The role of glutathione transferases M1 and T1 in individual susceptibility to bladder cancer in a Tunisian population

BACKGROUND: Susceptibility to bladder cancer is thought to depend on interplay between genetic factors and environmental chemical carcinogens. AIM: This study seeks to determine the role of the glutathione transferases M1 and T1 null genotypes (GSTM1*0 and GSTT1*0) in individual susceptibility to bladder cancer in a Tunisian population. METHOD: Sixty-two patients with transitional cell carcinoma of the bladder cancer and 79 controls were examined with respect to the frequency of GSTM1 and GSTT1 null genotypes. RESULTS: The frequencies of the GSTT1 null in the total group of bladder cancer cases vs. controls did not differ statistically. The proportion of GSTM1 null genotype in patients was 63% compared to 45% in controls group (OR = 2.03; 95% CI 0.97-4.24; p = 0.04). A significantly higher incidence of GSTM1 deletion genotype was found in smokers with bladder cancer compared to the controls (65.38% vs. 45.5%). Smokers lacking the GSTM1 gene are at an approximately 2.2-fold higher risk of bladder cancer (OR= 2.23, 95% CI 1-5.15; p = 0.03). CONCLUSION: This study suggests that in Tunisian subjects the GSTM1 null genotype may be associated with an increased risk of bladder cancer. This association appears to depend upon smoking status.     

Glutathione-S-transferase P1 gene polymorphism and susceptibility to endometriosis

BACKGROUND: Glutathione-S-tranferase (GST) is the part of the key phase II detoxifying enzyme system. Many studies have investigated the role of GSTM1 and GSTT1 gene polymorphisms in endometriosis. Although GSTP1 was found to be one of the most abundant types of GST in genital system, there are insufficient data about the importance of the role of GSTP1 gene polymorphism in endometriosis. METHODS: This case-control study involved 150 patients with endometriosis and 150 controls. The frequency of GSTP1 single nucleotide polymorphisms was evaluated using PCR and melting curve analysis. RESULTS: The proportion of GSTP1 ile/ile tended to be higher in patients with endometriosis than control group, although the difference was not significant [odds ratio (OR)=1.53; 95% confidence interval (CI)=0.95-2.46]. In contrast, GSTP1 val/val was significantly higher in control patients and seems protective for endometriosis (OR=0.10; 95% CI=0.02-0.42). CONCLUSION: The results of this study suggest that GSTP1 polymorphism might modulate the risk of endometriosis with significantly decreased risk for GSTP1 val/val and marginally increased risk for GSTP1 ile/ile. Further studies on not only the disease processes but also normal distribution of the enzyme in female genital tract may provide better understanding about the role of GST types and their polymorphs in endometriosis.     

Genetic polymorphisms of CYP2D6, GSTM1, and GSTT1 genes and bladder cancer risk in North India

The study consisted of 100 patients (97 males and 3 females) suffering from bladder cancer and 76 matching controls. The maximum number of patients in this study was in the age group of 61-70 years. The prevalence of genetic polymorphism in the CYP2D6, GSTM1, and GSTT1 genes has been investigated to find their association with risk of bladder cancer. While there was no association between the heterozygous (HEM) genotype of the CYP2D6 gene with the risk of bladder cancer [odds ratio (OR)=1.00; 95% confidence interval (CI)=0.46-2.16], it was 1.5-fold with poor metabolizers (PM) genotype. When stratified according to different grades of bladder cancer, a significant association was found with an OR=3.54 (95% CI=0.89-13.98) in grade II, 3.3 (95% CI=0.12-20.6) in grade III, and 1.67 (95% CI=0.15-18.45) in grade IV. When stratified in relation to smoking status, significant association of the disease was found in heavy smokers with an OR=2.13 (95% CI=0.71-6.43). Subjects with the null genotype for GSTM1 had a slightly significant association with the bladder cancer risk and the risk increased to 2-fold with the GSTT1 null genotype. Smoking status also revealed an impact on the prevalence of bladder cancer in the individuals with GSTM1 and GSTT1 null genotypes. The results indicated that there is a 3-fold increase in risk of developing this cancer in the presence of one copy of the variant CYP2D6 (HEM) allele and null GSTT1.     

Polymorphisms of the genes encoding the GSTM1, GSTT1 and GSTP1 in Korean women: no association with endometriosis

Endometriosis, one of the most common gynaecologic disorders, shows significantly elevated prevalence in industrial areas and there is also a possible genetic predisposition. Glutathione-S-transferases (GSTs) are enzymes involved in the metabolism of many disease-causing carcinogens and mutagens that are present in human environments. An association between the incidence of endometriosis and the GST genotypes of patients has been suggested. The objective of the present study was to investigate whether the polymorphisms of GSTM1, GSTT1 and GSTP1 are related to endometriosis. Blood samples were available from 259 controls and 194 patients with advanced endometriosis diagnosed by both pathology and laparoscopic findings. The proportion of the GSTM1, GSTT1 and GSTP1 genotypes of the control group were comparable to other populations. There was no significant evidence that the distribution of the GSTM1 and GSTT1 genotype differed between the patients and the controls, with an allelic odds ratio (OR)=1.074 [95% confidence interval (CI)=0.737-1.564] and 1.239 (95% CI = 0.853-1.799), respectively. Also, there was no significant difference in the proportion of GSTP1 genotypes between the women with endometriosis and the control group with the OR = 0.823 (95% CI = 0.536-1.264). The higher risk alleles were contended as GSTM1, GSTT1 null mutation and GSTP1 Ile105Ile polymorphism. There was no significant increase in the risk of endometriosis as the number of higher risk alleles of the GST family increased. In conclusion, our findings suggest that the GSTM1, GSTT1 and GSTP1 genetic polymorphisms are not associated with the development of endometriosis in Korean women.     

Genetic Polymorphism of Glutathione S Transferases M1 and T1 in Indian Patients with Hepatocellular Carcinoma

Objective: Our aim was to evaluate whether the association of GSTM1/T1 gene polymorphisms modifies the risk of Hepatocellular carcinoma (HCC) and what is its correlation with other predisposing risk factors like alcohol intake, cigarette smoking and hepatitis B and C infections. Study design/setting: It was a case-control study, included 254 HCC cases compared with 525 hospital-based age and sex matched cases of chronic liver disease without HCC as controls from Indian population. The GSTM1 and GSTT1 genotypes were detected using conventional multiplex PCR method. Results: In this case-control study, we observed a positive correlation between age, HBV and HCV infection, smoking habit of > 20 packs/year, alcohol consumption of > 100 g/day and risk of liver cancer. We found significantly increased risk associated with GSTM1 null genotype (OR = 3.49; 95% CI = 2.52–4.84) as well as GSTT1 null genotype (OR = 3.12; 95% CI = 2.19–4.45), respectively. However, an increased risk of HCC was observed among heavy drinkers with GSTM1 (OR = 2.01; 95% CI = 1.11–3.66). Further, cigarette smoking showed a non-significant association with GSTT1 (OR = 1.49; CI = 0.69–3.25). Conclusion: Our results suggest that the variants in low penetrance gene such as GSTM1 and GSTT1 are associated with an increased liver cancer risk. Further, an influence of GSTM1/T1 null genotypes may contribute in the etiology of HCC in patients with higher cigarette and alcohol consumption.     

Polymorphisms for chemical metabolizing genes and risk for cervical neoplasia

Infection with high-risk human papillomavirus (HPV) plays a major role in the etiology of cervical cancer (CC). However, most infected women do not develop cancer. Therefore, exposure to other carcinogenic agents may be a contributing risk factor for CC. We investigated the hypothesis that environmental exposure to cigarette smoke and inheritance of polymorphic chemical metabolizing genes (CYP2E1, GSTM1, and mEH) significantly increase the risk for neoplasia. We selected 76 cases with high-grade cervical neoplasia or with invasive CC and 75 matched healthy controls. The collected data support the well-established observation that infection with high-risk HPV is the major risk factor for CC (OR = 75; 95% CI = 26-220). In addition, our data show that women who smoked more than 15 "pack-year" had a significant 6.9-fold increase in risk (95% CI = 1.2-40.3) after adjustment for HPV infection. The CYP2E1 variant genotype did not significantly increase the risk for neoplasia. A significant increase in risk for neoplasia was observed for the low-activity mEH 113 His allele after adjustment for smoking (OR = 3.0; 95% CI = 1.4-6.3). The GSTM1 null genotype was associated with a significant 3.3-fold increased risk for neoplasia (95% CI = 1.0-11.8) compared to women who were GSTM1-positive after adjustment for smoking and HPV infection. Our study suggests that genetic differences in the metabolism of cigarette smoke, particularly GSTM1, may confer susceptibility to CC. Further studies using larger populations will be needed to confirm our observations and to validate data for disease prevention.     

Combined effect of smoking and inherited polymorphisms in arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1 on bladder cancer in a Tunisian population

Cigarette smoking is the predominant risk factor for bladder cancer in males and females. The tobacco carcinogens are metabolized by various xenobiotic metabolizing enzymes, such as the super-families of N-acetyltransferases (NAT) and glutathione S-transferases (GST). Polymorphisms in NAT and GST genes alter the ability of these enzymes to metabolize carcinogens. We have conducted this case-control study to assess the role of smoking, slow NAT2 variants, and GSTM1 and GSTT1 null genotypes in bladder cancer development in North Tunisia. In all groups of patients, we have shown that GSTM1 and GSTT1 null genotypes did not appear to be a factor affecting bladder cancer susceptibility. For the NAT2 slow acetylator genotype, the NAT2*5/*7 diplotype was found to have a 7-fold increased risk of bladder (OR=7.14; 95% CI: 1.30–51.41). Furthermore, we found that NAT2 slow acetylator individuals temporarily carrying wild-type GSTT1 or GSTM1 null genotypes have a strong increased risk of bladder cancer (OR= 26 and 22.17, respectively). This cumulative effect was estimated at 12 for smokers harboring slow or an intermediate NAT2, GSTM1 null, and wild-type GSTT1 genotypes compared to non-smokers carrying rapid NAT2, wild-type GSTM,1 and GSTT1 null genotypes (p=0.02; OR=12; CI 95% 1–323.76).     

Association between Glutathione S-Transferase T1, M1, and P1 Genotypes and the Risk of Colorectal Cancer

Glutathione S-transferases (GSTs) are enzymes which play an important role in the neutralization of toxic compounds and eradication of electrophilic carcinogens. Genetic polymorphisms within the genes encoding for GSTs may therefore cause variations in their enzyme activity, which may in turn influence the interindividual susceptibility to cancers. In this study, we aimed to investigate the association between genetic polymorphisms of GSTT1, GSTM1, and GSTP1 and the risk of colorectal cancer (CRC) in 264 cases and 317 controls in a Chinese population. Genotyping was performed by using multiplex PCR (for GSTT1 and GSTM1) and PCR-RFLP (for GSTP1) methods. The association between the polymorphic genotypes and CRC risk was evaluated by deriving odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis. Our results showed that individuals with GSTT1 and GSTM1 null genotypes exhibited a higher risk of CRC (GSTT1, OR,1.66; 95% CI, 1.20-2.31, P=0.003; GSTM1, OR,1.57; 95% CI,1.13-2.18, P=0.007), while no association was observed for GSTP1 (P_heterozygous=0.790 or P_variant=0.261). Furthermore, individuals who simultaneously carried the null genotypes for both GSTT1 and GSTM1 showed a stronger risk association (OR, 1.95; 95% CI, 1.33-2.85; P<0.001). In conclusion, the GSTT1 and GSTM1 polymorphisms, but not GSTP1, may modulate the CRC risk among Chinese.

Graphical Abstract

相似文献   

The role of glutathione transferases M1 and T1 in individual susceptibility to bladder cancer in a Tunisian population

Background: Susceptibility to bladder cancer is thought to depend on interplay between genetic factors and environmental chemical carcinogens.

Aim: This study seeks to determine the role of the glutathione transferases M1 and T1 null genotypes (GSTM1*0 and GSTT1*0) in individual susceptibility to bladder cancer in a Tunisian population.

Method: Sixty-two patients with transitional cell carcinoma of the bladder cancer and 79 controls were examined with respect to the frequency of GSTM1 and GSTT1 null genotypes.

Results: The frequencies of the GSTT1 null in the total group of bladder cancer cases vs. controls did not differ statistically. The proportion of GSTM1 null genotype in patients was 63% compared to 45% in controls group (OR?=?2.03; 95% CI 0.97–4.24; p?=?0.04). A significantly higher incidence of GSTM1 deletion genotype was found in smokers with bladder cancer compared to the controls (65.38% vs. 45.5%). Smokers lacking the GSTM1 gene are at an approximately 2.2-fold higher risk of bladder cancer (OR?=?2.23, 95% CI 1–5.15; p?=?0.03).

Conclusion: This study suggests that in Tunisian subjects the GSTM1 null genotype may be associated with an increased risk of bladder cancer. This association appears to depend upon smoking status.     

Association of GSTs gene polymorphisms with treatment outcome of advanced non-small cell lung cancer patients with cisplatin-based chemotherapy

We evaluated the association of GSTM1 null/present, GSTT1 null/present, and GSTP1 IIe105Val polymorphisms with the clinical response to chemotherapy and treatment outcome of NSCLC. Between October 2009 and October 2012, a total of 282 patients with advanced NSCLC were enrolled into our study, and they were followed up until October 2014. The genotypes of GSTM1, GSTT1, and GSTP1 IIe105Val were performed by polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). By logistic regression analysis, our study found that the Val/Val genotype of GSTP1 IIe105Val was associated with more CR+PR response to chemotherapy when compared with the IIe/IIe genotype, and the OR (95% CI) was 2.18 (1.16-4.12). By multivariate Cox proportional hazards regression analysis, we found the Val/Val genotype of GSTP1 was correlated with lower risk of death in advanced NSCLC (HR, 0.48; 95% CI, 0.25-0.93). However, no association was found between GSTT1 and GSTM1 polymorphisms and response to chemotherapy and overall survival of advanced NSCLC. Moreover, the IIe/Val + Val/Val genotypes of GSTP1 were associated with lower risk of death in never smokers, and the adjusted HR (95% CI) was 0.34 (0.12-0.93). In conclusion, we found that the GSTP1 polymorphism was correlated with better response to chemotherapy and lower risk of death in advanced NSCLC patients.     

Glutathione S-transferases genetic polymorphisms and human diseases: overview of epidemiological studies

Glutathione S-transferases (GST), xenobiotic-metabolising enzymes, are involved in the metabolic detoxification of various environmental carcinogens. Particular genetic polymorphisms of these enzymes have been shown to influence individual susceptibility against various pathologies including cancer, cardiovascular and respiratory diseases. The results from the meta-analysis indicate that GSTM1*0 null allele was associated with enhanced risk for lung (OR (95% IC) = 1,17 (1,07-1,27)), bladder (OR = 1,44 (1,23-1,68) and larynx cancer (OR = 1,42 (1,10-1,84)). GSTT1 null genotype was associated with increased astrocytomas (OR = 2,36 (1,41-3,94)) and meningiomas (OR = 3,57 (1,82-6,92)) cancer risk. GSTP1 allelic polymorphism influence the development of bladder cancer in smokers (OR = 2,40 (1,12-4,95)) and occupational asthma (OR = 3,5 (2,7-4,6)). Finally, GSTM1*0 null allele and GSTT1*1 functional allele were associated with increased risk for coronary heart diseases in smokers (OR = 2,30 (1,40-9,00)) and OR = 2,5 (1,30-4,80), respectively). The GSTT1*1 functional allele was also significantly associated with increased risk of lower extremity arterial disease (OR = 3,60 (1,40-9,00). These epidemiological data suggest that genetic GST polymorphisms influence the individual susceptibility to these diseases. Contrary to cardiovascular disease, no evidence of interaction between GST genotype and smoking status was found in lung cancer but it has not been studied in other cancers. Consequently, other works are necessary to study the potential interaction between GST genotype and environmental carcinogens including tobacco smoke extract.     

Interactive effect of the glutathione S-transferase genes and cigarette smoking on occurrence and severity of coronary artery risk

Cardiovascular diseases and cancer are the main causes of death in developed countries. Mortality trends for these diseases suggest that they share common pathogenetic mechanisms. Glutathione S-transferase (GST) is a family of enzymes that detoxify reactive electrophiles, particularly present in tobacco smoke. Glutathione S-transferase null M1 and T1 (GSTM1 and GSTT1) genotypes have often been associated with increased risk of developing cancer. Our hypothesis was that the polymorphic GSTM1 and GSTT1 genes modulate the risk of smoking-coronary artery disease (CAD). We evaluated the distribution of GST genotypes in 430 angiographically defined patients (308 CAD and 122 non-CAD). The frequencies of GST null genotypes did not differ significantly between patients with CAD and without CAD. However, smokers with GSTM1 and GSTT1 null genotypes had a significantly higher risk of CAD than never-smokers with these genotypes present (OR 2.2 and 3.4 for smokers with null GSTM1 and GSTT1 genes, respectively). There was also evidence of multiple interaction between GSTM1 and GSTT1 deleted genotypes and smoking. In nonsmokers carrying both null genotypes the risk of CAD was 0.66. In smokers with both present genotypes the OR was 1.5 and was significantly increased in smokers with concurrent lack for GSTM1 and GSTT1 genes (OR=4.0). Moreover, smokers lacking GST genes had both more stenosed vessels and a higher Duke score than smokers expressing the genes. We also examined the levels of DNA damage in 66 men patients using the micronucleus test, a sensitive assay for evaluating chromosome damage. Micronucleus levels were higher in smokers with null genes than in smokers with present genes. These observations suggest that GST-null genotypes strengthen the effect of smoking on CAD risk by modulating the detoxification of genotoxic atherogens.     

Associations of glutathione S-transferase P1, M1, and environmental tobacco smoke with wheezing illness in school children

BACKGROUND: Polymorphisms at the glutathione S-transferase (GST) were associated with asthma-related phenotypes. We hypothesized that the GSTP1 and GSTM1 genotypes could modify the effects of household environmental tobacco smoke (ETS) on childhood wheezing illness. METHODS: We conducted a case-control study comprised of 216 lifetime wheezing children and 185 nonwheezing controls, all of whom were selected from 2524 fourth- to ninth-grade school children in southern Taiwan. RESULTS: Homozygous GSTP1 Ile-105 was significantly associated with current wheezing (OR = 1.78, 95% CI 1.04-3.12), but insignificantly associated with ever wheezing (OR = 1.26, 95% CI 0.82-1.94). The risks of ever or current wheezing on GSTM1 null genotype were positive but not statistically significant. Although household ETS exposure was not associated with wheezing illness, after excluding subjects having in utero ETS or active smoking habits, the adverse effects of household ETS exposure differed significantly by GSTP1-105 genotypes. In children without any ETS exposure at home, GSTP1 Ile-105 homozygosity was significantly related to increased risks for both ever wheezing (OR = 2.29, 95% CI 1.17-4.49) and current wheezing (OR = 4.86, 95% CI 1.86-12.70). In children with household ETS exposure, the risks of wheezing illness did not increase for those carrying two GSTP1 Ile-105 alleles. Children carrying any GSTP1 Val-105 allele were at a significantly greater risk of both ever and current wheezing when exposed to ETS, with a clear dose-response relationship to the number of smokers at home. CONCLUSION: Household ETS exposure is a modifiable cause of wheezing illness in a genetically susceptible subpopulation.     

Glutathione S-transferase Mu null genotype affords protection against alcohol induced chronic pancreatitis

Glutathione S-transferases (GSTs) play critical roles in providing protection against electrophiles and products of oxidative stress, by catalysing the formation of glutathione conjugates and by eliminating peroxides. Most extensively studied are four main families of human cytosolic GST: GSTAlpha(A), GSTMu(M), GSTPi(P) and GSTTheta(T). Absence of GSTM1 or GSTT1 can be attributed to absence of the GSTM1 or GSTT1 gene products (null genotype) in approximately 50% and 20% of the Caucasian population, respectively. We investigated whether polymorphisms in the GSTM1, GSTT1 and GSTP1 genes modified the risk for chronic pancreatitis (CP). DNA samples were obtained from 142 adult CP patients with alcoholic (n = 79), hereditary (n = 21) or idiopathic (n = 42) origin. DNA from 204 healthy controls and from 57 alcoholic controls was analysed for comparison. Patients and controls were all of Caucasian origin. Genetic polymorphisms in GSTs were determined by PCR, eventually followed by restriction-fragment-length-polymorphism analyses in all subjects. The rates of GSTT1 and GSTP1 genotypes did not differ between CP patients and healthy controls. However, GSTM1 null genotypes were significantly less common in alcoholic CP patients (OR = 0.56, 95% CI: 0.33-0.95) as compared to healthy controls and to alcoholic controls (OR = 0.52, 95% CI: 0.26-1.04). Age- and sex-adjustment bolstered our finding (adjusted OR = 0.48, 95% CI: 0.26-0.89). The frequency of the GSTM1 null genotype is significantly lower in alcoholic CP patients, especially young female. This suggests that GSTM1 null alcohol users, particularly young female, are less susceptible to CP.     

Possible risk modification by CYP1A1, GSTM1 and GSTT1 gene polymorphisms in lung cancer susceptibility in a South Indian population

Susceptibility to lung cancer has been shown to be modulated by inheritance of polymorphic genes encoding cytochrome P450 1A1 (CYP1A1) and glutathione S transferases (GSTM1 and GSTT1), which are involved in the bioactivation and detoxification of environmental toxins. As the incidence of lung cancer is known to differ according to ethnicity, we have conducted a case-control study of 146 South Indian lung cancer patients along with 146 healthy controls, to assess any association between CYP1A1, GSTM1 and GSTT1 polymorphisms, either separately or in combination, with the likelihood of development of lung cancer in our population. The current weight of evidence from our study indicated that the frequency of CYP1A1 MspI homozygous variant alleles was significantly higher in cases (OR=3.178). We observed a considerable difference in the GSTT1 null deletion frequency in this population when compared with other populations (OR=2.472, 95% CI: 1.191–5.094, P=0.014). There was no relative risk in GSTM1 null genotype when analysed singly (P=0.453). Considering genotype combinations, risk of lung cancer increased remarkably significantly in individuals having one variant allele of CYP1A1, GSTM1, or GSTT1, suggesting gene–gene interactions. Rare genotypic combinations (such as CYP1A1 wild GSTM1 or GSTT1 either null; CYP1A1 variant both GSTM1 and GSTT1 present; CYP1A1 variant GSTM1 or GSTT1 either null), were at higher risk compared to the reference group. Moreover, patients who had smoked <20 pack years and harboured the CYP1A1 variant allele or the GSTT1 null genotype also had a significant risk of lung cancer. Hence our study—the first to analyse a South Indian population—suggests the importance of combined CYP1A1, GSTM1 and GSTT1 polymorphisms in the development of smoking-induced lung cancer.     

Impact of glutathione S-transferase M1 and T1 gene polymorphisms on the smoking-related coronary artery disease

Glutathione S-transferase (GST) plays a key role in the detoxification of xenobiotic atherogen generated by smoking. To analyze the effect of GSTM1/T1 gene polymorphisms on the development of smoking-related coronary artery disease (CAD), 775 Korean patients who underwent coronary angiography were enrolled. The subjects were classified by luminal diameter stenosis into group A (>50%), B (20-50%), or C (<20%). GSTM1 and GSTT1 gene polymorphisms were analyzed using multiplex polymerase chain reaction (PCR) for GSTM1/T1 genes and CYP1A1 gene for internal control. Of 775 subjects, 403 patients belonged to group A. They had higher risk factors for CAD than group B (N=260) and group C (N=112). The genotype frequencies of null GSTM1 and GSTT1 showed no significant differences among 3 groups. Considering the effect of GSTM1 gene polymorphisms on the smoking-related CAD, smokers with GSTM1 null genotype had more increased risk for CAD than non-smoker with GSTM1 positive genotype (odds ratios [OR], 2.07, confidence interval [CI], 1.06-4.07). Also the effect of GSTT1 gene polymorphism on smoking-related CAD showed the same tendency as GSTM1 gene (OR, 2.00, CI, 1.05-3.84). This effect of GSTM1/T1 null genotype on smoking-related CAD was augmented when both gene polymorphisms were considered simultaneously (OR, 2.76, CI, 1.17-6.52). We concluded that GSTM1/T1 null genotype contributed to the pathogenesis of smoking-related CAD to some degree.     

Genetic and environmental interactions on oral cancer in Southern Thailand

Many countries are interested in understanding the relationship between genetic susceptibility and their prevalent environmental cancers for disease prevention. In Thailand we conducted a population-based case-control study of 53 matched pairs to assess the risk of oral cancer in relation to genetic polymorphism of the glutathione-S-transferase genes (GSTM1 and GSTT1) in cigarette smokers, alcohol drinkers, and betel quid chewers. Interaction of the genes with other potential risk factors such as local bean consumption were also elucidated. Homozygous deletion of GSTM1 has a frequency of 56.6% (n = 30 over 53) among the patients and 30.2% (16/53) among the controls. This gene is associated with a 2.6-fold higher risk for development of oral cancer (95% CI 1.04-6.5). Among the null GSTM1 individuals, those who smoke, consume alcohol, and/or chew betel quid have a significantly increased risk for oral cancer with an odd ratio (OR) = 4.0 (95% CI = 1.2-13.7), OR = 7.2 (95% CI = 1.5-33.8), and OR = 4.4 (95% CI = 1.1-17.8), respectively. Interactions between any two of the lifestyle habits for oral cancer risk, however, are not found. The frequency of the GSTT1 null genotype is 34.0% (18/53) among the patients and 47.2% (25/53) among our controls. There is no association between the GSTT1 null allele and oral cancer risk. In conclusion, our study provides data to indicate that individuals who have homozygous deletion of the GSTM1 gene have increased risk for oral cancer. The risk increases further when these individuals are exposed to environmental toxicants such as chemicals in cigarette smoke, alcohol, and betel quid. These baseline data can be applied to a larger population-based study, both to verify the observation and to conduct mechanistic investigations.     

Genetic polymorphisms in the cytochrome P450 1A1, glutathione S-transferase M1 and T1, and susceptibility to colon cancer

Several polymorphic cytochrome P-450 and glutathione S-transferase (GST) enzymes are involved in the activation and detoxification of many potential carcinogens and may therefore be important in susceptibility to cancer induction. CYP1A1 MspI, GSTM1, and GSTT1 are polymorphic enzymes and some alleles have been correlated with an increased risk of developing some cancers. In the present study, we examined possible associations between genetic polymorphisms of CYP1A1 MspI, GSTM1, and GSTT1 and colon cancer in a United Kingdom population. An excess of CYP1A1 MspI, and GSTM1 null genotypes was observed amongst colon cancer patients, although this did not reach the level of statistical significance. We found no significant increase in the risk of colon cancer for either CYP1A1 MspI (OR = 1.39; 95%CI: 0.46-4.21) or GSTM1 null (OR = 1.41; 95%CI: 0.76-3.01) genotypes. Individuals with GSTT1 null genotype had no association with colon cancer (OR = 0.42; 95%CI: 0.09-2.02). No significant association was observed in the site of colon cancer (proximal vs. distal). This study suggests that the polymorphisms of CYP1A1 MspI, GSTM1, and GSTT1 are not associated with a significant risk of developing colon cancer in a United Kingdom population.     

Glutathione S-transferase T1-null genotype interacts synergistically with heavy smoking on lung cancer risk

We studied the influence of genotype for glutathione S-transferase T1 (GSTT1) on susceptibility to lung cancer among 184 Swedish lung cancer patients (88 never-smokers and 96 ever-smokers) and 162 matched population controls (79 never-smokers and 83 ever-smokers), with special emphasis on gene-environment interactions. Cases had significantly lower frequency of the GSTT1-null genotype than that of controls among never-smokers (4.6 vs. 16.5%, P = 0.02), whereas the frequencies were very close to each other among smokers (7.4 vs. 7.2%). Cases with high packyears of smoking, however, had a significantly higher frequency of the GSTT1-null genotype compared to that of cases with low packyears (18.3 vs. 5.6%, P = 0.005). Adjusted for age and gender, the GSTT1-null genotype appeared to be protective against lung cancer among never-smokers (odds ratio [OR] = 0.2, 95% confidence interval [CI] = 0.07-0.7), although it was associated with an increased risk for lung cancer among smokers (OR = 2.1, 95% CI = 0.8-5.9), mainly attributed to the group of heavy smokers (>23 packyears; OR = 3.5, 95% CI = 0.7-17.3). Heavy smoking conferred a threefold increased risk for lung cancer (OR = 2.6, 95% CI = 1.3-5.0) among GSTT1-positive individuals, but a ninefold increased risk when combined with the GSTT1-null genotype (OR = 9.3, 95% CI = 1.9-46.3, relative to GSTT1-positive light smokers). This joint effect was further demonstrated by a positive interaction between the GSTT1-null genotype and packyears of smoking. The risk of lung cancer increased steeply with increasing packyears among GSTT1-null smokers, whereas no such effect was seen among GSTT1-positive smokers. We conclude that the GSTT1-null genotype may strengthen the effect of heavy smoking on lung cancer risk.     

Association between polymorphisms in the biometabolism genes CYP1A1, GSTM1, GSTT1 and GSTP1 in bladder cancer

Numerous enzymes, including Cytochrome P450s (phase I) and Glutathione-S-transferases (phase II), are involved in the metabolic activation and detoxification of carcinogens. Epidemiological studies have consistently demonstrated that bladder cancer is strongly associated with cigarette smoking, and the risk for the development of this neoplasia may be modified by individual differences in carcinogen-metabolizing genes. We investigated the relationship between polymorphisms in the CYP1A1, GSTM1, GSTT1, and GSTP1 genes in a case–control study with 100 bladder cancer patients and 100 controls matched for age, gender, race, and smoking status. The GSTM1, GSTT1, CYP1A1 (A2455→G), and GSTP1 (A313→G) genotypes were determined using a multiplex PCR, an allele specific PCR, and a restriction fragment length polymorphism-PCR method. The present case–controlled association study did not detect any positive or negative association for the GSTM1 and GSTP1 genes [odds ratios (OR) = 1.35; 95% confidence interval (CI) = 0.76–2.41 and OR = 0.75; 95% CI = 0.41–1.38, respectively]. Notably, the genes GSTT1 and CYP1A1 exhibited a statistically significant association with bladder cancer (OR = 1.77; 95% CI = 1.01–3.12 and OR = 1.99; 95% CI = 1.07–3.73). No differences for GSTM1 and GSTP1 genotype prevalence between the bladder cancer cases and the controls were observed, however, the null genotype for the GSTT1 gene and the A/G and G/G variants of the CYP1A1 gene may contribute to the development of bladder cancer.