GSTM1 Null Polymorphism Research Articles

PXII-25 Diagnosis of congenital cytomegalovirus (CCMV) infection by PCR in dried samples

Due to their ability to metabolize xenobiotics, glutathione S-transferases (GSTs) play an important role in cellular protection. GST family members μ (GSTM1) and θ (GSTT1) exhibit a common polymorphism that results in the complete deletion of the gene (null allele). Homozygous deletions, which result in the absence of the enzyme, are considered a risk factor for several diseases, including cancer. We report a simple, low cost, and high throughput assay for the simultaneous analysis of the GSTM1 and GSTT1 null polymorphisms in a single step. The assay is based on multiplex real-time PCR in the presence of SYBR Green I and genotype discrimination by melting curve analysis in a LightCycler. We have genotyped 792 samples to compare this new approach with conventional PCR followed by gel electrophoresis. Comparison of the methods gave a good agreement, with κ values of 0.88 for GSTM1 and 0.64 for GSTT1. Reanalysis of discrepant samples indicated that absence of amplification of the larger GSTT1 fragment by conventional PCR accounted for most of the discrepancies. Moreover, the improved amplification efficiency of the real-time PCR results in a significant reduction of missing values. Due to its simplicity and low cost, this assay is well suited for the rapid analysis of GST-null genotypes in studies that involve large number of samples.

Genetic polymorphisms of glutathione S-transferase genes GSTP1, GSTM1, and GSTT1 and risk of esophageal and gastric cardia cancers

Glutathione S-transferase (GST) enzymes are known to metabolize tobacco-related carcinogens. Previous studies on the association of functional polymorphisms of GST genes with esophageal squamous cell carcinoma have yielded conflicting but overall null results. A few studies of esophageal adenocarcinoma were likewise conflicting, but the scarcity of data is striking. We aimed to study associations of the GSTM1 and GSTT1 null deletion polymorphisms as well as the GSTP1 Ile105Val polymorphism with risks for esophageal and gastric cardia cancers. DNA was prepared from 96 and 79 cases of esophageal adenocarcinoma and squamous cell carcinoma, respectively, 126 cardia cancer cases, and 471 population-based controls. Pyrosequencing typed the GSTP1 Ile105Val polymorphism, while multiplex PCR detected GSTM1 and GSTT1 deletions. Logistic regression modeling estimated odds ratios (ORs) with 95% confidence intervals (CIs). None of the studied polymorphisms were related to the risk of esophageal adenocarcinoma, but the variant GSTP1 Val(105) allele was associated with an increased risk of esophageal squamous cell carcinoma (OR = 1.7; 95% CI 1.0-2.9) and tended to be weakly, positively linked to cardia cancer (OR = 1.4; 95% CI 0.9-2.1). Finally, we performed a meta-analysis and found that GSTP1 polymorphism seems to be associated with the risk of esophageal squamous cell carcinoma among Caucasian population (OR = 1.4; 95% CI 1.0-2.2; p value for heterogeneity test 0.34).

Polymorphisms in glutathione S-transferase genes increase risk of prostate cancer biochemical recurrence differentially by ethnicity and disease severity

ObjectiveGenetic polymorphisms that modify the detoxifying activity of glutathione S-transferases (GSTs) can affect the level of carcinogenic metabolites created by endogenous steroid hormones and exogenous chemical substances. Although the GSTM1 null genotype has been shown to increase prostate cancer mortality in Caucasians, potential associations between GST polymorphisms and prostate cancer biochemical recurrence (BCR) have not been well studied, particularly in African-Americans.MethodsWe examined potential associations between the GSTM1 null, GSTT1 null and GSTP1 Ile105Val polymorphisms and BCR, after prostatectomy, in 168 African-American and 226 Caucasian patients treated at Henry Ford Hospital in Detroit, Michigan using Cox proportional hazards modeling.ResultsWe found that African-Americans with the GSTT1 null genotype had increased BCR risk compared to those having GSTT1 present (hazard ratio (HR) = 2.30; 95% CI = 1.01–5.18; p = 0.04); and African-Americans with the GSTT1 null genotype and high grade tumors had an even greater risk (HR = 7.82; 95% CI = 2.49–24.50; p < 0.001). In Caucasians, an increased risk was observed in those patients with high grade tumors and the GSTM1 null genotype (HR = 2.88; 95% CI = 1.16–7.14; p = 0.02). Similar associations were observed for advanced stage and more aggressive (high grade or advanced stage) disease.ConclusionOur results suggest GSTs may hold promise as therapeutic targets in more advanced prostate cancers, particularly, in African-Americans.

Glutathione S-Transferase Polymorphisms and Risk of Second Primary Malignancy after Index Squamous Cell Carcinoma of the Head and Neck

Glutathione S-transferases (GST) detoxify carcinogens in tobacco smoke, which plays a major role in development of not only squamous cell carcinoma of the head and neck (SCCHN) but also second primary malignancy (SPM) after index SCCHN. We hypothesized that GSTM1 null, GSTT1 null, GSTP1 Ile(105)Val, and GSTP1 Ala(114)Val polymorphisms would individually and, more likely, collectively show an association with risk of SPM after index SCCHN. One thousand three hundred seventy-six incident SCCHN patients were prospectively recruited between May 1996 and December 2006, genotyped, and followed for SPM development. One hundred ten patients (8%) developed SPM: 43 (39%) second SCCHN, 38 (35%) other tobacco-associated sites, and 29 (26%) other non-tobacco-associated sites. Patients with GSTP1 Ile(105)Val polymorphism had a statistically significant association with risk of SPM development (adjusted hazard ratio, 1.7; 95% confidence interval, 1.1-2.5). However, no statistically significant associations were observed with GSTM1, GSTT1, or GSTP1 Ala(114)Val polymorphisms. After combining risk genotypes for all four polymorphisms, rates of SPM development with 0 to 1, 2, 3, and 4 risk genotypes were 6.4%, 8.4%, 10.9%, and 15.1%, respectively, and a stepwise increase in SPM risk was observed with increasing number of risk genotypes (P = 0.004 for trend). Patients with 3 to 4 risk genotypes had a 1.7-fold increased risk for SPM compared with patients with 0 to 2 risk genotypes (hazard ratio, 1.70; 95% confidence interval, 1.2-2.5). This large prospective cohort study supports a modestly increased risk of SPM after index SCCHN with GSTP1 Ile(105)Val polymorphism and an even greater risk of SPM with multiple combined GST risk genotypes.

Glutathione-S-Transferase and Microsomal Epoxide Hydrolase Polymorphism and Viral-Related Hepatocellular Carcinoma Risk in India

Hepatocellular carcinoma (HCC) is the fourth most common cancer worldwide, the main etiological factors being chronic infections with hepatitis B and C viruses. Genetic polymorphic forms of glutathione-S-transferase (GST) and microsomal epoxide hydrolase (mEPHX) have been associated with risk for various malignancies. The present study was undertaken to evaluate the association of GSTT1 and GSTM1 null genotypes and mEPHX polymorphisms with hepatitis virus-related HCC risk in an Indian population. Three groups of subjects were considered, control (n = 169), chronic viral hepatitis (n = 174), and HCC (n = 63). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for this polymorphic study. Genotype distributions between categories were compared using the chi2 test; odds ratios (ORs) and 95% confidence interval were calculated to express the relative risk. GSTT1 null genotype was associated with 2.23-fold (p < 0.05) increased risk for HCC development as compared to the control group. However, GSTM1 null genotype was found to have a protective effect when hepatitis patients were considered. In case of mEPHX, R139R imposed a risk factor for HCC with both control (OR = 1.81) and chronic hepatitis-infected (OR = 2.06) subjects. Combination of heterozygous mutant genotypes at mEPHX exons 3 and 4 revealed a twofold risk (nonsignificant) for HCC. Further, combination of GSTM1 and T1 genotypes with either of exon 3 or 4 polymorphism of mEPHX displayed synergistic associations (risk or protective) for HCC development. GST and mEPHX variants share a positive association with viral-related HCC risk in Indian population, although a larger sample size is still required to confirm the results.

The role of glutathione- S-transferase polymorphisms on clinical outcome of ALI/ARDS patient treated with N-acetylcysteine

Oxidative stress has a proven role in pathophysiology of acute respiratory distress syndrome. The antioxidant drugs, especially N-acetylcysteine (NAC) have been used for years to overcome oxidative stress effects in patients. In the present study we have investigated the effects of NAC treatment (IV NAC in 150mg/kg at the first day followed by 50mg/kg/day for three days) on 27 ICU patients with ALI/ARDS considering the glutathione-S-transferase genetic variations, as an important enzyme contributing in oxidative stress pathways. The results indicated that NAC improved oxygenation (increase in PaO(2)/FiO(2)) and decreased mortality rate in treated patients compared to control group (p<0.05). Evaluation of three isoforms of glutathione-S-transferase (GST M1, P1 and T1), in these patients have showed an association between GST M1 null, and GST M1 and T1 double null polymorphisms with increased mortality in control group, suggesting antioxidant therapy critical for this group of patients.

THE CYP1A1 AND GSTM1 GENETIC POLYMORPHISMS AND SUSCEPTIBILITY TO ENDOMETRIOSIS IN WOMEN FROM SOUTH INDIA

Background: Endometriosis is one of the most commonly encountered benign problems in gynaecology. It is frequently associated with chronic pelvic pain, dysmenorrhoea, menorrhagia and dyspareunia, which lead to infertility. We determined the possible association between CYP1A1 MspI and GSTM1 null polymorphism in the pathogenesis of endometriosis. Materials and Methods: Ninety seven cases of endometriosis diagnosed by laparoscopy and one hundred two women without endometriosis were laparoscopically confirmed. Genomic DNA of heparinised blood were collected and null gene polymorphisms in GSTM1 and CYP1A1 genes coding for detoxification enzymes were identified by the PCR-based restriction fragment length polymorphism (RFLP) method. Results: The GSTM1 null mutation showed significant association (p<0.03) found between risk of endometriosis and GSTM1 null deletion with an odd ratio (OR) of 2.12, 95% CI: 1.04-4.31.The number of null genotype was more in stage III-IV cases compared to stage I-II. In contrast, we did not find significant association with the CYP1A1 MspI genotype. Conclusion: The study results suggest that women having high risk association with the GSTM1null polymorphism, but no association with the CYP1A1 MspI polymorphism for endometriosis in south Indian women.

Do glutathione-S-transferase polymorphisms influence response to intravenous cyclophosphamide therapy in idiopathic nephrotic syndrome?

The response to cyclophosphamide (CP) is variable and difficult to predict in children with idiopathic nephrotic syndrome (INS). The polymorphic expression of glutathione-S-transferase (GST) may affect the remission rate after CP therapy. In this study, we evaluated the correlation of GST polymorphism and response to CP in INS. We studied GST polymorphism in 74 children with steroid-sensitive (44) and steroid-resistant (30) INS receiving intravenous cyclophosphamide (IVCP) therapy. We correlated GSTM1, GSTT1, and GSTP1 genotypes with response to IVCP. Thirty-seven (50%) out of 74 children responded to CP therapy. A synergistic effect of three genotypic combinations showed significant correlation with remission in the steroid-sensitive group. These combinations were GSTP1 and GSTM1 null genotype (p = 0.013) and GSTP1 together with GSTM1 and GSTT1 null genotypes (p = 0.026). Further, a significant difference was observed with a combination of GSTM1 and GSTT1 null genotypes and Val105 polymorphism. No association was observed among steroid-resistant patients. Our results indicate that among children with steroid-sensitive NS, there is an association with response to IVCP therapy and combination of GSTP1 Val105 polymorphism and the null genotypes of GSTT1 and GSTM1. GST polymorphism may be of significance in the management of children with INS receiving CP therapy.

GSTM1-null polymorphism as possible risk marker for hypertension: Results from the aging and longevity study in the Sirente Geographic Area (ilSIRENTE study)

Background Involvement of various gene mutations in hypertension have been already reported, including GST (detoxification Phase II enzymes), with contrasting results. This study analyzes a possible association between GSTM1-null and GSTT1-null polymorphisms and the hypertension status in a very old population (> 80 years). Methods 354 old patients were collected (255 were hypertensive and 99 were not). Results GSTM1-null individuals ( n = 156) were significantly associated with increased risk of hypertension [OR = 2.25 (1.36–3.72); p = 0.005]. This association was confirmed both in 115 male and 239 female subjects. In contrast, no significant association was observed [ p = 0.52, OR = 1.24 (0.67–2.29)] in the 57 hypertensive GSTT1-null genotypes vs 198 wild-type individuals. The above mentioned significances were obtained by multivariate logistic regression analysis after adjusting for confounder variables. Alcohol consumption and/or smoke habits were not significantly different between the two groups, as well as gender, marital status, education, number of concomitant diseases, and presence of cardiovascular diseases. No synergistic association was observed for the combined null genotypes of GSTT1 and GSTM1. Conclusions The knowledge of GSTM1 variant status seems to be potentially useful to predict a possible hypertensive status after 80 years of age. This study underlines a possible importance of the GSTM1 enzyme for blood pressure regulation.

CYP1A1, mEH, and GSTM1 Polymophisms and Risk of Oral and Pharyngeal Cancer: A Spanish Case-Control Study

Background. Genetic polymorphisms of drug metabolizing enzymes involved in the detoxification pathways of carcinogenic substances may influence cancer risk. Methods. Case-control study that investigates the relationship between CYP1A1 Ile/Val, exon 4 mEH, and GSTM1 null genetic polymorphism and the risk of oral and pharyngeal cancer examining the interaction between these genes, tobacco, and alcohol. 92 incident cases and 130 consecutive hospital-based controls have been included. Results. No significant associations were found for any of the genotypes assessed. The estimated risk was slightly elevated in subjects with the wild type of the mEH gene and the null GSTM1 genotype. For exon 4 mEH heterozygous polymorphism, the risk was slightly lower for heavy smokers than for light smokers. The inverse association was observed for the GSTM1 null genotype. Conclusions. The results suggest that exon 4 mEH and GSTM1 null polymorphisms might influence oral and pharyngeal cancer.

Self-reported skin color, genomic ancestry and the distribution of GST polymorphisms

Skin color and self-reported ethnicity have systematically been used in the pharmacogenetic/-genomic literature as phenotypic proxies for geographical ancestry. Population admixture, however, challenges the appropriateness of this approach. We compared the effectiveness of color-based and marker-based biogeographical ancestry classifications in typing polymorphisms in GSTM1, GSTM3 and GSTT1 in the heterogeneous Brazilian population. Individual DNA from 335 healthy Brazilians was typed for a set of insertion/deletion polymorphisms, previously validated as ancestry informative markers. GSTM1-null and GSTT1-null polymorphisms were detected by multiplex PCR and the GSTM3*B polymorphism by restriction-fragment length polymorphism. Nonlinear logistic regression modeling was developed to describe the association between the GST polymorphisms and ancestry estimated by the ancestry informative markers. Analysis of the ancestry informative markers data with the Structure software revealed the existence of only two significant clusters, one of which was inferred to be an estimate of the African component of ancestry. Nonlinear logistic regression showed that the odds of having the GSTM1-null genotype decreases (P<0.0004, Wald statistics), whereas the odds of having the GSTM3*B allele increases (P<0.0001) with the increase of the African component of ancestry, throughout the range (0.13-0.95) observed in the population sample. The African component of ancestry proportion was not associated with GSTT1-null frequency. Within the self-reported Black and Intermediate groups, there were significant differences in ancestry informative markers between GSTM1-null and non-null individuals, and between carriers and noncarriers of the GSTM3*B allele. Interethnic admixture is a source of cryptic population structure that may lead to spurious genotype-phenotype associations in pharmacogenetic/-genomic studies. Logistic regression modeling of GST polymorphisms shows that admixture must be dealt with as a continuous variable, rather than proportioned in arbitrary subcategories for the convenience of data quantification and analysis.

Pharmacogenetics of Oxazaphosphorines and its Clinical Implications

The oxazaphosphorines including cyclophosphamide and ifosfamide represent an important group of drugs because of their wide use as antitumor and immuno-modulating agents. This review highlights the effects of polymorphisms of genes involved in the action, distribution, metabolism, and transport of oxazaphosphorines on their pharmacokinetic variability and therapeutic outcomes. Emerging data indicate that polymorphisms of genes encoding cytochrome P450 (CYP) enzymes (CYP3A4, CYP2B6, and CYP2C9), aldehyde dehydrogenases (ALDH1A1, ALDH3A1), glutathione S-transferases (GSTT1, GSTM1, GSTP1), multidrug resistance-associated proteins (ABCC1 and ABCC2), and methylgua-nine-DNA methyltransferase (MGMT) play an important role in the wide interindividual pharmacokinetic variability and altered clinical outcome of oxazaphosphorine chemotherapy. For example, CYP2B6*5 (C1459T giving rise to an Arg487Cys substitution) and CYP2C19*2 (C430T) are associated with altered response, toxicity, and survival in patients with proliferative lupus nephritis when treated with pulse cyclophosphamide regimens. In paediatric patients with corticosteroid-sensitive nephrotic syndrome, treatment with cyclophosphamide in patients with a GSTM1 null polymorphism gave a significantly higher rate of sustained remission than in patients with the heterozygous or homozygous GSTM1 wildtype. Preliminary preclinical and clinical studies indicate that a number of genetic polimorphisms can affect the disposition and action of oxazaphosphorines, causing large interpatient variability in their pharmacokineties, response rate and toxicity. A full identification of the role of these genetic polymorphisms would allow the identification of useful and novel strategies to overcome the resistance and toxicity of oxazaphosphorines and to design optimal therapeutic regimens.

Association of GST M1 null polymorphism with Parkinson's disease in a Chilean population with a strong Amerindian genetic component

We have studied the association of a null mutation of Glutathione Transferase M1 (GST M1*0/0) with Parkinson's disease (MIM 168600) in a Chilean population with a strong Amerindian genetic component. We determined the genotype in 349 patients with idiopathic Parkinson's disease (174 female and 175 male; 66.84 ± 10.7 years of age), and compared that to 611 controls (457 female and 254 male; 62 ± 13.4 years of age). A significant association of the null mutation in GST M1 with Parkinson's disease was found ( p = 0.021), and the association was strongest in the earlier age range. An association of GSTM1*0/0 with Parkinson's disease supports the hypothesis that Glutathione Transferase M1 plays a role in protecting astrocytes against toxic dopamine oxidative metabolism, and most likely by preventing toxic one-electron reduction of aminochrome.

GST genotypes and lung cancer susceptibility in Asian populations with indoor air pollution exposures: A meta-analysis

About half of the world's population is exposed to smoke from heating or cooking with coal, wood, or biomass. These exposures, and fumes from cooking oil use, have been associated with increased lung cancer risk. Glutathione S-transferases play an important role in the detoxification of a wide range of human carcinogens in these exposures. Functional polymorphisms have been identified in the GSTM1, GSTT1, and GSTP1 genes, which may alter the risk of lung cancer among individuals exposed to coal, wood, and biomass smoke, and cooking oil fumes. We performed a meta-analysis of 6 published studies (912 cases; 1063 controls) from regions in Asia where indoor air pollution makes a substantial contribution to lung cancer risk, and evaluated the association between the GSTM1 null, GSTT1 null, and GSTP1 105Val polymorphisms and lung cancer risk. Using a random effects model, we found that carriers of the GSTM1 null genotype had a borderline significant increased lung cancer risk (odds ratio (OR), 1.31; 95% confidence interval (CI), 0.95-1.79; p=0.10), which was particularly evident in the summary risk estimate for the four studies carried out in regions of Asia that use coal for heating and cooking (OR, 1.64; 95% CI, 1.25-2.14; p=0.0003). The GSTT1 null genotype was also associated with an increased lung cancer risk (OR, 1.49; 95% CI, 1.17-1.89; p=0.001), but no association was observed for the GSTP1 105Val allele. Previous meta- and pooled-analyses suggest at most a small association between the GSTM1 null genotype and lung cancer risk in populations where the vast majority of lung cancer is attributed to tobacco, and where indoor air pollution from domestic heating and cooking is much less than in developing Asian countries. Our results suggest that the GSTM1 null genotype may be associated with a more substantial risk of lung cancer in populations with coal exposure.

Molecular Epidemiology of Cardiovascular Diseases and Glaucoma

SS3-05 Introduction: Several chronic degenerative diseases share common pathogenic mechanisms such as DNA damage, oxidative stress, and chronic inflammation. Methods: Bulky DNA adducts and 8-oxo-dG were measured by 32P postlabeling in human and rat tissues. Metabolic polymorphisms were evaluated by RFLP-PCR. Results and Discussion: DNA adducts in abdominal aorta smooth muscle cells (SMCs) from 85 atherosclerotic patients were significantly correlated with atherogenic risk factors, including age, number of cigarettes, hypertension, blood triglycerides, and total/high-density lipoprotein cholesterol, fluorescent DNA adducts, and 8-oxo-dG. 8-Oxo-dG levels were 3-fold higher in the aorta inner layer than in the corresponding medium layer. Ethenodeoxyadenosine was significantly higher in SMC from current smokers than in SMC from nonsmokers or former smokers. The 4977-bp mtDNA deletion was detected in aorta SMC. Plasma malondialdehyde was correlated with the number of cigarettes. Plasma homocysteine was higher in 84 atherosclerotic patients than in 74 controls. In atherosclerotic patients, plasma homocysteine was positively correlated with blood triglycerides and inversely correlated with total glutathione and fruit consumption. Moreover, it was increased by homozygosity for slow MTHFR. DNA adducts were increased in patients having a null GSTM1 genotype, whereas GSTT1, NAT1, and NAT2 did neither affect DNA adducts nor 8-oxo-dG. Thrombophilic polymorphisms affected the 4% to 5% of the atherosclerotic patients. Formation of DNA adducts in the thoracic aorta of smoke-exposed rats was modulated by the oral administration of chemopreventive agents. DNA adducts in rodent heart accumulate with age and with exposure to cigarette smoke. The heart was quite sensitive to smoke-induced DNA alterations and was not effective in their removal. Because cardiac myocytes are perennial cells, they are not prone to develop cancer in adults, but occurrence of DNA damage is presumably associated with degenerative conditions. Interestingly, smoke-induced DNA adducts in the rat heart were increased by the simultaneous ingestion of alcohol, whereas they were attenuated by chemopreventive drugs and dietary agents. Glaucoma is the most frequent cause of irreversible blindness worldwide. We demonstrated that a significant increase of 8-oxo-dG correlated with the increase of intraocular pressure and with visual field defects occurs in trabecular meshwork cells of patients with open-angle glaucoma. Both within controls and patients with glaucoma, 8-oxo-dG levels were significantly higher in subjects having a GSTM1-null polymorphism. Conclusions: The results obtained in both humans and animal models suggest that DNA alterations occur not only in cancer but also in cardiovascular diseases and glaucoma.

Comparison of Polymorphisms in Genes Involved in Polycyclic Aromatic Hydrocarbon Metabolism with Urinary Phenanthrene Metabolite Ratios in Smokers

The hypothesis that interindividual differences among smokers in the metabolism of polycyclic aromatic hydrocarbons (PAH) are related to lung cancer risk has been extensively investigated in the literature. These studies have compared lung cancer risk in groups of smokers with or without polymorphisms in genes involved in PAH metabolism. We believe that carcinogen metabolite phenotyping, involving the actual measurement of PAH metabolites, would be a better way to investigate differences in lung cancer risk. With this goal in mind, we have developed methods for quantifying phenanthrene metabolites in urine. Phenanthrene is the simplest PAH with a bay region, a feature closely associated with carcinogenicity. The urinary metabolite r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT) is a measure of metabolic activation, whereas phenanthrols (HOPhe) are a measure of detoxification. In this study, we quantified urinary PheT/HOPhe ratios in 346 smokers who were also genotyped for 11 polymorphisms in genes involved in PAH metabolism: CYP1A1MspI, CYP1A1I462V, CYP1B1R48G, CYP1B1A119S, CYP1B1L432V, CYP1B1N453S, EPHX1Y113H, EPHX1H139R, GSTP1I105V, GSTP1A114V, and GSTM1 null. The geometric mean molar PheT/3-HOPhe ratio was 4.08 (95% confidence interval, 3.79-4.39). Ten percent of the smokers had PheT/3-HOPhe ratios of > or =9.90. We found a significant association between the presence of the CYP1A1I462V polymorphism and high PheT/3-HOPhe ratios (P = 0.02). This effect was particularly strong in females and in combination with the GSTM1 null polymorphism. In contrast, the CYP1B1R48G and CYP1B1A119S polymorphisms were associated with significantly lower PheT/3-HOPhe ratios, particularly in Blacks. There were no consistent significant effects of any of the other polymorphisms on PheT/3-HOPhe ratios. The highest 10% of PheT/3-HOPhe ratios could not be predicted by the presence of any of the 11 polymorphisms individually or by certain combinations. The effects of the CYP1A1I462 polymorphism observed here, particularly in combination with GSTM1 null, are quite consistent with reports in the literature. However, the results of this study indicate that genotyping is not an effective way to predict PAH metabolism at least as represented by PheT/HOPhe ratios.

GSTT1 and GSTM1 polymorphism in cigarette smokers with head and neck squamous cell carcinoma

SummaryGene variability related to carcinogen activation and detoxification may interfere with susceptibility to head and neck cancer.AimTo investigate the relation between GSTT1 and GSTM1 null polymorphisms and the risk of head and neck squamous cell carcinoma in cigarette smokers.Material and MethodA case-control study conducted at the Sao Jose do Rio Preto Medical School, Brazil. GSTM1 and GSTT1 null genotype frequencies were evaluated by multiplex PCR in 45 cigarette smokers with head and neck squamous cell carcinomas and 45 cigarette smokers without this disease.ResultsThe oral cavity was the most prevalent tumor site for squamous cell carcinoma. The GSTT1 null genotype was found in 33.3% of the Experimental Group and 23.3% of the Control Group (p= 0.311). Experimental and Control Groups had GSTM1 null genotype frequencies of 35% and 48.3% (p=0.582). No association between alcohol consumption and GSTT1 and GSTMI null genotypes was found in these groups (p-values>0.05). There were more men, and alcohol consumption was prevalent in both groups.ConclusionIn this study we were unable to show a correlation between GSTM1 and GSTT1 genotypes and the development of head and neck squamous cell carcinomas in cigarette smokers.

Genetic polymorphisms of CYP1A1, CYP2E1, GSTM1, and GSTT1 associated with head and neck cancer

Alcohol intake and tobacco smoke, in addition to other environmental and genetic factors, have been associated with head and neck cancer. We evaluated the role of metabolic enzyme polymorphisms on the risk of head and neck cancer in a hospital-based case-control study. CYP1A1MspI, CYP2E1PstI, GSTM1, and GSTT1polymorphisms were evaluated in 103 histologically confirmed head and neck cancer cases and 102 controls by means of polymerase chain reaction-restriction fragment length polymorphism methods. GSTM1null increased the risk of head and neck cancer (odds ratio [OR], 2.2; 95% confidence interval [95% CI], 1.24-3.79), oral cancer (OR, 2.8; 95% CI, 1.28-5.98), and pharyngeal cancer (OR, 2.2; 95% CI, 1.08-4.63). CYP2E1PstI polymorphism indicated a risk for oral cancer (OR, 3.6; 95% CI, 1.29-11.56). The joint effect of GSTM1 null and CYP1A1 polymorphism increased the risk of head and neck cancer (OR, 2.4; 95% CI, 1.13-5.10). GSTM1 null alone or associated with CYP1A1 increased the risk of head and neck cancer; the CYP2E1PstI mutated allele increased the risk for only oral cancer.

Five glutathione s-transferase gene variants in 23,452 cases of lung cancer and 30,397 controls: meta-analysis of 130 studies.

BackgroundGlutathione S-transferases (GSTs) are known to abolish or reduce the activities of intracellular enzymes that help detoxify environmental carcinogens, such as those found in tobacco smoke. It has been suggested that polymorphisms in the GST genes are risk factors for lung cancer, but a large number of studies have reported apparently conflicting results. Methods and FindingsLiterature-based meta-analysis was supplemented by tabular data from investigators of all relevant studies of five GST polymorphisms ( GSTM1 null, GSTT1 null, I105V, and A114V polymorphisms in the GSTP1 genes, and GSTM3 intron 6 polymorphism) available before August, 2005, with investigation of potential sources of heterogeneity. Included in the present meta-analysis were 130 studies, involving a total of 23,452 lung cancer cases and 30,397 controls. In a combined analysis, the relative risks for lung cancer of the GSTM1 null and GSTT1 null polymorphisms were 1.18 (95% confidence interval [CI]: 1.14–1.23) and 1.09 (95% CI: 1.02–1.16), respectively, but in the larger studies they were only 1.04 (95% CI: 0.95–1.14) and 0.99 (95% CI: 0.86–1.11), respectively. In addition to size of study, ethnic background was a significant source of heterogeneity among studies of the GSTM1 null genotype, with possibly weaker associations in studies of individuals of European continental ancestry. Combined analyses of studies of the 105V, 114V, and GSTM3*B variants showed no significant overall associations with lung cancer, yielding per-allele relative risks of 1.04 (95% CI: 0.99–1.09), 1.15 (95% CI: 0.95–1.39), and 1.05 (95% CI: 0.89–1.23), respectively. ConclusionsThe risk of lung cancer is not strongly associated with the I105V and A114V polymorphisms in the GSTP1 gene or with GSTM3 intron 6 polymorphism. Given the non-significant associations in the larger studies, the relevance of the weakly positive overall associations with the GSTM1 null and the GSTT1 null polymorphisms is uncertain. As lung cancer has important environmental causes, understanding any genetic contribution to it in general populations will require the conduct of particularly large and comprehensive studies.

GSTM1 polymorphism and oral leukoplakia

Molecular epidemiological studies have now provided evidence that an individual susceptibility to cancer is mediated by genetic and environmental factors. Genetic polymorphisms have been described for enzymes involved in the metabolism of tobacco carcinogens and cancer risk is determined by the degree of expression and/or activity of enzymes involved in carcinogen activation or deactivation. The objective of this study was to investigate the GSTM1 null polymorphism and the risk for oral leukoplakia in individuals with tobacco-smoking habit in a Brazilian population. A total of 52 tobacco-smoking patients with oral leukoplakia and 52 tobacco-smoking controls were recruited in a Brazilian population. The GSTM1 genotypes were studied by polymerase chain reaction-based methods. The frequency of the GSTM1 null genotype in the group with oral leukoplakia (57.7%) was statistically different from the controls (34.6%; OR: 2.57, 95% CI: 1.16-5.69, P < 0.05). The stratification of the samples according to the level of dysplasia showed increased prevalence of GSTM1 null genotype on lesions with moderate/severe histological dysplasia (68.2%) compared with the control group (31.9%). This difference was statistically significant (OR: 4.59, 95% CI: 1.29-16.33, P < 0.05). In conclusion, the GSTM1 null genotype may increase the risk for oral leukoplakia development.