Dataset Information

Polymorphisms in GSTT1, GSTZ1, and CYP2E1, disinfection by-products, and risk of bladder cancer in Spain.

ABSTRACT: Bladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water.In this study we investigated the combined influence of DBP exposure and polymorphisms in glutathione S-transferase (GSTT1, GSTZ1) and cytochrome P450 (CYP2E1) genes in the metabolic pathways of selected by-products on bladder cancer in a hospital-based case-control study in Spain.Average exposures to trihalomethanes (THMs; a surrogate for DBPs) from 15 years of age were estimated for each subject based on residential history and information on municipal water sources among 680 cases and 714 controls. We estimated effects of THMs and GSTT1, GSTZ1, and CYP2E1 polymorphisms on bladder cancer using adjusted logistic regression models with and without interaction terms.THM exposure was positively associated with bladder cancer: adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 1.2 (0.8-1.8), 1.8 (1.1-2.9), and 1.8 (0.9-3.5) for THM quartiles 2, 3, and 4, respectively, relative to quartile 1. Associations between THMs and bladder cancer were stronger among subjects who were GSTT1 +/+ or +/- versus GSTT1 null (P(interaction) = 0.021), GSTZ1 rs1046428 CT/TT versus CC (P(interaction) = 0.018), or CYP2E1 rs2031920 CC versus CT/TT (P(interaction) = 0.035). Among the 195 cases and 192 controls with high-risk forms of GSTT1 and GSTZ1, the ORs for quartiles 2, 3, and 4 of THMs were 1.5 (0.7-3.5), 3.4 (1.4-8.2), and 5.9 (1.8-19.0), respectively.Polymorphisms in key metabolizing enzymes modified DBP-associated bladder cancer risk. The consistency of these findings with experimental observations of GSTT1, GSTZ1, and CYP2E1 activity strengthens the hypothesis that DBPs cause bladder cancer and suggests possible mechanisms as well as the classes of compounds likely to be implicated.

SUBMITTER: Cantor KP

PROVIDER: S-EPMC2974691 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Polymorphisms in GSTT1, GSTZ1, and CYP2E1, disinfection by-products, and risk of bladder cancer in Spain.

Cantor Kenneth P KP Villanueva Cristina M CM Silverman Debra T DT Figueroa Jonine D JD Real Francisco X FX Garcia-Closas Monserrat M Malats Nuria N Chanock Stephen S Yeager Meredith M Tardon Adonina A Garcia-Closas Reina R Serra Consol C Carrato Alfredo A Castaño-Vinyals Gemma G Samanic Claudine C Rothman Nathaniel N Kogevinas Manolis M

Environmental health perspectives 20101101 11

<h4>Background</h4>Bladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water.<h4>Objectives</h4>In this study we investigated the combined influence of DBP exposure and polymorphisms in glutathione S-transferase (GSTT1, GSTZ1) and cytochrome P450 (CYP2E1) genes in the metabolic pathways of selected by-products on bladder cancer in a hospital-based case-control study in Spain.<h4>Methods</h4>Average exposures to trihalomethanes (THMs; a surrogate ...[more]

PMID: 20675267

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Project description:BackgroundBy-products are formed when disinfectants react with organic matter in source water. The most common class of disinfection by-products, trihalomethanes (THMs), have been linked to bladder cancer. Several studies have shown exposure-response associations with THMs in drinking water and bladder cancer risk. Few epidemiologic studies have evaluated gene-environment interactions for total THMs (TTHMs) with known bladder cancer susceptibility variants.ObjectivesIn this study, we investigated the combined effect on bladder cancer risk contributed by TTHMs, bladder cancer susceptibility variants identified through genome-wide association studies, and variants in several candidate genes.MethodsWe analyzed data from two large case-control studies-the New England Bladder Cancer Study (n/n=989 cases/1,162 controls), a population-based study, and the Spanish Bladder Cancer Study (n/n=706 cases/772 controls), a hospital-based study. Because of differences in exposure distributions and metrics, we estimated effects of THMs and genetic variants within each study separately using adjusted logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CI) with and without interaction terms, and then combined the results using meta-analysis.ResultsOf the 16 loci showing strong evidence of association with bladder cancer, rs907611 at 11p15.5 [leukocyte-specific protein 1 (LSP1 region)] showed the strongest associations in the highest exposure category in each study, with evidence of interaction in both studies and in meta-analysis. In the highest exposure category, we observed OR=1.66 (95% CI: 1.17, 2.34, p-trend=0.005) for those with the rs907611-GG genotype and p-interaction=0.02. No other genetic variants tested showed consistent evidence of interaction.DiscussionWe found novel suggestive evidence for a multiplicative interaction between a putative bladder carcinogen, TTHMs, and genotypes of rs907611. Given the ubiquitous exposure to THMs, further work is needed to replicate and extend this finding and to understand potential molecular mechanisms. https://doi.org/10.1289/EHP9895.

Dataset Information

Polymorphisms in GSTT1, GSTZ1, and CYP2E1, disinfection by-products, and risk of bladder cancer in Spain.

Publications

Polymorphisms in GSTT1, GSTZ1, and CYP2E1, disinfection by-products, and risk of bladder cancer in Spain.

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