Alcohol consumption, glutathione S-transferase M1 and T1 genetic polymorphisms and breast cancer risk

To evaluate the potential association between GSTM1 and GSTT1 genotypes and development of breast cancer, a hospital based case-control study was conducted in a South Korean study population consisting of 189 histologically confirmed incident breast cancer cases and their 189 age-matched control subjects with no present or previous history of cancer. A multiplex polymerase chain reaction method was used for the genotyping analyses and statistical evaluations were performed by unconditional logistic regression model. The GSTM1 null genotype was significantly associated with breast cancer risk in premenopausal women [odds ratio (OR) = 2.0, 95% confidence interval (CI) = 1-3.7], but not in the postmenopausal women (OR = 0.9, 95% CI = 0.5-1.9), nor in all women grouped together (OR = 1.3, 95% CI = 0.8-1.1). The GSTT1 null genotype posed a similar risk of breast cancer with an OR of 1.6 (95% CI = 1.0-2.5) for the total breast cancer group, OR of 1.7 (95% CI = 0.9-3.2) for pre-menopausal women, and OR of 1.3 (95% CI = 0.6-2.8) for post-menopausal women. The breast cancer risk associated with concurrent lack of both GSTM1 and GSTT1 genes was 2.2 (95% CI = 1.1-4.5), and the risk increased as the number of null genotype increased (P for trend = 0.03). When the data were stratified by the known risk factors of breast cancer, a significant interaction was observed between the GSTM1 genotypes and alcohol consumption (P for interaction = 0.03). An especially remarkable risk of breast cancer was observed for alcohol-consuming premenopausal women lacking both the GSTM1 and GSTT1 genes (OR = 5.3, 95% CI = 1.0-27.8) compared to those with both of the genes. Our findings thus suggest a novel gene-environment interaction which plays an important role in the individual susceptibility to breast cancer. p6     

Glutathione S-transferases mu 1, theta 1, pi 1, alpha 1 and mu 3 genetic polymorphisms and the risk of colorectal and gastric cancers in humans

INTRODUCTION: Glutathione S-transferases (GSTs) are considered to be cancer susceptibility genes as they play a role in the detoxification of carcinogenic species. This study aimed to elucidate the influence of several GST polymorphisms on colorectal and gastric cancer risk. PATIENTS AND METHODS: GST mu1 (GSTM1), theta1 (GSTT1), pi1 (GSTP1), alpha1 (GSTA1) and mu3 (GSTM3) genotypes were determined in 144 colorectal cancer patients, 98 gastric cancer patients and 329 healthy control individuals. RESULTS: Colorectal cancer: the risk is greater for carriers of the GSTM1 null genotype (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.25-2.91), for carriers of the GSTT1 null genotype (OR = 3.62, 95% CI = 2.34-5.62), and for simultaneous carriers of both GSTM1 and GSTT1 null genotypes (OR = 4.98, 95% CI = 2.77-9.00). Carriers of the GSTP1 104 Val/Val genotype are at a lower risk (OR = 0.31, 95% CI = 0.09-0.88). Among carriers of the GSTP1 Ile/Ile genotype, smoking increases the risk compared with nonsmoking (OR = 2.35, 95% CI = 1.11-4.99). Gastric cancer: the risk is greater for carriers of the GSTT1 null genotype (OR = 2.58, 95% CI = 1.53-4.36) and for simultaneous carriers of both GSTM1 and GSTT1 null genotypes (OR = 3.32, 95% CI = 1.62-6.77). Carriers of the GSTP1 104 Val/Val genotype are at a lower risk (OR = 0.20, 95% CI = 0.02-0.86). DISCUSSION: The GSTT1 null genotype, particularly if it is associated with the GSTM1 null genotype, greatly increases the risk for colorectal and gastric cancers. The GSTP1 104 Val/Val genotype may protect from both malignant tumors. CONCLUSION: This study indicates that GST polymorphisms, in particular the GSTM1/GSTT1 double-null haplotype, can be considered low-penetrance genes for gastrointestinal cancer.     

Association between glutathione S-transferase A1, M1 and T1 polymorphisms and hypertension

The importance of oxidative stress in hypertension has recently received increasing attention. The association between the incidence of hypertension and a super family of antioxidant enzymes, glutathione S-transferase (GST)A1, GSTM1 and GSTT1, polymorphisms was investigated in 468 Japanese participants in a health screening program. The frequency of the GSTA1*B allele carriers was significantly higher in hypertensive patients than normotensive participants [adjusted odds ratio (OR): 1.8; 95% confidence interval (CI): 1.1-2.9]. The risk of hypertension was significantly increased in the GSTA1*B allele carriers having also the GSTM1 null genotype or both the GSTM1 and GSTT1 null genotypes (adjusted OR: 2.4; 95% CI: 1.2-4.9; adjusted OR: 3.1; 95% CI: 1.0-9.5, respectively). This is the first report identifying the GSTA1*B allele as a genetic risk factor for hypertension. The determination of the GST genotypes may help in identifying individuals at high-risk for hypertension.     

Polymorphisms of glutathione S-transferases M1 and T1 do not account for interindividual differences for smoking behavior

To identify whether the polymorphisms of glutathione S-transferase M1 (GSTM1) and GSTT1 genes predict a high-tended risk of using tobacco, the GSTM1 and GSTT1 genotypes of 369 Iranian males (254 nonsmokers and 115 smokers) and 314 Iranian females (245 nonsmokers and 69 smokers) were determined. The frequencies of GSTM1 (males: OR=0.98, 95% CI=0.62-1.57, P=.974; females: OR=1.34, 95% CI=0.75-2.39, P=.358) and GSTT1 (males: OR=1.25, 95% CI=0.76-2.04, P=.412; females: OR=0.84, 95% CI=0.46-1.51, P=.626) null genotypes were similar in nonsmokers and smokers. The risk of being a smoker was to be equally frequent in each combination of the genotypes. The present results revealed that there was no difference between smokers and nonsmokers for these two genetic polymorphisms.     

NAT2 slow acetylation and GSTM1 null genotypes may increase postmenopausal breast cancer risk in long-term smoking women

N-acetyltransferase (NAT) 1 and 2 and glutathione S-transferase (GST) M1 and T1 are phase II enzymes that are important for activation and detoxification of carcinogenic heterocyclic and aromatic amines, as present in cigarette smoke. We studied whether genetic polymorphisms in these genes modifies the relationship between smoking and breast cancer. A nested case-control study was conducted among participants in a Dutch prospective cohort. Breast cancer cases (n=229) and controls (n=264) were frequency-matched on age, menopausal status and residence. Compared to never smoking, smoking 20 cigarettes or more per day increased breast cancer risk statistically significant only in postmenopausal women [odds ratio (OR)=2.17; 95% confidence interval (CI) 1.04-4.51]. Neither NAT1 slow genotype, or GSTT1 null genotype, alone or in combination with smoking, affected breast cancer risk. However, compared to individuals with rapid NAT2 genotype, women with the very slow acetylator genotype (NAT2*5), who smoked for 20 years showed an increased breast cancer risk (OR=2.29; 95% CI 1.06-4.95). Similarly, the presence of GSTM1 null genotype combined with high levels of cigarette smoking (OR=3.00; 95% CI 1.46-6.15) or long duration (OR=2.53; 95% CI 1.24-5.16), increased rates of breast cancer. The combined effect of GSTM1 null genotype and smoking high doses was most pronounced in postmenopausal women (OR=6.78; 95% CI 2.31-19.89). In conclusion, our results provide support for the view that women who smoke and who have a genetically determined reduced inactivation of carcinogens (GSTM1 null genotype or slow NAT2 genotype (especially very slow NAT2 genotype)) are at increased risk of breast cancer.     

Genetic polymorphisms involved in toxicant-metabolizing enzymes and the risk of chronic benzene poisoning in Chinese occupationally exposed populations

Benzene is a recognized haematotoxin and leukaemogen, but its mechanism of action and the role of genetic susceptibility are still unclear. Cytochrome P450 2E1 (CYP2E1) and myeloperoxidase (MPO) are involved in benzene activation; and NAD (P)H:quinine oxidoreductase 1 (NQO1), glutathione S-transferase theta 1 (GSTT1) and glutathione S-transferase mu 1 (GSTM1) participate in benzene detoxification. The common, well-studied single-nucleotide polymorphisms (SNPs) were analysed in these genes drawn from the toxicant-metabolizing pathways. A total of 100 workers with chronic benzene poisoning (CBP) and 90 controls were enrolled in China. There was a 2.82-fold (95% CI = 1.42-5.58) increased risk of CBP in the subjects with the NQO1 609C > T mutation genotype (T/T) compared with those carrying heterozygous (C/T) and wild-type (C/C). The subjects with the GSTT1 null genotype had a 1.91-fold (95% CI = 1.05-3.45) increased risk of CBP compared with those with GSTT1 non-null genotype. There was no association of CYP2E1 and MPO genotype with CBP. A three genes' interaction showed that there was a 20.41-fold (95% CI = 3.79-111.11) increased risk of CBP in subjects with the NQO1 609C > T T/T genotype and with the GSTT1 null genotype and the GSTM1 null genotype compared with those carrying the NQO1 609C > T C/T and C/C genotype, GSTT1 non-null genotype, and GSTM1 non-null genotype. The study provides evidence of an association of a gene-gene interaction with the risk of CBP.     

Glutathione S-transferase GSTM1 and GSTT1 null genotypes as potential risk factors for urothelial cancer of the bladder

 Onehundred-and-thirteen patients with cancer of the urinary bladder (cases) were examined with respect to the frequency of null genotypes of the polymorphic glutathione S-transferases GSTM1 and GSTT1. The allelic background in the German population of the area was evaluated by analysing 170 newborns (controls). The frequency of GSTM1 and GSTT1 null genotypes in this population, using methods based upon internal standard controlled polymerase chain reaction (PCR), was 0.54 and 0.18 respectively. An elevated relative bladder cancer risk of GSTM1 null genotype carriers was indicated by comparison of this background with the data of the bladder cancer cases (OR = 1.81; 95% CI [1.10, 2.98]; p = 0.019). The frequencies of the GSTT1 null genotype in the total group of bladder cancer cases versus controls did not differ statistically. However, a significantly higher relative risk of bladder cancer for the GSTT1 null genotype was detected in the cases-subgroup of non-smokers (OR = 3.84; 95% CI [1.21, 12.23]; p = 0.023). Thus, the GSTT1 null genotype might represent a minor risk factor for human bladder cancer which should be further investigated. Received: 2 May 1996 / Accepted: 16 July 1996     

Glutathione transferase isozyme genotypes in patients with prostate and bladder carcinoma

Genotype distributions for GSTP1, GSTM1, and GSTT1 were determined in 91 patients with prostatic carcinoma and 135 patients with bladder carcinoma and compared with those in 127 abdominal surgery patients without malignancies. None of the genotypes differed significantly with respect to age or sex among controls or cancer patients. In the group of prostatic carcinoma patients, GSTT1 null allele homozygotes were more prevalent (25% in carcinoma patients vs. 13% in controls, Fisher P =0.02, chi2 P=0.02, OR=2.31, CI = 1.17-4.59) and the combined M1-/T1 -null genotype was also more frequent (9% vs. 3%, chi2 P=0.02, Fisher P = 0.03). Homozygosity for the GSTM1 null allele was more frequent among bladder carcinoma patients (59% in bladder carcinoma patients vs 45% in controls, Fisher P=0.03, chi2 P=0.02, OR=1.76, CI=1.08-2.88). In contrast to a previous report, no significant increase in the frequency of the GSTP1b allele was found in the tumor patients. Except for the combined GSTM1-/ T1-null genotype in prostatic carcinoma, none of the combined genotypes showed a significant association with either of the cancers. These findings suggest that specific single polymorphic GST genes, that is GSTM1 in the case of bladder cancer and GSTT1 in the case of prostatic carcinoma, are most relevant for the development of these urological malignancies among the general population in Central Europe.     

Glutathione-S-transferase M1, M3, T1 and P1 polymorphisms and susceptibility to non-small-cell lung cancer subtypes and hamartomas.

Polymorphic glutathione-S-transferase (GST) genes causing variations in enzyme activity may influence individual susceptibility to lung cancer. In this case-control study (consisting of 389 Caucasian lung cancer patients, including 151 adenocarcinomas (ACs) and 172 squamous cell carcinomas (SCCs), and 353 hospital control subjects without malignant disease, genotype frequencies for GSTM1, GSTM3, GSTP1 and GSTT1 were determined by polymerase chain reaction (PCR)/ restriction fragment length polymorphism (RFLP)-based methods. While adjusted odds ratios (ORs) indicated no significantly increased risk for lung cancer overall due to any single GST genotype, the risk alleles for GSTM1, GSTM3 and GSTP1 conferring reduced enzyme activity were present at higher frequency in SCC than in AC patients. This is consistent with a reduced detoxification of carcinogenic polycyclic aromatic hydrocarbons (PAHs) from cigarette smoke that are more important for the development of SCC than for AC. An explorative data analysis also identified statistically significantly increased ORs for the combinations GSTT1 non-null and GSTP1 GG or AG for lung cancer overall (OR 2.23, CI 1.11-4.45), and for SCC (OR 2.69, CI 1.03-6.99). 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). Additionally, in 28 patients with hamartomas, the GSTT1 null genotype was also protective (P = 0.013), while GSTP1 variant allele carriers were overrepresented (OR 2.48, CI 1.06-6.51). In conclusion, GST genotypes may act differently, either by detoxifying harmful tobacco carcinogens and/or by eliminating lung cancer chemopreventive agents. The latter role for GSTT1 would explain the observed lower risk of SCC and hamartoma associated with GSTT1 null. Further confirmatory studies are required.     

Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1 and glutathione S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to tobacco-related cancers: studies in upper aerodigestive tract cancers

Glutathione S-transferase GSTM1, GSTM3 and GSTT1 and cytochrome P450 CYP2D6, CYP1A1 and CYP2E1 loci are susceptibility candidates for cancers of the upper aerodigestive tract because putatively protective and risk genotypes have been identified from studies in other diseases associated with alcohol and tobacco consumption. We describe genotype frequencies in 398 oral, pharyngeal and laryngeal squamous cell carcinoma patients and 219 control individuals. Of the genotypes presumed to be protective, only GSTM1 A/B influenced susceptibility; the GSTM1 A/B frequency was lower in the patients than the control individuals both before [odds ratio = 0.3, 95% confidence interval (CI) 0.1-0.7] and after correction for imbalances in age, sex, smoking and alcohol consumption (odds ratio = 0.2, 95% CI 0.1-0.5). Of the putatively risk genotypes, GSTM3 AA, previously associated with susceptibility to skin cancer, was higher in the cases (odds ratio = 1.6, 95% CI 1.1-2.4). Dividing cases into oral/pharyngeal and laryngeal squamous cell carcinoma showed the GSTM3 AA frequency was higher in laryngeal squamous cell carcinoma than control individuals (odds ratio = 1.6, 95% CI 1.1-2.5) and the difference between control individuals and oral/pharyngeal squamous cell carcinoma approached significance (odds ratio = 1.7, 95% CI 1.0-2.8). The putatively protective GSTM3 BB genotype was lower in patients with glottic (1.0%) than supraglottic (3.0%) squamous cell carcinoma. We identified no differences between patients and control individuals in the frequencies of presumed risk genotypes (e.g. CYP2D6 EM, CYP1A1 m1/m1, CYP1A1 Ile/Ile, CYP2E1 DD, CYP2E1 c1c1, GSTT1 null) or, interactions between genotypes and smoking or alcohol consumption. We conclude, first, that mu class glutathione S-transferase influence risk of upper aerodigestive tract cancers thereby complementing studies in skin cancer patients showing GSTM1 A/B is protective, while GSTM3 AA moderately increases risk. The influence of GSTM1 A/B, but not GSTM1 A or GSTM1 B (mostly heterozygotes with GSTM1*0) suggests that two expressed alleles may attenuate risk. While we found immunohistochemical evidence of GSTM3 expression in the cilia lining the larynx, the biochemical consequences of the polymorphism are unclear. Indeed, the influence of the gene may reflect linkage disequilibrium with another gene. However, we did not find an association with GSTM1 genotypes. Second, we conclude that the CYP2D6, CYP2E1, CYP1A1 and GSTT1 alleles studied, although putatively good candidates, either do not determine the effectiveness of detoxification of tobacco-derived carcinogens in the upper aerodigestive tract or, that chronic consumption of tobacco and alcohol overwhelms enzyme defences, irrespective of genotype.     

Polymorphisms of glutathione S-transferase genes (GSTM1, GSTP1 and GSTT1) and bladder cancer susceptibility in the Turkish population

We investigated the effect of the GSTM1 and GSTT1 null genotypes, and GSTP1 313 A/G polymorphism on bladder cancer susceptibility in a case control study of 121 bladder cancer patients, and 121 age- and sex-matched controls of the Turkish population. The adjusted odds ratio for age, sex, and smoking status is 1.94 [95% confidence intervals (CI) 1.15-3.26] for the GSTM1 null genotype, and 1.75 (95% CT 1.03-2.99) for the GSTP1 313 A/G or G/G genotypes. GSTT1 was shown not to be associated with bladder cancer. Combination of the two high-risk genotypes. GSTM1 null and GSTP1 313 A/G or G/G, revealed that the risk increases to 3.91-fold (95% CI 1.88-8.13) compared with the combination of the low-risk genotypes of these loci. In individuals with the combined risk factors of cigarette smoking and the GSTM1 null genotype, the risk of bladder cancer is 2.81 times (95% CI 1.23-6.35) that of persons who both carry the GSTM1-present genotype and do not smoke. Similarly, the risk is 2.38-fold (95% CI 1.12-4.95) for the combined GSTP1 313 A/G and G/ G genotypes and smoking. These findings support the role for the GSTM1 null and the GSTP1 313 AG or GG genotypes in the development of bladder cancer. Furthermore, gene-gene (GSTM1-GSTP1) and gene-environment (GSTM1-smoking, GSTP1-smoking) interactions increase this risk substantially.     

Comparison of GSTM polymorphisms and risk for oral cancer between African-Americans and Caucasians

Two members of the mu class of glutathione S-transferase (GST) genes, GSTM1 and GSTM3, have polymorphic alleles which have been associated with altered levels of GST mu protein expression and may be linked to increased risk for several tobacco-related cancers. Oral cancer is a tobacco-related disease that affects African-American men at a significantly higher incidence than Caucasian men. To examine the potential role of GSTM polymorphisms in risk for oral cancer in African-Americans and Caucasians, the prevalences of the GSTM1 null and GSTM3 intron 6 polymorphisms were examined in 63 African-American and 101 Caucasian patients with histologically confirmed primary oral cancer, as well as in 133 African-American and 213 Caucasian matched control subjects. In African-Americans, the odds ratio for oral cancer associated with the GSTM1 (0/0) genotype was 3.1 [95% confidence interval (CI) = 1.1-8.5], with the association between the GSTM1 (0/0) genotype and oral cancer risk strongest in heavy smokers [i.e. > 24 pack-years; odds ratio (OR) = 5.4, 95% CI = 1.2-24]. Using the potentially most protective GSTM1 [+]/GSTM3 (B/B) genotype as the reference group, increased risk for oral cancer was observed in African-Americans with the GSTM1 [+]/GSTM3 [(A/A) + (A/B)] (OR = 2.2, 95% CI = 0.82-6.0), GSTM1 (0/0)/GSTM3 (B/B) (OR = 4.3, 95% CI = 1.1-16), and GSTM1 (0/0)/GSTM3 [(A/A) + (A/B)] (OR = 6.6, 95% CI = 1.2-38) genotypes (P < 0.01, trend test). No significant associations were observed between GSTM genotype and oral cancer risk in Caucasians. These results suggest that the GSTM1 null and GSTM3 intron 6 polymorphisms play an important role in risk for oral cancer among African-Americans and implicates the mu class of GSTs as important tobacco carcinogen detoxifying enzymes in this population.     

Association between cancer risk and drug-metabolizing enzyme gene (CYP2A6, CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1) polymorphisms in cases of lung cancer in Japan

Genetic polymorphisms of enzymes involved in the metabolism of carcinogens are suggested to modify an individual's susceptibility to lung cancer. The purpose of this study was to investigate the relationship between lung cancer cases in Japan and variant alleles of cytochrome P450 (CYP) 2A6 (CYP2A6*4), CYP2A13 (CYP2A13*1-*10), CYP4B1 (CYP4B1*1-*7), sulfotransferase 1A1 (SULT1A1*2), glutathione S-transferase M1 (GSTM1 null), and glutathione S-transferase T1 (GSTT1 null). We investigated the distribution of these polymorphisms in 192 lung cancer patients and in 203 age- and sex-matched cancer-free controls. The polymorphisms were analyzed using various techniques including allele-specific PCR, hybridization probe assay, multiplex PCR, denaturing high-performance liquid chromatography (DHPLC), and direct sequencing. We also investigated allele and genotype frequencies and their association with lung cancer risk, demographic factors, and smoking status. The prevalence of the CYP2A6*4/*4 genotype in lung cancer cases was 3.6%, compared with 9.4% in the controls (adjusted OR = 0.36, 95% CI = 0.15-0.88, P = 0.025). In contrast, there was no association between the known CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1 polymorphisms and lung cancer. These data indicate that CYP2A6 deletions may be associated with lung cancer in the Japanese population studied.     

GSTM1、GSTT1及GSTP1(rs1695)基因多态性与乳腺癌蒽环和（或）紫杉类药物化疗血液毒性关系的研究

【摘要】目的 研究乳腺癌外周血中谷胱甘肽转硫酶（GST）M1、GSTT1和GSTP1（rs1695）基因多态性与乳腺癌患者采用蒽环类和（或）紫杉类药物化疗发生血液毒性的关系。方法 应用多重PCR技术（M-PCR）和高分辨熔解曲线技术（HRM）检测3个基因在252例女性乳腺癌患者外周血中的基因多态性。结果 采用紫杉类、蒽环联合紫杉类药物化疗,携带GSTP1(rs1695)AG/GG的患者是发生Ⅲ~Ⅳ度中性粒细胞减低的危险因素(OR=6.111, 95%CI1.526~24.469, P＜0.05和OR=9.257, 95%CI2.903~29.522, P<0.01),而GSTM1(+)与GSTM1(-)、GSTT1(+)与GSTT1(-)患者Ⅲ~Ⅳ度血液毒性的发生率差异均无统计学意义;采用蒽环类药物化疗,GSTM1(+)和GSTM1(-)、GSTT1(+)和GSTT1(-)、GSTP1AA和GSTP1AG/GG患者Ⅲ~Ⅳ度血液毒性发生率差异均无统计学意义(P>0.05)。结论 GSTP1(rs1695)基因多态性可作为预测乳腺癌患者采用紫杉类药物化疗发生中性粒细胞毒性的标志。     

Polymorphism in glutathione-S-transferases: A risk factor in alcoholic liver cirrhosis

In a case-control study, association of polymorphism in glutathione-S-transferases (GSTM1, GSTT1, GSTP1), involved in detoxification of reactive oxygen species (ROS), was studied with alcoholic liver cirrhosis. The study included 175 alcoholic cirrhotic patients (ACPs), 140 non-alcoholic cirrhotic patients (NACPs), visiting Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGI), Lucknow, India, 255 non-alcoholic controls and 140 alcoholic controls. The data showed an increase in risk to alcoholic cirrhosis in ACPs with GSTM1 (null) genotype when compared with non-alcoholic controls (OR: 1.7; 95% CI: 1.15–2.56) or alcoholic controls (OR: 1.7; 95% CI: 1.07–2.73). Significant increase in risk was also observed in ACPs with variant genotype of GSTP1 when compared with non-alcoholic controls (OR: 1.65; 95% CI: 1.12–2.43). A much higher risk to alcoholic liver cirrhosis was observed in patients carrying combination of null genotypes of GSTM1 and GSTT1 (OR: 2.8; 95% CI: 1.3–6.06) or variant genotype of GSTP1 and null genotype of GSTM1 (OR: 2.8; 95% CI: 1.58–4.90) or GSTT1 (OR: 2.16; 95% CI: 1.08–4.28). Likewise, greater risk for alcoholic cirrhosis was observed in patients carrying combination of GSTM1, GSTT1 (null) and variant genotype of GSTP1 (OR: 5.8; 95% CI: 2.17–15.80). Our data further showed that interaction of GSTs with variant genotype of manganese superoxide dismutase (MnSOD), which detoxifies free radicals, or cytochrome P450 2E1, which generates free radicals, resulted in several fold increase in risk to alcoholic liver cirrhosis in ACPs when compared with non-alcoholic controls thus demonstrating the role of gene–gene interactions in modulating the risk to alcoholic liver cirrhosis.     

Glutathione S-transferase genotypes and allergic responses to diisocyanate exposure

Diisocyanates are the most common low molecular weight chemicals to cause occupational asthma. However, only some 5-10% of exposed workers develop asthma, which suggests an underlying genetic susceptibility. Diisocyanates and their metabolites may be conjugated with glutathione by glutathione S-transferases (GSTs). We examined whether polymorphisms in the GSTM1, GSTM3, GSTP1 and GSTT1 genes modify allergic responses to diisocyanate exposure. The study population consisted of 182 diisocyanate exposed workers, 109 diagnosed with diisocyanate-induced asthma and 73 without asthma. Lack of the GSTM1 gene (null genotype) was associated with a 1.89-fold risk of diisocyanate-induced asthma [95% confidence interval (CI) 1.01-3.52]. Moreover, among the asthma patients, the GSTM1 null genotype was associated with lack of diisocyanate-specific immunoglobulin (Ig)E antibodies [odds ratio (OR) 0.18, 95% CI 0.05-0.61] and with late reaction in the specific bronchial provocation test (OR 2.82, 95% CI 1.15-6.88). Similarly, GSTM3 AA genotype was related to late reaction in the specific bronchial provocation test (OR 3.75, 95% CI 1.26-11.2). The GSTP1 Val/Val genotype, on the other hand, was related to high total IgE levels (OR 5.46, 95% CI 1.15-26.0). The most remarkable effect was seen for the combination of GSTM1 null and the GSTM3 AA genotype which was strongly associated with lack of diisocyanate-specific IgE antibodies (OR 0.09, 95% CI 0.01-0.73) and with late reaction in the bronchial provocation test (OR 11.0, 95% CI 2.19-55.3). The results suggest, for the first time, that the polymorphic GSTs, especially the mu class GSTs, play an important role in inception of ill effects related to occupational exposure to diisocyanates.     

Polymorphisms within glutathione S-transferase genes and initial response to glucocorticoids in childhood acute lymphoblastic leukaemia

In children with acute lymphoblastic leukaemia (ALL) treated according to protocols of the Berlin-Frankfurt-Münster (BFM) study group, the initial response to prednisone is the strongest predictor of therapy outcome. Glutathione S-transferases (GSTs) have been implicated in glucocorticoid resistance. In order to assess a potential association of phenotypically relevant GST polymorphisms with prednisone response in childhood ALL, we conducted a case-control study of 45 prednisone poor-responders (cases) and 90 prednisone good-responders (controls) who were frequency matched according to initial white blood cell count. In addition, we analysed the association of GST genotypes with relapse of leukaemia. In univariate analysis, homozygous deletion of GSTT1 (null genotype) conferred a 6.7-fold reduction in risk of prednisone poor-response compared to individuals who were either heterozygous or homozygous for GSTT1 [odds ratio (OR) = 0.15, P = 0.071; multivariate odds ratio = 0.18, P = 0.117]. GSTM1 and GSTP1 genotypes did not show any association with prednisone response. In addition, risk of relapse was predicted strongest by the GSTT1 genotype. In univariate analysis, the GSTT1 null genotype conferred a 5.9-fold reduction in risk of relapse compared to the heterozygous or homozygous presence of GSTT1 (OR = 0.17, P = 0.095; multivariate OR = 0.23; P = 0.173). No associations of the GSTM1 genotype with risk of relapse were observed. GSTP1 codon 105 and codon 114 polymorphisms were predominantely associated with central nervous system relapse. Our results add further support to the hypothesis that genetic polymorphisms within specific GST genes might be of clinical importance in childhood ALL.     

Laryngeal cancer risk in Caucasians is associated with alcohol and tobacco consumption but not modified by genetic polymorphisms in class I alcohol dehydrogenases ADH1B and ADH1C,and glutathione-S-transferases GSTM1 and GSTT1

OBJECTIVE: Alcohol and tobacco consumption are recognized risk factors for upper aerodigestive tract tumours, however individual susceptibility to these environmental factors varies. As part of the Rhein-Neckar Larynx-case-control study, this study investigated the potential risk-modifying effect of genetic polymorphisms in enzymes involved in ethanol and tobacco carcinogen metabolism for laryngeal cancer in Germany. METHODS: Two hundred and forty-five cases and 251 population-based controls, matched by age and gender, were genotyped for genetic polymorphisms in ADH1B, ADH1C, GSTM1 and GSTT1, using genomic DNA isolated from peripheral lymphocytes and employing PCR and PCR/restriction fragment length polymorphism-based methods. RESULTS: Neither the putative risk genotypes ADH1B*2/*1 (OR 0.86, 95% confidence interval (CI): 0.41-1.82) or ADH1C*1/*1 (OR 1.06, CI 0.7-1.62) nor GSTM1 null (OR 0.94, CI 0.62-1.42) or GSTT1 null (OR 1.34, CI 0.74-2.42) were associated with an overall increased risk for laryngeal cancer. Stratified analyses were carried out to determine the gene-environment interaction in relation to laryngeal cancer risk. However, ADH1B or ADH1C genotypes did not markedly modify the risk observed after stratification by alcohol consumption, and stratification by cumulative smoking exposure (in packyears) did not show an association of GSTM1 or GSTT1 genotype with laryngeal carcinoma either. CONCLUSION: The lack of risk modification by the studied genotypes emphasizes the importance of environmental exposure to tobacco smoke and alcohol as major risk factors for laryngeal cancer in the German study population.     

Higher glutathione transferase GSTM1 0/0 genotype frequency in young thyroid carcinoma patients

OBJECTIVE: Glutathione S-transferases (GSTs) comprise a large supergene family and detoxify a variety of endogenous and exogenous electrophilic compounds. Since many GSTs are polymorphic, there has been considerable interest in determining whether particular allelic variants are associated with altered risk for various disorders. RESEARCH DESIGN AND METHODS: In this study the association between the variant GSTM1 0/0 genotype and thyroid carcinoma was investigated. A hospital-based, case-controlled study was carried out. Polymorphisms of GSTM1 0/0 (i.e. the null allele of GSTM1) in samples from 32 cases and 44 controls were detected by polymerase chain reaction (PCR) methodology. The proportions of GSTM1 deleted genotype in cases and controls were 59.4% and 54.5%, respectively. RESULTS: There were significant increments of GSTM 0/0 genotype frequency in a group of patients aged under 40 (p = 0.033, odds ratio (OR) = 4.78, 95% confidence interval (CI) = 1.30-7.13) and in former smokers compared with controls (p = 0.039, OR 2.45, 95% CI 0.216-4.72). CONCLUSION: GSTM1 deleted genotype may be a useful genetic biomarker for thyroid carcinoma susceptibility in young subjects. The absence of this enzyme seems to have a role in the development of thyroid carcinoma; however, the mechanism still needs further study.     

SNPs of GSTM1, T1, P1, epoxide hydrolase and DNA repair enzyme XRCC1 and risk of urinary transitional cell carcinoma in southwestern Taiwan

A hospital-based case-control study was conducted near a former black-foot disease (BFD)-endemic area in southwestern Taiwan to examine the possible risk factors and genetic susceptibility for urinary transitional cell carcinoma (TCC). A total of 221 patients with pathologically confirmed TCC and 223 age-sex-matched control subjects from urology outpatient clinics were recruited between 1998 and 2002. The results showed that residency in the BFD area and consumption of well water for more than 10 years was a strong factor on urinary cancer risk (odds ratio [OR],8.16, 95% confidence interval [CI],3.34-19.90, p<0.0001). Dose response relationship between average arsenic concentration in well water and TCC risk was also observed. Cigarette smoking played a relatively minor role in urinary carcinogenesis in this study. The GSTP1 Ile105Val A-->G polymorphism was significantly associated with cancer risk (A/G+G/G: OR=0.60, 95%CI=0.39-0.94, p=0.02), and the effect of Val105 allele was largely confined to the subjects diagnosed earlier than 55 years old (A/G+G/G: OR,0.29; 95% CI, 0.09-0.87, p=0.03). The results suggest that GSTP1 is a candidate for susceptibility locus and Ile105 allele may predispose individuals to early-onset urinary TCC. The GSTM1 null genotype was associated with tumors of high-invasiveness (OR,2.21; 95% CI, 1.34-4.73) as well as with early-onset TCC risk (OR,2.53; 95% CI, 0.97-6.59). Our preliminary results showed the XRCC1 Arg194Trp were associated with arsenic-related urinary TCC and the interaction between the genotype and the exposure was statistically significant. The modulating effect of the GSTM1, GSTT1, GSTP1 Ile105Val, EPHX Tyr113His and XRCC1 Arg280His on arsenic-related TCC risk was also suggestive. These observations implied that impaired metabolism of carcinogenic exposure as well as impaired DNA repair function play an important role in arsenic-related urinary transitional cell carcinogenesis.