Polymorphisms in GSTT1, GSTZ1, and CYP2E1, disinfection by-products, and risk of bladder cancer in Spain.
BACKGROUND
Bladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water.


OBJECTIVE
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 (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.


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.
Cantor
Kenneth P
KP
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892-7240, USA. cantork@nih.gov
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
D000328:Adult; D004202:Disinfectants / Q000633:toxicity*; D004203:Disinfection; D004781:Environmental Exposure / Q000032:analysis / Q000706:statistics & numerical data; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013030:Spain / Q000453:epidemiology; D022882:Trihalomethanes / Q000633:toxicity*; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics*; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D014881:Water Supply / Q000032:analysis / Q000706:statistics & numerical data
D004202:Disinfectants; D022882:Trihalomethanes; D014874:Water Pollutants, Chemical