSTs are a family of antioxidant enzymes that responsible for the detoxification of many carcinogens.Glutathione S-transferases are polymorphic in humans and the null genotypes are results in lack ofenzyme activity.In many studies the polymorphisms of GSTM1, GSTT1 have been associated withcancers of the lung, bladder, breast and colon.GOAL:In this research we aimed to establish PCR condition for obtaining “long” PCR product for detectionof deletions in GSTT1, GSTM1 genes using various master mixes, which would help us further todetect heterozygous variants for these two genes in Mongolian population.MATERIALS AND METHODS:Three kinds of commercial master mixes as Go Taq PCR master mix (USA), Taq 2x Dual master mix(Mongolia), and DyNAzyme EXT buffer were tested at various PCR conditions on 117 DNA samples,isolated in three ways such as phenol chloroform extraction method, guanidine hydrochloride methodand using Promega Wizard Genomic Fragment DNA Extraction Kit from fresh blood lymphocytes,buccal swabs and dried blood spots.RESULTS:Three types of samples were used for DNA extraction such as buccal swabs, dried onto soft tissueblood spots and fresh peripheral blood lymphocytes, using three kind extraction methods from whichDNA template obtained from fresh blood isolated by guanidine chloride method had best quality.Combination as template DNA from fresh blood, guanidine chloride DNA extraction method and Taq2x Dual master mix (Mongolia) resulted in all four band, whereas other combination did not displaydesired results.CONCLUSIONS:Out of three kinds commercial master mixes tested in this study for various PCR templateDNApreparation and PCR conditions we observed that:1. PCR with Taq 2x Dual master mix (Mongolia) resulted in all four initially desiredPCR productsas 625bp for GSTM1, 969bp for GSTT1 genes and 4748bp for GSTM1, 3106bp for GSTT1 genedeletions correspondingly;2. Template genome DNA prepared from fresh peripheral blood lymphocytes by guanidinehydrochloride extraction methods suited best for “long” PCR reaction;3. Using Taq 2x Dual master mix produced in Mongolia saved us time and was cheaper.4. Multplex primer mix is excellent tool in research of GST gene polymorphism.

Glutathione S-Transferase Enzyme (GSTT1 and GSTM1) Gene Polymorphisms and Oxidative Stress in Egyptian Patients with End Stage Renal Disease.

Glutathione S-transferase enzyme (GSTT1 and GSTM1) gene polymorphisms have been associated with the genetic susceptibility to end stage renal disease (ESRD) in different populations. We investigated the association between GSTT1 and GSTM1 genes, and ESRD in Egyptian population. The samples of 133 ESRD and 91 control subjects were collected, and their clinical characteristics were assayed. Glutathione S-transferase enzyme (GSTT1 and GSTM1) gene polymorphisms were detected by polymerase chain reaction (PCR). Serum level of malondialdehyde (MDA), the oxidative stress and lipid peroxidation biomarker, and plasma glutathione S-transferase enzyme (GST), the antioxidant enzyme, were estimated in the ESRD patients as well as in the control subjects. We demonstrated the association of MDA and GST enzyme levels with GSTT1 and GSTM1 genotypes. We investigated the association between MDA and lipid parameters in the ESRD patients. Increased of the GSTM1 deletion genotype, (GSTT1/0) and both deletion genotypes (0/0) in the ESRD patients when compared with the control subjects (P < 0.0001, OR = 3.786, 95% CI = 2.151-6.664), (P = 0.001, OR = 3.172, 95% CI = 1.595-6.308) and (P = 0.045, OR = 1.945, 95% CI = 1.009-3.749), respectively. Highly significant increase of MDA level in the ESRD patients as compared with the control subjects (P < 0.0001). Highly significant decrease of GST enzyme level in the ESRD patients as compared with the control subjects (P < 0.0001).The level of MDA is significantly increased in all GST genotypes in the ESRD patients as compared with the control group. Also, there were significant association between The genetic risk factors of GSTT1 and GSTM1 genes in the ESRD, and high level of MDA in the ESRD patients, while the level of GST enzyme is significantly decreased in GST genotypes except the both deletion (0/0) genotypes, in which the level of GST enzyme is not significantly decreased in the ESRD patients as compared with the control subjects. There are significant association between the genetic risk factors of GSTT1 and GSTM1 genes in the ESRD, (GSTM1 null and GSTT1/0 genotypes), and low level of GST enzyme in the ESRD patients. There were significant positive correlation between MDA and total cholesterol, triglyceride, and LDL-cholesterol, and significant negative correlation between MDA and HDL-cholesterol in the ESRD patients as compared with the control subjects. In conclusion, the GSTM1 (null) genotype, (GSTT1/0) and (0/0) genotypes are independent risk factors for ESRD. The oxidative stress and lipid abnormalities are associated with ESRD in the studied Egyptian population.

GSTM1, GSTT1, and GSTP1 polymorphisms, breast cancer risk factors and mammographic density in women submitted to breast cancer screening / Polimorfismos GSTM1, GSTT1 e GSTP1, fatores de risco para câncer de mama e densidade mamográfica em mulheres submetidas a rastreamento mamográfico

Genetic polymorphisms in genes related to the metabolism of xenobiotics, such as genes of the glutathione S-transferases (GSTM1, GSTT1, and GSTP1) superfamily have been associated with an increased risk for breast cancer (BC). Considering the high incidence of BC in the city of Porto Alegre in southern Brazil, the purpose of this study was to characterize genotypic and allelic frequencies of polymorphisms in GSTM1, GSTT1, and GSTP1, and correlate these molecular findings with established risk factors for breast cancer including mammographic density, in a sample of 750 asymptomatic women undergoing mammographic screening. Molecular tests were performed using the multiplex polymerase chain reaction (PCR) for GSTM1 and GSTT1, and quantitative PCR for GSTP1 polymorphisms. Overall, the frequencies of GSTM1 and GSTT1 null genotypes were 45% and 21%, respectively. For GSTP1 polymorphism, genotypic frequencies were 44% for the Ile/Ile genotype, 44% for the Ile/Val genotype, and 12% for Val/Val genotype, with an allelic frequency of 66% for the wild type allele in this population, similar to results of previous international publications. There was a statistically significant association between the combined GSTM1 and GSTT1 null genotypes (M-/T-) and mammographic density in post menopausal women (p = 0.031). When the GSTT1 null (T-) genotype was analyzed isolated, the association with mammographic density in post menopausal women and in the overall sample was also statistically significant (p = 0.023 and p = 0.027, respectively). These findings suggest an association of GSTM1 and GSTT1 null genotypes with mammographic density.

Polimorfismos genéticos em genes relacionados com o metabolismo de xenobióticos, como os genes da superfamília das glutationa S-transferases (GSTM1, GSTT1 e GSTP1) têm sido associados com o aumento do risco para câncer de mama (CM). Considerando a alta incidência de CM na cidade de Porto Alegre, região Sul do Brasil, a proposta deste estudo foi caracterizar genótipos e frequências alélicas dos polimorfismos GSTM1, GSTT1 e GSTP1, e correlacionar esses achados moleculares com fatores de risco já estabelecidos para câncer de mama, incluindo densidade mamográfica, em uma amostra de 750 mulheres assintomáticas durante o rastreamento mamográfico. Para os testes moleculares foi utilizado multiplex da reação em cadeia de polimerase (PCR) para GSTM1 e GSTT1, e PCR quantitativo para o polimorfismo GSTP1. As frequências dos genótipos GSTM1 e GSTT1 nulos foram 45% e 21%, respectivamente. Para o polimorfismo GSTP1, as frequências genotipicas foram: 44% para o genótipo Ile/Ile, 44% para o genótipo Ile/Val e 12% para o genótipo Val/Val. A frequência do alelo lle nesta população foi 66%, semelhante a outros estudos. Houve uma associação significativa entre a combinação dos genótipos (T-/M-) nulos e densidade mamográfica nas mulheres pós-menopáusicas (p = 0,031). Quando analisamos isoladamente o genótipo GSTT1 nulo (T-) também encontramos uma associação significativa com a densidade mamográfica nas mulheres pós-menopáusicas (p = 0,027) e na amostra total. Estes achados sugerem uma associação dos genótipos (T-/M-) nulos com densidade mamográfica.

Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients

Isoniazid (INH), one of the most important drugs used in antituberculosis (anti-TB) treatment, is also the major drug involved in hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, such as NAT2, CYP2E1, GSTM1 and GSTT1, that code for drug-metabolising enzymes. Our goal was to examine the polymorphisms in these enzymes as susceptibility factors to anti-TB drug-induced hepatitis in Brazilian individuals. In a case-control design, 167 unrelated active tuberculosis patients from the University Hospital of the Federal University of Rio de Janeiro, Brazil, were enrolled in this study. Patients with a history of anti-TB drug-induced acute hepatitis (cases with an increase to 3 times the upper limit of normal serum transaminases and symptoms of hepatitis) and patients with no evidence of anti-TB hepatic side effects (controls) were genotyped for NAT2, CYP2E1, GSTM1 and GSTT1 polymorphisms. Slow acetylators had a higher incidence of hepatitis than intermediate/rapid acetylators [22 percent (18/82) vs. 9.8 percent (6/61), odds ratio (OR), 2.86, 95 percent confidence interval (CI), 1.06-7.68, p = 0.04). Logistic regression showed that slow acetylation status was the only independent risk factor (OR 3.59, 95 percent CI, 2.53-4.64, p = 0.02) for the occurrence of anti-TB drug-induced hepatitis during anti-TB treatment with INH-containing schemes in Brazilian individuals.

Avaliação epidemiológica da influência dos genes GSTM1 e GSTT1 na susceptibilidade ao câncer de mama em mulheres atendidas em um hospital do Sul do Brasil: um estudo-piloto / Epidemiological evaluation of the influence of GSTM1 and GSTT1 genes in susceptibility to breast cancer in women cared for at a hospital in South Brazil: a pilot study

Introdução: A glutationa S-transferase (GST) é uma família de enzimas intracelulares que catalisam a conjugação de compostos eletrolíticos diversos, promovendo a formação de substâncias menos reativas e mais solúveis em água. Os genes GSTM1 e GSTT1 são polimórficos em humanos, e estão presentes ou ausentes de forma homozigótica em diferentes populações étnicas. Indivíduos com a deleção homozigótica destes genes podem ser mais susceptíveis ao desenvolvimento de doenças atribuídas à exposição de carcinógenos. O objetivo deste estudo foi verificar se a ocorrência de deleções homozigóticas dos genes GSTM1 e GSTT1 estão associadas com o aumento da susceptibilidade ao câncer de mama. Métodos: Estudo de caso-controle incluindo 15 mulheres portadoras de câncer e 30 mulheres sem câncer. A deleção homozigótica dos genes GSTM1 e GSTT1 foi identificada através da reação em cadeia da polimerase. Os dados obtidos foram analisados no software SPSS 12.0. Resultados: Entre os dados epidemiológicos analisados nenhum foi associado com o risco para o desenvolvimento de câncer de mama. Foi observado um percentual de 44,4% e 46,7% de deleção homozigótica para os genes GSTM1 e GSTT1, respectivamente. A dupla deleção homozigótica foi observada em uma frequência significativamente maior entre os casos [RR = 7,9 (95%, IC: 1,637,7~ p<00,1)]. Conclusão: A dupla deleção homozigótica está associada com a susceptibilidade ao câncer de mama na população estudada, entretanto novos estudos devem ser realizados para confirmar esses achados. A detecção precoce da ausência desses genes poderia permitir uma melhor abordagem diagnóstica e um planejamento mais adequado do tratamento de mulheres com câncer de mama

Introduction: Glutathione S transferase (GST) is a family of intracellular enzymes that catalyze the conjugation of various electrolytic compounds, promoting the formation of substances which are less reactive and more soluble in water. Genes GSTM1 and GSTT1 are polymorphic in humans and are present or absent in homozygous form in different ethnic populations. Individuals with homozygous deletion of these genes may be more susceptible to development of diseases attributed to exposure to carcinogens. The aim of this study was to determine whether the occurrence of homozygous deletions of GSTM1 and GSTT1 are associated with increased susceptibility to breast cancer. Methods: A case-control study including 15 women with cancer and 30 women without cancer. Homozygous deletion of GSTM1 and GSTT1 genes was identified by polymerase chain reaction. Data were analyzed with SPSS 12.0. Results: Among the epidemiological data analyzed none was associated with risk for developing breast cancer. We found percentages of 44.4% and 46.7% for homozygous deletion of GSTM1 and GSTT1, respectively. Double homozygous deletion was detected in a significantly higher frequency among the cases [OR = 7.9 (95% CI: 1,637,7, p <0.1)]. Conclusion: Double homozygous deletion is associated with susceptibility to breast cancer in this population. However, further studies should be conducted to confirm these findings. Early detection of the absence of these genes could provide better diagnosis and more appropriate planning of care for women with breast cancer

Cáncer gástrico y genes detoxificadores en una población colombiana / Gastric cancer and detoxifying genes in a colombian population

El objetivo fue establecer si hay asociación entre el cáncer gástrico (CG) y los polimorfismos desfavorables de los genes desintoxicadores GSTM1, GSTP1 y GSTT1. A la vez, se exploró si el hábito del tabaquismo, el consumo de alcohol y el nivel socioeconómico también interactúan como factores de riesgo en una población colombiana con alta incidencia de CG. Participaron 87 pacientes afectados por CG e igual número de controles del mismo grupo poblacional del departamento de Caldas. Todos fueron genotipíficados por medio de PCR para los polimorfismos GSTM1-nulo, GSTP1-val y GSTT1-nulo. Se colectó información acerca del tabaquismo, consumo de alcohol y nivel socioeconómico. Los resultados encontrados sugieren que es factor de riesgo significativo portar el genotipo GSTT1-nulo o el alelo GSTP1-val y pertenecer a los niveles socioeconómicos bajo o medio. También se detectó un interacción significativa entre el tabaquismo, el nivel socioeconómico bajo y el riesgo a CG. En conclusión, se evidencia interacción significativa entre ambiente-gen, particularmente entre el genotipo GSTT1-nulo, el alelo GSTP1-val, el nivel socioeconómico bajo, el tabaquismo y el riesgo a desarrollar CG en la población de esta región colombiana.

The objective was to establish whether there are associations between gastric cancer (GC) and unfavorable polymorphisms in GSTM1, GSTP1 and GSTT1 detoxifying genes. Simultaneously interactions of smoking habits, alcohol consumption and socioeconomic levels were investigated as possible risk factors in a Colombian population with a high incidence of GC. 87 patients affected by GC and 87 controls from the same population group in the Department of Caldas participated in the research. All patients were genotyped by PCR for GSTM1-null, GSTP1-val and GSTT1-null polymorphisms. Information about tobacco smoking, alcohol consumption and socioeconomic levels was collected. Results suggest that the GSTM1-nul genotype and GSTP1-val allele are significant risk factors as are low and medium socioeconomic levels. Significant interaction between tobacco smoking, low socioeconomic levels and GC risks were also detected. To conclude, there is significant interaction between environment and genes, particularly between the GSTT1-nulle genotype and GSTP1-val allele and low socioeconomic levels, tobacco smoking and the risk of GC development within this Colombian region’s population.

Effect of GSTM1 and GSTT1 double deletions in the development of oxidative stress in diabetic nephropathy patients.

Association of diabetic nephropathy (DN) with the deletion of GSTT1 and GSTM1 genes is well reported. Oxidative stress (OS) has also been associated with the development of DN. The present study was conducted to find out, whether these deletions had any contributory role in the development of OS in patients with DN. Pre-dialysis venous blood samples were obtained from 60 patients with diabetic end-stage renal disease (stages 4 and 5). Reduced-glutathione (GSH), glutathione S-transferase (GST) activity and malondialdehyde (MDA) levels were measured for the assessment of OS. Genetic polymorphism analysis of DN patients revealed the following distribution pattern: GSTM1 null 46.7%; GSTT1 null 55%; both null 30% and both positive 28.3%. Patients with both null genotypes were found to have significantly increased levels of MDA and low GST activity as compared to other genotypic groups. Lower GSH levels were observed in all the genotypic groups as compared to both positives. Double deletions involving GSTT1 and GSTM1 may result in decreased GST levels, leading to increased OS as reflected by increased MDA levels. As GST is a multi-functional enzyme involved in xenobiotic metabolism, this double null genotype population has a greater risk of development of DN. Further studies using increased sample size to find out the allelic distribution and their role in the development of DN are in progress.

Case-control study of the polymorphisms of CYP2E1-RsaⅠ and STT1 genes and susceptibility to pancreatic cancer / 西安交通大学学报(医学版)

Objective To investigate the correlation between the combination of smoking with CYP2E1-RsaⅠ and GSTT1 genes polymorphisms and pancreatic cancer. Methods The genetic polymorphisms of CYP2E1-RsaⅠ and GSTT1 were analyzed by polymorphism-polymerase chain reaction (PCR) technique in peripheral blood leukocytes of 150 pancreatic cancer cases and 150 non-cancer controls. Results The frequency of CYP2E1-RsaⅠ(c1/c1) and GSTT1(-) was 38.7% and 69.3% in pancreatic cancer cases and 20.7% and 44.7% in healthy controls, respectively. Statistical tests showed significant differences in the frequencies between the two groups (χ~2=15.75, P<0.01; χ~2=18.62, P<0.01). The risk of pancreatic cancer patients with CYP2E1-RsaⅠ(c1/c1) was significantly higher than that of controls (OR=3.19, 95% CI=2.53-4.26). The individuals who carried with GSTT1(-) had a higher risk of pancreatic cancer (OR=2.85, 95% CI=1.92-4.64). Combined analysis of the polymorphisms showed that the percentage of CYP2E1-RsaⅠ(c1/c1)/GSTT1(-) in pancreatic cancer and control groups was 30.7% and 6.7%, respectively (χ~2= 42.39, P<0.01). People who carried with CYP2E1-RsaⅠ(c1/c1)/GSTT1(-) had a higher risk of pancreatic cancer (OR=16.63, 95% CI=8.94-22.01). The smoking ratewas significantly higher in the case group than in the control group (OR=2.74, 95% CI=1.32-4.58, P<0.01), and statistical analysis suggested an interaction between smoking and CYP2E1-RsaⅠ(c1/c1) or GSTT1(-) genotypes polymorphisms which increased the risk of pancreatic cancer (OR=8.84, 95% CI=5. 51-11.62; OR=20.40, 95% CI=4.98-29.53). Conclusion CYP2E1-RsaⅠ(c1/c1) and GSTT1(-) are the risk factors in pancreatic cancer. Smoking is also related to the susceptibility to pancreatic cancer. There may be a synergetic interaction among CYP2E1-RsaⅠ(c1/c1) and GSTT1(-) and smoking on the elevated susceptibility of pancreatic cancer.

Glutathione S-transferase mu 1 (GSTM1) and theta 1 (GSTT1) genetic polymorphisms and atopic asthma in children from Southeastern Brazil

Xenobiotics can trigger degranulation of eosinophils and mast cells. In this process, the cells release several substances leading to bronchial hyperactivity, the main feature of atopic asthma (AA). GSTM1 and GSTT1 genes encode enzymes involved in the inactivation of these compounds. Both genes are polymorphic in humans and have a null variant genotype in which both the gene and corresponding enzyme are absent. An increased risk for disease in individuals with the null GST genotypes is therefore, but this issue is controversial. The aim of this study was to investigate the influence of the GSTM1 and GSTT1 genotypes on the occurrence of AA, as well as on its clinical manifestations. Genomic DNA from 86 patients and 258 controls was analyzed by polymerase chain reaction. The frequency of the GSTM1 null genotype in patients was higher than that found in controls (60.5 percent versus 40.3 percent, p = 0.002). In individuals with the GSTM1 null genotype the risk of manifested AA was 2.3-fold higher (95 percentCI: 1.4-3.7) than for others. In contrast, similar frequencies of GSTT1 null and combined GSTM1 plus GSTT1 null genotypes were seen in both groups. No differences in genotype frequencies were perceived in patients stratified by age, gender, ethnic origin, and severity of the disease. These results suggest that the inherited absence of the GSTM1 metabolic pathway may alter the risk of AA in southeastern Brazilian children, although this must be confirmed by further studies with a larger cohort of patients and age-matched controls from the distinct regions of the country.

Polymorphisms of cytochrome P450 1A1, glutathione s-transferases M1 and T1 genes in ouangolodougou (Northern Ivory Coast)

In this study, the frequencies of CYP1A1, GSTM1, and GSTT1 gene polymorphisms were determined in 133 healthy individuals from Ouangolodougou, a small rural town situated in the north of the Ivory Coast. As appeared in several published studies, ethnic differences in these frequencies have been found to play an important role in the metabolism of a relevant number of human carcinogens. In the studied sample, the frequencies of Ile/Ile (wild type), Ile/Val (heterozygous variant), and Val/Val (homozygous variant) CYP1A1 genotypes were 0.271, 0.692, and 0.037, respectively. Frequencies of GSTM1 and GSTT1 null genotypes were 0.361 and 0.331, respectively. No significant differences were noted between men and women. In contrast to published data for Africans, CYP1A1 *Val Allele frequency (0.383) was significantly high (p < 0.001) in this specific population. For the GSTT1 null genotype, no differences were found between the studied and other African populations, the contrary to what occurred for the GSTM1 null genotype in relation to Gambia and Egypt.

GST null genotype and antioxidants: Risk indicators for oral pre-cancer and cancer.

Objectives : This study was undertaken to detect the gene polymorphism of detoxification enzymes and estimate the antioxidant enzyme status in patients with oral cancer, oral leukoplakia and oral submucous fibrosis (OSF). Materials and Methods : The GSTM1 and GSTT1 gene polymorphism was evaluated using polymerase chain reaction; the antioxidant enzyme was estimated using biochemical methods. Statistical analyses were performed using student t-test and odds-ratio to estimate relative risk (RR). Results : The RR at 95% confidence interval (CI) for GSTM1 and GSTT1 was statistically significant for all groups. The mean values of glutathione were significantly raised in all groups. The mean values of ceruloplasmin and malonaldehyde was statistically significant among cancer and OSF patients but was insignificant in smokers and cases with leukoplakia. Conclusion : Several genes perform the same function which implies the need to test for several genetic polymorphisms to identify individuals at high risk. The level of antioxidant enzymes correlate with the degree of oxidative damage. The need for further studies is emphasised.

No contribution of GSTM1 and GSTT1 null genotypes to the risk of neutropenia due to benzene exposure in Southeastern Brazil

Exposure to benzene has been associated with haematological diseases such as neutropenia (NEB) and acute myeloid leukaemia (AML). We tested whether the null genotypes of the GSTM1 and GSTT1 genes, involved in benzene inactivation, altered the risk for NEB in southeastern Brazil. Genomic DNA from 55 NEB patients and 330 controls was analysed by multiplex-polymerase chain reaction. The frequency of the GSTM1, GSTT1 and combined null genotypes was similar in patients and controls (GSTM1, 27.3 percent vs. 38.8 percent, p = 0.16; GSTT1, 25.5 percent vs. 19.7 percent, p = 0.24; GSTM1/GSTT1, 12.7 percent vs. 6.7 percent, p = 0.26; respectively). The distribution of genotype classes in NEB patients was similar to normal controls, suggesting that GSTM1 and GSTT1 null genotypes make no specific contribution to the risk of NEB. As the GSTM1 and GSTT1 null genotypes were previously associated with increased risk for AML in Brazil and elsewhere, we hypothesise that different thresholds of chemical exposure relative to distinct GSTM1 and GSTT1 genotypes may determine whether AML or NEB manifests in benzene exposed individuals from southeastern Brazil. Although indicative, our results still require support by prospective and large scale epidemiological studies, with rigorous assessment of daily chemical exposures and control of the possible contribution of other polymorphic genes involved in benzene metabolism.

Características mamográficas do câncer de mama associadas aos polimorfismos GSTM1 e GSTT1 / Polymorphisms GSTM1 and GSTT1 and sporadic breast cancer mammographic features

INTRODUÇÃO: As enzimas do sistema da glutationa S-transferase (GST) modulam os efeitos da exposição a vários agentes citotóxicos e genotóxicos. Os genes GSTM1 e GSTT1 são polimórficos em humanos e suas deleções têm sido associadas ao aumento do risco de várias neoplasias, dentre elas o câncer de mama. OBJETIVO: Comparar a freqüência das deleções dos genes GSTM1 e GSTT1 em mulheres sadias e com câncer de mama e comparar as características mamográficas do câncer entre mulheres portadoras e não portadoras das referidas deleções. MÉTODOS: Foram determinadas as freqüências das referidas deleções por PCR em 100 pacientes portadoras de câncer de mama esporádico tratadas de setembro de 2004 a junho de 2005 e em 169 mulheres sadias doadoras de sangue no mesmo período e comparadas através do odds ratio (OR) com seus respectivos IC 95 por cento. Foram revistos os prontuários e as mamografias das pacientes com câncer e avaliadas características mamográficas (padrão de distribuição do parênquima fibro-glandular, achados mamográficos ao diagnóstico e classificação BI-RADS), correlacionando-as às deleções gênicas através do cálculo da RP (razão de prevalência) com seus respectivos IC 95 por cento. RESULTADOS: O GSTM1 esteve deletado em 40 por cento dos cânceres e em 44,4 por cento dos controles (OR=1,20; IC 95 por cento 0,70-2,04; p=0,5659) enquanto o GSTT1 em 20 por cento e 19,5 por cento, respectivamente (OR=0,73; IC 0,37-1,44; p=0,4124). O padrão mamográfico denso esteve associado à deleção homozigótica do GSTM1 (RP= 2,43; IC 1,11-4,08). Não se observou associação entre as deleções do sistema GST e achados mamográficos ao diagnóstico e classificação BI-RADS. CONCLUSÃO: A deleção homozigótica do gene GSTM1 associou-se ao padrão mamográfico denso.

INTRODUCTION: Enzymes of the Glutathione S-transferase system (GST) modulate the effects of exposure to several cytotoxic and genotoxic agents. The GSTM1 and GSTT1 genes are polymorphic in humans and their deletions have been associated to increased risk of many cancers, including breast cancer. OBJECTIVE: To evaluate the occurrence of homozygous deletions of the GSTM1 and GSTT1 genes in women with sporadic breast cancer and in women without cancer and to compare breast cancer mammographic features between patients with and without these deletions. METHODS: The study evaluated 100 patients with sporadic breast cancer treated from September 2004 to June 2005 and 169 women without cancer, determining the frequency of the above-mentioned deletions by PCR and calculating the odds ratios and their 95 percent confidence intervals. Medical files and mammograms of 100 patients with breast cancer were evaluated and correlated with mammographic features such as density, mammographic findings and the BI-RADS classification. These findings were correlated with the genetic deletions by the PR (Prevalence-Ratio) with their respective 95 percent confidence intervals. RESULTS: The GSTM1 gene was deleted in 40 percent of the cancers and in 44.4 percent of controls (OR = 1.20; CI 95 percent 0.70 - 2.04; p=0.5659) while the GSTT1 gene was deleted in 20 percent and 19.5 percent, respectively (OR = 0.73; CI 95 percent 0.37-1.44; p=0.4124). High mammographic density had been associated with GSTM1 deletion (PR 2.43; CI 1.11 to 4.08). GST deletions were not associated with predominant mammographic findings and the BI-RADS classification. CONCLUSION: GSTM1 homozygous deletion was associated with high mammographic density.

Polymorphisms in the glutathione S-transferase theta and mu genes and susceptibility to myeloid leukemia in Brazilian patients

The null genotype for glutathione S-transferase (GST, EC 2.5.1.18) gene polymorphisms is considered a risk factor for leukemia in different populations. In this work we investigated the GSTT1 and GSTM1 polymorphisms using multiplex PCR in 53 patients with chronic myeloid leukemia (CML), 23 with acute promyelocytic leukemia (APL) and 304 apparently healthy controls. In this association study we found that the GSTT1null genotype was more frequent in our group of APL patients than in the control group [OR = 2.75 (95 percent CI = 1.10-6.88)], providing evidence that a deletion in the GSTT1 gene could be a risk factor for this type of leukemia.

A Case Control-study on the Associations between Polymorphism of GSTT1,GSTM1 and Susceptibility for Breast Cancer / 中国慢性病预防与控制

Objective To explore the relation of the polymorphism of GSTT & GSTM1 genes with the susceptibility of breast cancer.Methods A hospital-based case-control study was conducted,and 105 normal women as a control group and 100 women cases with breast cancer were recruited.The polymorphism of GSTT1 and GSTM1 were assessed by polymerase chain reaction(PCR).Logistic regression was conducted to evaluate the odds ratio of breast cancer in relation to single,multiple gene and estrogen exposure factors.Results The results showed that significant difference was found in the distribution of GSTT1,GSTM1 between controls and cases.There was a negative correlation between CSTT1 & GSTM1 and the risk of breast cancer with OR of 2.133 and 2.458,respectively.Polygenic model analysis indicated that there was a statistically significant correlation of the vacancy of GSTT1 & GSTM1 with breast cancer.Furthermore,it was also revealed that individual in simultaneous lack of GSTT1 and GSTM1 would run 12 times as high risk as normal controls did(OR=12.338).Results from unconditional logistic regression analysis showed that GSTT1 and GSTM1 were significantly associated with the occurrence of breast cancer.Conclusion The study indicated that the polymorphisms of estrogen-metabolizing genes were related to the risk of breast cancer.