Background: Human genetic polymorphisms in metabolic activation and detoxification pathways are a major source of inter-individual variation in susceptibility to environmentally induced disease.Accomplishments:1.Our recent study suggested that glutathione S-transferases M1 and T1 (GSTM1/GSTT1) mediate the risk of coronary heart disease through exposure to smoking. Since GSTs are able to detoxify numerous products of oxidative stress, we hypothesize that GST genotypes may modify smoking-induced chronic inflammatory response. A cross-sectional analysis, using a subset of participants in a large (n=15,792) biracial cohort, was used to measure the mean levels of 9 markers of inflammation by different combinations of GST genotypes and smoking status. Smoking more than 20 pack-years was found to be associated with significant higher levels of ICAM-1, white blood cell count (WBC) , fibrinogen , C-reactive protein (CRP) [Geometric Mean Ratio=1.6 (95%CI 1.0, 2.5)], and lower levels of albumin [D=-0.09g/dl ]. Participants with the GSTM1 null genotype and more than 20 pack-years of smoking had the highest mean levels of fibrinogen, CRP, ICAM-1, VCAM-1, and von Willebrand factor and lowest mean levels of albumin. In contrast, participants who had the GSTT1 functional allele (GSTT1-1) genotype and smoked ? 20 pack-years had the highest mean levels of only fibrinogen and CRP. The results of this study suggest that GSTM1 and GSTT1 polymorphisms modify the effect of smoking on chronic inflammation.2. We have followed up our finding linking GST genotypes to smoking-induced cardiovascular disease by examining how GST genotypes modify risk for an early markers of atherosclerosis (corotid intermedial thickness, IMT). IMT determined by B-mode ultrasound in asymptomatic individuals was used as an index of generalized atherosclerosis. We tested 526 cases with mean IMT >0.935 mm and 868 non-cases for GSTM1 and GSTT1 null genotype. We found evidence for a smoking and gluthathione s-transferase gene interaction in the development of thickened corotid arteries. There was a suggestion of an interaction between the functional GSTT1-1 genotype (GSTT-1) and heavy smoking (>20 pack-years & GSTT1-1, odds ratio = 4.7, 95% confidence interval [CI]=1.9-11.8; >20 pack-years & GSTT1-0 OR=1.7, CI=0.5-5.5; non-smokers & GSTT1-1 OR=0.7; CI=0.3-1.5).3. DNA damage from polycyclic aromatic hydrocarbons (PAH) has been implicated as a risk factor for lung cancer, as have common polymorphisms in the glutathione S-transferase (GST) genes involved in carcinogen detoxification. In this matched case-control study nested within the prospective Physicians Health Study, we evaluated whether biomarkers measured in white blood cells (WBC) significantly predicted risk. Aromatic/hydrophobic-DNA adducts and polymorphisms in GSTM1 and GSTP1 genes were analyzed in 89 cases of primary lung cancer and 173 controls, matched in a 1:2 ratio on smoking, age, and duration of follow up. Among current smokers, adducts were significant predictors of lung cancer risk (after adjusting for GST genotypes, OR=3.10, 95% CI 1.07, 9.01). The combined GSTM1 null / GSTP1 Val genotype was associated with lung cancer overall and especially among former smokers, before and after adjusting for adducts (OR for former smokers = 4.21, CI 1.08, 16.41; adjusted OR=4.68, CI 1.17, 18.71). Among cases only, adducts were significantly higher among current or former smokers with the GSTM1 non-null / GSTP1 Ile genotype. The two risk factors (adducts and genotypes) appear to be independent predictors of risk. The findings underscore the complex and important role of biological susceptibility as a determinant of risk from carcinogens found in tobacco smoke and other environmental compounds.4. Permanent hair dyes and bladder cancer: risk modification by cytochrome P4501A2 and N-acetyltransferases 1 and 2. Genetic variation in N-acetyltransferase-1 (NAT1), NAT2, glutathione S-transferase-M1, -T1 and -P1 (GSTM1/ T1/P1), and cytochrome P 450 1A2 (CYP1A2), can also potentially affect the hair dye-bladder cancer relationship due to their participation in the metabolism of arylamines, the putative carcinogenic substances in hair dyes. These genotypes were assessed in 159 (70%) female case patients and 164 (74%) female control subjects who participated in the Los Angeles case-control study. Among NAT2 slow acetylators, permanent hair dye use was associated with a 2.9 fold (95% CI = 1.2, 7.5) increased risk of bladder cancer. Among lifelong nonsmoking women, individuals exhibiting the non-NAT1*10 genotype show a statistically significant increase in bladder cancer risk associated with permanent hair dye use (RR = 6.8, 95% CI = 1.7, 27.4). Frequency- and duration-related dose-response relationships confined to individuals possessing the non-NAT1*10 genotype were positive and statistically significant suggesting that NAT1*10 genotype may protect against hair dye-induced bladder cancer.5. Glutathione transferases and CYP2E1 metabolize compounds (e.g., polycyclic aromatic hydrocarbons, solvents) that may play a role in the etiology of brain cancer. We evaluated associations between polymorphisms in GSTM1, GSTT1, GSTP I105V, GSTP A114V, CYP2E1 RsaI, and CYP2E1 (Ins96) in 782 patients with brain tumors and 799 controls. The GSTP1 105 Val/Val variant was associated with increased glioma incidence (odds ratio [OR]=1.8, 95% confidence limits [CL]: 1.2, 2.7). The CYP2E1 RsaI variant was weakly associated with the incidence of glioma (OR=1.4, 95% CL: 0.9, 2.4) and acoustic neuroma (OR=2.3, 95% CL: 1.0, 5.3). Previously observed associations between the GSTT1 genotype and glioma incidence were not replicated in this study, but a weak association with meningioma was observed (OR=1.5, 95% CL: 1.0, 2.3). If replicated in other populations, these findings may provide clues to both the genetic and environmental determinants of brain tumors.6. XRCC1 Polymorphisms and Head and Neck Cancer. A recent case-control study of squamous cell carcinoma of the head and neck (SCCHN) reported associations with two polymorphisms ( exon 6, Arg194Trp and exon 10, Arg399Gln) of the XRCC1 DNA repair gene. We conducted an analysis of these two XRCC1 polymorphisms using data from a hospital-based case-control study (160 SCCHN cases and 184 controls). We found no association with the Arg194Trp polymorphism [odds ratio (OR)= 1.1; 95% confidence interval (CI)= 0.5- 2.2] and a statistically significant decreased risk for the Arg399Gln polymorphism (OR=0.6; CI=0.3- 0.9). We also found that heavy smokers with the 399 Arg/Arg genotype had a two-fold greater risk in comparison to heavy smokers with the 399 Arg/Gln or Gln/Gln genotypes. 7. We used a prospective cohort study of 190 incident cases of SCCHN with an estimated median survival of 42 months to evaluate the prognostic ability of lifetime consumption of tobacco and alcohol, polymorphisms of carcinogen metabolizing enzymes GSTT1, GSTM1, GSTP1, and NAT1, and polymorphisms of the DNA repair gene XRCC1 for three clinical endpoints: all-cause mortality, disease-specific mortality, and locoregional recurrence for patients diagnosed with squamous cell carcinoma of the head and neck (SCCHN). Neither lifetime dose nor duration of tobacco or alcohol was prognostic for any outcome (Hazard Ratio (HR) 0.83 (95% CI 0.27, 2.60). Individuals without the GSTT1 null genotype were twice as likely to die from any cause (HR 2.4 95% CI 1.13, 4.97) and were three times as likely to die from SCCHN (HR 3.4 95% CI 1.33, 8.41). Individuals with the XRCC1 399 Gln genotype were less likely to develop a locoregional recurrence (HR 0.38 95% CI 0.18, 0.81). If confirmed these results suggest that markers of carcinogen metabolism and DNA repair capability may serve a role as prognostic indicators of disease recurrence and death.
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