Polymorphisms within glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia: a case-control study

Glutathione S-transferases (GSTs) have been associated with outcome in human cancers treated with cytotoxic chemotherapy. In a case-control study, we investigated the association between polymorphisms within the GSTM1, GSTT1, and GSTP1 genes and risk of relapse in childhood acute lymphoblastic leukemia (ALL). Cases were relapsed patients. Controls were successfully treated patients with a minimum follow-up of 5 years. The null genotype (absence of both alleles) for GSTM1 or GSTT1 conferred a 2-fold (OR = 0.5, 95% CI = 0. 23-1.07, P =.078) and 2.8-fold (OR = 0.36, 95% CI = 0.13-0.99, P =. 048) reduction in risk of relapse, respectively, relative to the presence of the GSTM1 or GSTT1 gene. The GSTP1 Val(105)/Val(105) genotype showed a 3-fold decrease in risk of relapse (OR = 0.33, 95% CI = 0.09-1.23, P =.099) in comparison to the combined category of Ile(105)/Val(105) and Ile(105)/Ile(105 )genotypes. No particular associations with relapse were observed for the GSTP1 polymorphism at codon 114. The risk of relapse when having 1 of the low-risk genotypes (GSTM1 null, GSTT1 null, GSTP1 Val(105)/Val(105)) decreased 1.9-fold (OR = 0.53, 95% CI = 0.24-1.19, P =.123), and the risk when having 2 or 3 low-risk genotypes 3.5-fold (OR = 0.29, 95% CI = 0.06-1.37, P =.118), compared with individuals having no low-risk genotype (P for trend =.005). Our results suggest that polymorphisms within genes of the GST superfamily may be associated with risk of relapse in childhood ALL. (Blood. 2000;95:1222-1228)     

Role of CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 genes in the susceptibility to acute leukemias

Acute leukemias (ALs) are heterogeneous diseases. Functional polymorphisms in the genes encoding detoxification enzymes cause inter-individual differences, which contribute to leukemia susceptibility. The CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 polymorphisms in ALL (n = 156) and AML (n = 94) patients and 140 healthy controls were genotyped by PCR and/or PCR-RFLP using blood or bone marrow samples. No association was observed between the GSTT1 gene deletion and patients (OR = 0.8, 95% CI = 0.4-1.7 for AMLs and OR = 0.9, 95% CI = 0.5-1.6 for ALLs). Patients with ALL and AML had a higher prevalence of the GSTM1 deletions compared to controls but only the difference among adult AML patients (OR = 2.1, 95% CI = 1.0-4.2) was statistically significant. The CYP2D6*3 variant allele frequency was lower in the overall acute leukemia patients (0.6%) compared to controls (P = 0.03). CYP2D6*1/*3 genotype frequency also showed a protective association in AML patients (OR = 0.09, 95% CI = 0.01-1.7; P = 0.04). We also found a risk association for CYP2E1*5 in ALL and AML (OR = 3.6, 95% CI = 1.4-9.4 and OR = 3.9, 95% CI = 1.4-10.5, respectively). No association was found for the studied CYP2D6*4, CYP1A1*2A, and GSTT1"null" variants and the risk of acute leuke-mia (ALL or AML). This case-control study suggests a contribution of CYP2E1, CYP2D6, and GSTM1 "null" variants to the development of acute leukemias.     

Study of genetic polymorphism of xenobiotic enzymes in acute leukemia.

The work studied possible association between genetic polymorphisms of CYP2D6, GSTM1, GSTT1and NQO1 and altered susceptibility to leukaemia, correlating these genetic polymorphisms with clinical prognostic data, response to therapy and relapse. The study included 32 leukaemia patients, 19 with acute myeloid leukemia (AML) and 13 with acute lymphoid leukaemia (ALL), and 11 normal individuals (control group). Basic investigations for the diagnosis of AML and ALL were performed, including blood picture, bone marrow aspirate, cytochemistry and immunophenotyping for detection of subtypes. Detection of CYP2D6, NQO1, GSTM1 and GSTT1 genetic polymorphisms used a polymerase chain reaction-restriction fragment length polymorphism. A follow-up was made for association between the outcome of patients and different patterns of genetic polymorphisms. Results demonstrate a significant increase in the frequency of CYP2D6 wild-type and GSTM1 null genotypes in the acute leukaemia group compared with the control. Studying the relationship between polymorphisms of these genes and the outcome of our cases revealed the wild genotype of CYP2D6 significantly influenced the outcome of acute leukaemia particularly in AML cases, while GSTM1 null genotype was associated with bad prognosis among the ALL group. The study also revealed that patients with combined mutant CYP2D6/present GSTM1/present GSTT1 achieved the best prognosis, suggesting synergistic impact of these genetic polymorphisms on the outcome of acute leukaemia cases. This case-control study suggests a contribution of CYP2D6 and GSTM1 null variants in the development of acute leukaemia. In addition, GSTM1 and GSTT1 genotypes were apparently related to response, side effects and prognosis of patients with AML.     

Polymorphisms of drug-metabolizing enzymes and risk of childhood acute lymphoblastic leukemia

The involvement of phase I and II enzymes is well documented in the metabolism of a wide range of drugs and xenobiotics. Single-nucleotide polymorphisms (SNPs) of these enzymes are also known to alter their protein expression and function. Moreover, genetic susceptibility and environmental exposure have been proposed to be an etiology of cancer. We hypothesized that polymorphisms of these enzymes might affect the risk of childhood acute lymphoblastic leukemia (ALL). CYP 1A1, CYP 3A4*1B, CYP 3A5*3, CYP 3A5*6, GSTM1, and GSTT1 polymorphisms were genotyped by using PCR-RFLP in 107 children with ALL and 320 healthy controls. Allele and genotype frequencies of each of the SNPs were compared between two groups. It was found that the allele frequencies of CYP 1A1*1, *2A, *2B, and *4 were not different between cases and controls. CYP 3A4*1B allele frequency was only 0.8% and 0.9% in ALL and controls, respectively. CYP 3A5*1/*1, *1/*3, and *3/*3 genotype frequencies showed no statistically significant difference between patients and controls. CYP 3A5*6 was not detected in our population. The GSTM1 null genotype was significantly increased in children with ALL (OR 1.7; 95% CI, 1.0, 2.7). In contrast, the GSTT1 null genotype did not show this effect. Our data thus demonstrate that the GSTM1 null genotype might increase the risk of childhood ALL in a Thai population.     

Susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms

Although acute lymphoblastic leukemia (ALL) is the most common childhood cancer, factors governing susceptibility to this disease have not yet been identified. As such, ALL offers a useful opportunity to examine the glutathione S-transferase and cytochrome P450 genes in determining susceptibility to pediatric cancers. Both enzymes are involved in carcinogen metabolism and have been shown to influence the risk a variety of solid tumors in adults. To determine whether these genes played a similar role in childhood leukemogenesis, we compared the allele frequencies of 177 childhood ALL patients and 304 controls for the CYP1A1, CYP2D6, GSTM1, and GSTT1 genes. We chose the French population of Quebec as our study population because of its relative genetic homogeneity. The GSTM1 null and CYP1A1*2A genotypes were both found to be significant predictors of ALL risk (odds ratio [OR] = 1.8). Those possessing both genotypes were at an even greater risk of developing the disease (OR = 3.3). None of the other alleles tested for proved to be significant indicators of ALL risk. Unexpectedly, girls carrying the CYP1A1*4 were significantly underrepresented in the ALL group (OR = 0.2), suggesting that a gender-specific protective role exists for this allele. These results suggest that the risk of ALL may indeed be associated with xenobiotics-metabolism, and thus with environmental exposures. Our findings may also explain, in part, why ALL is more prevalent among males than females.     

GSTT1, GSTM1 and CYP2E1 genetic polymorphisms in gastric cancer and chronic gastritis in a Brazilian population

MIM:To test the hypothesis that,in the Southeastern Brazilian population,the GSTT1,GSTM1 and CYP2E1 polymorphisms and putative risk factors are associated with an increased risk for gastric cancer.METHODS:We conducted a study on 100 cases of gastric cancer(GC),100 cases of chronic gastritis(CG),and 150 controls(C).Deletion of the GSTT1 and GSTM1 genes was assessed by multiplex PCR.CYP2E1/PsА genotyping was performed using a PCR-RFLP assay.RESULTS:No relationship between GSTT1/GSTM1 deletion and the c1/c2 genotype of CYP2E1 was observed among the three groups.However,a significant difference between CG and C was observde,due to a greater number of GSTT1/GSTM1 positive genotypes in the CG group.The GSTT1 null genotype occurred more frequently in Negroid subjicts,and the GSTM1 null genotype was observed mainly in individuals with chronic gastritis infected with H pylori.CONCLUSION:Our findings indecate that there is no obvious relationship between the GSTT1,GSTM1 and CYP2E1 polymorphisms and gastric cancer.     

CYP1A1, GST gene polymorphisms and risk of chronic myeloid leukemia

PRINCIPLES: Associations between polymorphisms for genes encoding enzymes involved in biotransformation of xenobiotics and susceptibility to several cancers have been shown in several studies. The aim of the present study is to investigate the influence of cytochromes P450 (CYP450) 1A1*2C and Glutathione S-transferases (GSTs) (T1 and M1) gene polymorphisms in susceptibility to chronic myeloid leukaemia (CML). METHODS: The frequency of CYP1A1 Ile/Val alleles and of GSTT1 and GSTM1 homozygous deletions was examined in 107 patients with CML and 132 healthy controls by PCR and/or PCRRFLP methods using blood samples. RESULTS: The frequency of CYP1A1 Val allele was found to be 19.2% in CML patients and 4.4% for controls, indicating that persons carrying this allele had an increased risk of CML (OR = 5.10, 95% CI: 2.60-9.97). The frequency of individuals carrying the GSTT1 null genotype was higher among CML patients (40.2%) compared to controls (19.2%) (OR = 2.82, 95% CI: 1.58-5.05; p <0.001). Therefore, GSTT1 present genotype may be a protective factor for CML. Although GSTM1 null genotype frequency was slightly higher in the patient group (44.9%) than in the controls (42.3%), this difference was not statistically significant (OR = 1.11, 95% CI: 0.66-1.86; p = 0.693). Individuals with GSTM1 null genotypes without the T allele have a 5.981 higher risk for CML than those who have the T allele. CONCLUSIONS: This data suggests that polymorphic CYP1A1 and GSTT1 genes appear to affect susceptibility to CML.     

谷胱甘肽硫转移酶M1和T1基因多态性与燃煤型砷中毒发病的关系

目的探讨谷胱甘肽硫转移酶M1和T1（GSTM1、GSTT1）基因多态性与燃煤污染型砷中毒发病风险的关系。方法采用多重等位基因特异聚合酶链反应技术检测贵州省130名燃煤型砷中毒患者及140名健康个体的GSTM1和GSTT1基因多态性，并分析不同基因型与砷中毒发病的关系。结果砷中毒病例组和对照组GSTT1纯合缺失基因型（GSTT1^（-/-））的频率分别为58．5％和45．0％，组间比较差异有统计学意义（Х^2=6．246，P〈0．05）；携带GSTT1^（-/-）基因型个体发生砷中毒的风险是携带GSTT1非纯合缺失基因型（GSTT1^（＋/＋）or（-/-））个体的2．18倍[比值比（OR）adj=2．18，95％可信区间（CI）：1．183～4．018]。砷中毒病例组和对照组间GSTM1纯合缺失基因型（GSTM1^（-/-））频率的差异无统计学意义（P〉0．05）。基因型联合分析显示：携带GSTM1^（-/-）和GSTT1^（-/-）联合基因型的个体，其砷中毒的发病风险显著增加（ORadj=2．931，95％CI：1．024～8．387）。结论GSTT1^（-/-）基因型可能是燃煤型砷中毒发生的重要危险内因之一。     

Polymorphisms of the glutathione S-transferases mu-1 (GSTM1) and theta-1 (GSTT1) and the risk of advanced alcoholic liver disease

OBJECTIVE: The aim of this study was to determine whether null genotypes for glutathione transferase mu-1 (GSTM1) and theta-1 (GSTT1) influence the risk of development of advanced alcoholic liver disease. MATERIAL AND METHODS: GSTM1 and GSTT1 genotypes were identified on DNA through multiple analysis with polymerase chain reaction in 153 subjects diagnosed with advanced alcoholic liver disease and in 241 healthy controls. RESULTS: The frequency of the GSTM1 null genotype was not different between patients and controls (36.6% versus 41.1%, non-significant). The GSTT1 null genotype was more frequently found in patients than in controls (32% versus 22%, odds ratio 1.67, 95% CI 1.03-2.71, p =0.027). Moreover, patients were more likely to be simultaneous carriers of both GSTM1 and GSTT1 null genotypes (odds ratio 4.30, 95% CI 1.89-9.97, p =0.0003). CONCLUSIONS: The GSTT1 null genotype is more frequent among patients with advanced alcoholic liver disease than in controls. The coincidence of this genotype with the GSTM1 null genotype is four times more likely in patients. We suggest that polymorphisms affecting the activity of the glutathione S-transferase isoforms M1 and T1 may be associated with the risk of developing chronic severe ethanol liver damage.     

Glutathione S-transferase gene polymorphisms in Japanese patients with rheumatoid arthritis

OBJECTIVE: To investigate the role of polymorphisms of the glutathione S-transferase M1 (GSTM1), GSTT1, and GSTP1 genes in determining susceptibility to rheumatoid arthritis (RA) and association with the clinical features. METHODS: Polymorphisms of the GSTM1, GSTT1, and GSTP1 genes in 108 Japanese patients with RA and in 143 healthy controls were analyzed by polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism. RESULTS: The frequency of the GSTM1 null genotype was significantly higher among RA patients than among control subjects (60.2% and 44.1%, respectively. P = 0.011). Moreover, the female patients with GSTM1 homozygous null genotype showed significantly higher serum MMP-3 level than the female patients with non-null genotype (P = 0.030). Frequencies of the GSTT1 and GSTP1 gene polymorphism were not different between RA patients and controls. CONCLUSION: The GSTM1 homozygous null genotype could be a genetic factor that determines susceptibility to RA and may have influence on the disease process.     

Glutathione sulfur transferase M1 and T1 genotypes in chronic lymphoblastic leukemia

Glutathione sulfur transferases (GSTs) is a group of enzymes involved in the detoxification process of carcinogens and other substances. The genes encoding isoenzymes M1 and T1 are polymorphic in humans and the phenotypic absence of enzyme activity (null genotype) may have an effect on the risk of chronic lymphoblastic leukemia (CLL). Our purpose was to examine whether the GSTM1 and GSTT1 homozygous null genotypes altered the risk of CLL. DNA was extracted from the peripheral blood of 27 patients with CLL and 147 cancer-free controls; both groups originated from a defined population (residents of the Ioannina region, northwestern Greece) and were similar with regard to mean age, race and sex; GSTM1 and GSTT1 were simultaneously analyzed by a multiplex polymerase chain reaction (PCR) method and Fisher's exact test was used for comparisons between the two groups. A significantly increased incidence of the GSTM1 null genotype was found in the group of patients compared to the controls (74.07 versus 34.69%, P = 0.0002). Additionally, the incidence of the GSTT1 null genotype was comparable in patients and controls (25.92 versus 10.20%, P = 0.05). The frequency of the combined GSTM1 null/T1 null genotype was significantly different between patients and controls (14.81 versus 2.04%, P = 0.012). However, there was no relationship between the advanced stage of the disease and the GSTs status. Individuals with the GSTM1 and GSTT1 null genotypes may have enhanced susceptibility to CLL.     

谷胱甘肽S-转移酶M1、T1基因多态与散发性大肠腺癌遗传易感性

目的　探讨谷胱甘肽S 转移酶 (GST)M1、T1基因多态与散发性大肠腺癌 (SCRAC)遗传易感性的关联。方法　应用多重聚合酶链反应 (PCR)技术 ,对经病理组织学确诊的 10 4例SCRAC患者及同期在本院体检的无血缘关系的 10 1例健康人 ,检测其GSTM1和GSTT1基因多态性。结果　 (1)在健康人和SCRAC患者 ,GSTM1、GSTT1空白基因型的频率差异均无显著性 (前者 4 6 5 % :5 6 7% ,χ2 =2 13,P >0 0 5 ;后者 4 7 5 % :6 0 6 % ,χ2 =3 5 2 ,P >0 0 5 )。 (2 )GSTM1空白基因型频率在近端与远端SCRAC患者间、在老年与非老年SCRAC间的频率差异均无显著性 ;而GSTT1空白基因型的频率差异有显著性 (前者 4 4 4 % :6 6 2 % ,χ2 =3 97,P <0 0 5 ;后者 70 9% :4 9 0 % ,χ2 =5 2 1,P <0 0 5 )。 (3)GSTM1、GSTT1均为空白基因联合型的个体患SCRAC的危险性升高 4 33倍 (9 6 % :2 6 9% ,χ2 =7 89,ν =3,P <0 0 5 )。结论　单独的GSTM1或GSTT1空白基因型与SCRAC遗传易感性无关 ,但GSTT1空白基因型与远端SCRAC遗传易感性有关 ,且多见于老年患者。GSTM1、GSTT1均为空白基因的联合基因型是SCRAC的易感基因型。     

Glutathione S-transferase genotype and risk of systemic lupus erythematosus in Koreans

Oxidative stress caused by poor detoxification efficiency of reactive oxygen species (ROS) may play a role in the development of systemic lupus erythematosus (SLE). Glutathione S-transferase (GST) is involved in the detoxification of ROS and genetic polymorphisms of GSTM1, GSTT1 and GSTP1 are associated with altered enzyme activity. The aim of this study was to determine whether GSTMI (deletion), GSTT1 (deletion) and GSTP1 (Ile(105)-->Val(105)) polymorphisms are associated with susceptibility to SLE or frequency of clinical manifestations according to the ACR diagnostic criteria. DNA was isolated from blood samples collected from 330 patients with SLE and 270 age- and sex-matched controls. GST genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. No associations were observed between GSTM1, GSTT1, and GSTP1 genotypes and risk of SLE. Among SLE patients, the GSTM1 null genotype was associated with a lower frequency of hematological disorders (P = 0.012), and a higher SSA(+)/SSB(-) autoantibody profile (P = 0.042). Compared to SLE patients with the GSTT1 non-null genotype, those with the GSTT1 null genotype had a lower frequency of discoid rash (P = 0.018), and nephritis (P = 0.033). Our findings suggest that genetic polymorphisms of GSTM1, GSTT1, and GSTP1 do not influence the risk of SLE, but a deletion of either GSTM1 or GSTT1 may influence certain clinical manifestations of the disease.     

Correlation of EPHX1, GSTP1, GSTM1, and GSTT1 genetic polymorphisms with antioxidative stress markers in chronic obstructive pulmonary disease

This study was undertaken to ascertain if a relationship existed between oxidative status and polymorphisms of microsomal epoxide hydrolase X1 (EPHX1), glutathione S-transferase P1 (GSTP1), GSTM1, and GSTT1 in chronic obstructive pulmonary disease (COPD). Erythrocyte glutathione peroxidase (GSH-px), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and plasma GST activities and total antioxidant status (TAS) as antioxidative stress markers were determined and compared either with individual and combined genotypes of EPHX1 exon 3, GSTP1 exon 5, GSTM1, and GSTT1 polymorphisms in COPD patients and healthy controls from the central area of Tunisia. Statistical data processing revealed significantly lower GSH-px, GR, SOD, CAT, GST, and TAS values in COPD patients in comparison to the control group (P < .001). As for genotypes, there was a no significant association in each of the 6 parameters and individual genotypes (P > .05). A significant correlation between the studied parameters and combined null GSTM1/null GSTT1 (GSH-px: P < .001, GR: P = .026, CAT: P = .018, GST: P = .022, TAS: P = .046), His113His EPHX1/null GSTM1 (GSH-px: P = .001, GST: P = .0012, TAS: P = .013), His113His EPHX1/Val105Val GSTP1 (GSH-px: P = .048, CAT: P = .026, GST: P = .031), and null GSTM1/Val105Val GSTP1 (GSH-px: P = .011, GR: P = .0028, GST: P = .0054, TAS: P = .032) was found in patients. In conclusion, combined genetic polymorphisms of GSTM1, GSTT1, GSTP1, and EPHX1 may have favorable effects on redox balance in COPD patients.     

Glutathione S-transferase genotypes,genetic susceptibility,and outcome of therapy in childhood acute lymphoblastic leukemia

The glutathione S-transferase (GST) genes are involved in the metabolism of environmental carcinogens and of some classes of chemotherapy drugs. GSTM1 and GSTT1 genotypes are polymorphic in humans, and the phenotypic absence of enzyme activity is caused by a homozygous inherited deletion of the gene. Previous, smaller studies of childhood acute lymphoblastic leukemia (ALL) provided contrasting data on the role of the GST genotype in susceptibility and treatment outcomes. We analyzed GST genotypes in 710 children with ALL treated by the Children's Cancer Group. Frequencies were compared with those of normal controls, and outcomes were analyzed according to genotype. Comparisons of gene frequencies in ALL case and control patients showed similar frequencies (54% vs 53% GSTM1 null in whites, P =.9; 40% versus 32% in blacks, P =.45; 16% versus 15% GSTT1 null in whites, P =.8; 17% versus 28% in blacks, P =.3). ALL was not associated with the GSTM1-null genotype or the double-null genotype in blacks or whites, in contrast to previous reports. Stratification of cases by age at diagnosis, sex, white blood cell count at diagnosis, B or T lineage, or cytogenetics revealed no differences in genotype frequencies. Analysis of treatment outcomes showed no differences in outcome according to GST genotype; in particular, there were no differences in frequencies of relapse at any site. These data, representing a larger series than any reported previously, suggest that GST genotype does not affect etiology or outcome of childhood ALL.     

Relationship between glutathione S-transferase M1, T1, and P1 polymorphisms and chronic lymphocytic leukemia

Interindividual differences in susceptibility to hematologic malignancies may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The glutathione S-transferases (GSTs) have been implicated as susceptibility genes in this context for a number of cancers. The aim of this study was to examine whether polymorphic variation in GSTs confers susceptibility to chronic lymphocytic leukemia (CLL). GSTM1, GSTT1, and GSTP1 genotypes were determined in 138 patients and 280 healthy individuals. The frequency of both GSTM1 and GSTT1 null genotypes and the GSTP1-Ile allele was higher in cases than in controls. There was evidence of a trend in increasing risk with the number of putative "high-risk" alleles of the GST family carried (P =.04). The risk of CLL associated with possession of all 3 "high-risk" genotypes was increased 2.8-fold (OR = 2.8, 95% confidence interval: 1.1-6.9). Our findings suggest that heritable GST status may influence the risk of developing CLL.     

Increased prevalence of GSTM(1) null genotype in patients with myelodysplastic syndrome: a case-control study

BACKGROUND AND OBJECTIVE: Myelodysplastic syndromes (MDS) are clonal disorders of bone marrow stem cells characterized by ineffective hematopoiesis leading to blood cytopenia; they often progress to acute myeloid leukemia (AML). The glutathione S-transferases (GST) detoxify various agents, including those implicated in MDS. Both GSTM(1) and GSTT(1) genes have "null" alleles and are polymorphic. We studied the impact of GTM(1) and GSTT(1) null genotypes on the MDS susceptibility, disease severity and laboratory indices with prognostic value for the syndrome. MATERIAL AND METHODS: In a hospital-based case-control study we analyzed lymphocyte DNA samples from 54 patients with MDS and 60 cancer-free controls matched for age, sex, smoking habits and origin. A multiplex polymerase chain reaction was used to genotype both GSTM(1) and GSTT(1) simultaneously. The chi(2) test was used for statistical evaluation of the data and the odds ratios and attributable risk and population attributable risk were also calculated. RESULTS: A significantly increased frequency of GSTM(1) null genotype was found among MDS patients (57.4%) compared to controls (33.3%) (p < 0.01), while the frequency of GSTT(1) null genotype was not significantly higher in MDS patients (11.1% vs. 6.66%). Neither GSTM(1) and GSTT(1) null genotype was associated with a particular category of the French-American-British (FAB) classification in the patients studied. Additionally, GSTM(1) null genotype was associated with a significant decrease in the absolute number of neutrophils among the MDS patients. CONCLUSIONS: Individuals with GSTM(1) null genotype may have increased susceptibility to MDS. Null genotypes do not seem to have be associated with FAB classification while they may be associated with putative prognostic factors.     

Glutathione-S-transferase gene polymorphisms (GSTT1, GSTM1, GSTP1) as increased risk factors for asthma

OBJECTIVES: Asthma is a complex multifactorial disease with an obvious genetic predisposition, immunological aberration, and involvement of noxious environmental factors. Polymorphisms of the glutathione-S-transferase (GST) genes are known risk factors for some environmentally-related diseases. In the present study, the hypothesis that polymorphisms in the GSTT1, GSTM1 and GSTP1 genes are associated with atopic and nonatopic asthma was examined. METHODOLOGY: The study population consisted of 103 unrelated healthy individuals and 101 patients with bronchial asthma (64 atopic, 37 nonatopic). Asthma was diagnosed according to the American Thoracic Society statement. Genotyping of polymorphisms in the GSTT1, GSTM1 and GSTP1 genes was performed using real time polymerase chain reaction with a Light Cycler instrument and hybridization probes in combination with the Light Cycler DNA master hybridization probes kit. RESULTS: Patients with atopic asthma (34.4%) had a higher prevalence of the GSTT1 null genotype than the nonatopic asthma patients (13.5%; OR = 3.83; 95% CI, 1.24-11.78). Asthma patients (63.4%) had a higher prevalence of the GSTM1 null genotype than the control group (40.8%; OR = 2.34; 95% CI, 1.31-4.20). Subjects with the GSTP1 homozygous Val/Val genotype had a 3.55-fold increased risk of having atopic asthma compared to nonatopic asthma (OR = 3.55; 95% CI, 1.10-12.56). CONCLUSIONS: These results suggest that the GSTT1 and GSTM1 null genotypes and the GSTP1 Val/Val polymorphism may play important roles in asthma pathogenesis. It is possible that intermediate electrophilic metabolites, arising in the first phase of detoxification, are not metabolized by GST enzymes in asthmatic patients and are not excreted. These intermediate metabolites may damage cells and generate oxidative stress, and so contribute to the pathogenesis of asthma.     

Glutathione S-transferase M null homozygosity and risk of systemic lupus erythematosus associated with sun exposure: a possible gene-environment interaction for autoimmunity

OBJECTIVE: Multiple genetic factors modulate predisposition to systemic lupus erythematosus (SLE). The glutathione S-transferase (GST) genes GSTM1, GSTT1, and GSTP1 catalyze metabolic pathways for the excretion of reactive oxygen species that may be generated by cellular oxidative stress induced by ultraviolet radiation in sunlight. We hypothesized that risk of SLE associated with occupational sun exposure is modulated by GSTM1, GSTT1, and GSTP1 genotypes. METHODS: DNA samples and occupational history were collected from 243 cases and 298 controls in the Carolina Lupus Study, a population based case-control study of patients with recently diagnosed SLE. RESULTS: There was no independent association between SLE and presence of the homozygous null GSTM1 or GSTT1 genotype, the homozygous Val/Val or heterozygous Val/Ile GSTP1 genotype, or occupational sunlight exposure. The prevalence of Ro autoantibodies was significantly increased among Caucasians with the GSTM1 null genotype (OR 2.6, 95% CI 1.0, 6.8), but was somewhat weaker among African-Americans (OR 1.5, 95% CI 0.7, 3.5). In the combined analysis of occupational sunlight exposure and GSTM1 genotype, the effect of sun exposure among Caucasians varied depending on GSTM1 genotype. There was a 3-fold increased risk (OR 3.1, 95% CI 0.9, 10.8) of SLE associated with 24 or more months' occupational sun exposure among Caucasians with the GSTM1 null genotype, but sun exposure was not associated with risk among GSTM1 positive Caucasians (OR 0.6, 95% CI 0.3, 1.5). The interaction was statistically significant (p = 0.028). CONCLUSION: Our results suggest that GSTM1 homozygous null genotype may modify the effect of occupational sun exposure on the risk of SLE in caucasians.     

Increased risk for acute myeloid leukaemia in individuals with glutathione S-transferase mu 1 (GSTM1) and theta 1 (GSTT1) gene defects

OBJECTIVES: Glutathione S-transferases (GST) modulate the effects of exposure to various cytotoxic and genotoxic agents, including those associated with increased risks of the myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML) and aplastic anemia (AA). Both the GST mu 1 (GSTM1) and GST theta 1 (GSTT1) genes have a null variant allele in which the entire gene is absent. In this study, we tested whether null genotypes for the GSTM1 and GSTT1 genes altered the risks for MDS, AML and AA. METHODS: Genomic DNA from 49 MDS, 38 AML and 37 AA patients and 276 controls was analysed using the polymerase chain reaction (PCR). RESULTS: The frequencies of GSTM1 (73.6%) and GSTT1 (34.2%) null genotypes were significantly higher in AML patients than in the controls (36.9 and 18.1%, respectively). A higher frequency of the combined null genotype for both genes was also observed in patients with AML (26.3% compared with 5.0% in the controls). In contrast, no differences in the frequencies of the null genotypes were found among MDS patients, AA patients and the controls. CONCLUSION: Our observation of a 4.7-fold (95% CI: 2.1-11.0) and 2.3-fold (95% CI: 1.0-5.2) increased risk associated with the GSTM1 and GSTT1 null genotypes, respectively, and a 6.6-fold (95% CI: 2.4-7.9) increased risk associated with the combined null genotype presents preliminary evidence that the inherited absence of this carcinogen detoxification pathway may be an important determinant of AML.