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

Kenneth P. Cantor, Cristina M. Villanueva, Debra T. Silverman, Jonine D. Figueroa, Francisco X. Real, Monserrat Garcia-Closas, Nuria Malats, Stephen Chanock, Meredith Yeager, Adonina Tardon, Reina Garcia-Closas, Consol Serra, Alfredo Carrato, Gemma Castaño-Vinyals, Claudine Samanic, Nathaniel Rothman, Manolis Kogevinas

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1545-1550
Number of pages6
JournalEnvironmental Health Perspectives
Volume118
Issue number11
DOIs
StatePublished - Nov 2010
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP2E1
Disinfection
Urinary Bladder Neoplasms
Spain
Trihalomethanes
Logistic Models
Odds Ratio
Metabolic Networks and Pathways
Drinking Water
Cytochrome P-450 Enzyme System
Case-Control Studies
History
Confidence Intervals
Water
Enzymes
Genes

Keywords

  • Bladder cancer
  • Cyp2e1
  • Disinfection by-products
  • Drinking water
  • Gstt1
  • Gstz1
  • Trihalomethanes

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Public Health, Environmental and Occupational Health

Cite this

Cantor, K. P., Villanueva, C. M., Silverman, D. T., Figueroa, J. D., Real, F. X., Garcia-Closas, M., ... Kogevinas, M. (2010). Polymorphisms in GSTT1, GSTZ1, AND CYP2E1, disinfection by-products, and risk of bladder cancer in Spain. Environmental Health Perspectives, 118(11), 1545-1550. https://doi.org/10.1289/ehp.1002206

Polymorphisms in GSTT1, GSTZ1, AND CYP2E1, disinfection by-products, and risk of bladder cancer in Spain. / Cantor, Kenneth P.; Villanueva, Cristina M.; Silverman, Debra T.; Figueroa, Jonine D.; Real, Francisco X.; Garcia-Closas, Monserrat; Malats, Nuria; Chanock, Stephen; Yeager, Meredith; Tardon, Adonina; Garcia-Closas, Reina; Serra, Consol; Carrato, Alfredo; Castaño-Vinyals, Gemma; Samanic, Claudine; Rothman, Nathaniel; Kogevinas, Manolis.

In: Environmental Health Perspectives, Vol. 118, No. 11, 11.2010, p. 1545-1550.

Research output: Contribution to journalArticle

Cantor, KP, Villanueva, CM, Silverman, DT, Figueroa, JD, Real, FX, Garcia-Closas, M, Malats, N, Chanock, S, Yeager, M, Tardon, A, Garcia-Closas, R, Serra, C, Carrato, A, Castaño-Vinyals, G, Samanic, C, Rothman, N & Kogevinas, M 2010, 'Polymorphisms in GSTT1, GSTZ1, AND CYP2E1, disinfection by-products, and risk of bladder cancer in Spain', Environmental Health Perspectives, vol. 118, no. 11, pp. 1545-1550. https://doi.org/10.1289/ehp.1002206
Cantor KP, Villanueva CM, Silverman DT, Figueroa JD, Real FX, Garcia-Closas M et al. Polymorphisms in GSTT1, GSTZ1, AND CYP2E1, disinfection by-products, and risk of bladder cancer in Spain. Environmental Health Perspectives. 2010 Nov;118(11):1545-1550. https://doi.org/10.1289/ehp.1002206
Cantor, Kenneth P. ; Villanueva, Cristina M. ; Silverman, Debra T. ; Figueroa, Jonine D. ; Real, Francisco X. ; Garcia-Closas, Monserrat ; Malats, Nuria ; Chanock, Stephen ; Yeager, Meredith ; Tardon, Adonina ; Garcia-Closas, Reina ; Serra, Consol ; Carrato, Alfredo ; Castaño-Vinyals, Gemma ; Samanic, Claudine ; Rothman, Nathaniel ; Kogevinas, Manolis. / Polymorphisms in GSTT1, GSTZ1, AND CYP2E1, disinfection by-products, and risk of bladder cancer in Spain. In: Environmental Health Perspectives. 2010 ; Vol. 118, No. 11. pp. 1545-1550.
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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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