TY - JOUR
T1 - Polymorphisms in GSTT1, GSTZ1, AND CYP2E1, disinfection by-products, and risk of bladder cancer in Spain
AU - Cantor, Kenneth P.
AU - Villanueva, Cristina M.
AU - Silverman, Debra T.
AU - Figueroa, Jonine D.
AU - Real, Francisco X.
AU - Garcia-Closas, Monserrat
AU - Malats, Nuria
AU - Chanock, Stephen
AU - Yeager, Meredith
AU - Tardon, Adonina
AU - Garcia-Closas, Reina
AU - Serra, Consol
AU - Carrato, Alfredo
AU - Castaño-Vinyals, Gemma
AU - Samanic, Claudine
AU - Rothman, Nathaniel
AU - Kogevinas, Manolis
PY - 2010/11
Y1 - 2010/11
N2 - Background: Bladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water. Objectives: 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. Methods: 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.Results: 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 (pinteraction = 0.021), GSTZ1 rs1046428 CT/TT versus CC (pinteraction = 0.018), or CYP2E1 rs2031920 CC versus CT/TT (pinteraction = 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.Conclusions: 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.
AB - Background: Bladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water. Objectives: 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. Methods: 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.Results: 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 (pinteraction = 0.021), GSTZ1 rs1046428 CT/TT versus CC (pinteraction = 0.018), or CYP2E1 rs2031920 CC versus CT/TT (pinteraction = 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.Conclusions: 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.
KW - Bladder cancer
KW - Cyp2e1
KW - Disinfection by-products
KW - Drinking water
KW - Gstt1
KW - Gstz1
KW - Trihalomethanes
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U2 - 10.1289/ehp.1002206
DO - 10.1289/ehp.1002206
M3 - Article
C2 - 20675267
AN - SCOPUS:78149343540
SN - 0091-6765
VL - 118
SP - 1545
EP - 1550
JO - Environmental health perspectives
JF - Environmental health perspectives
IS - 11
ER -