Polymorphisms in GSTT1 and GSTZ1 modify bladder cancer risk associated with exposure to disinfection byproducts in drinking water Free

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Bladder cancer risk has been linked in several studies with exposure to disinfection byproducts (DBP), a complex mixture of halogenated compounds found in chlorinated drinking water. Two major chemical families of the mixture are trihalomethanes and haloacetic acids. Experimental evidence shows activation of brominated trihalomethanes (THM) by GSTT1 and detoxification of haloacetic acids by GSTZ1. We hypothesized that polymorphisms in these genes may modify the risk posed by DBP, and investigated this in a large case-control study in Spain where elevated risk associated with DBP has been reported.

Methods: We created individual exposure profiles to DBP by combining information from residential histories from a personal interview with separately gathered historical water utility data. DBP exposure was estimated by the average household trihalomethane (THM) level from age 15 to interview. We investigated the joint effects on bladder cancer risk of THM exposure and polymorphisms in GSTT1 and GSTZ1 as well as two polymorphisms previously associated with bladder cancer in this study, NAT2 and GSTM1. The independent and joint relative risks of these factors were estimated by odds ratios (OR) from logistic regression models.

Results: After exclusions for incomplete THM and/or genetic data, 680 cases and 714 controls were available for analysis. Independent of THM exposure, subjects with at least one non-deleted GSTT1 allele (+/+ or +/-) or one or two copies of the variant allele for GSTZ1 M82T (Exon7+29C>T, rs 1046428)) showed small and non-significant increases in risk (OR (95%CI)=1.2 (0.9-1.6) and 1.1 (0.8-1.3), respectively). Risk increased with increasing average THM level: OR(CI)=1.2 (0.8-1.8), 1.8 (1.1-2.9), and 1.8 (0.9-3.5) for THM quartiles 2,3,& 4 relative to quartile 1 (p(trend)=0.029). Among subjects carrying both GSTT1 +/+ or +/- and GSTZ1 variant, ORs for increasing THM quartiles relative to quartile 1 were 1.2 (0.5-3.1), 2.9 (1.1-8.2), and 6.2 (1.5-25.8) (p(trend)=0.0059), whereas for subjects with both GSTT1 (-/-) and the GSTZ1 wildtype, ORs were 1.0 (0.3-3.6), 0.97 (0.2-4.0), and 1.3 (0.2-8.2) (p(trend)=0.90). A significant interaction was observed between THM level and combined GSTT1+/+ or +/- and GSTZ1 (p=0.0019). Statistically significant interactions for risk were also found between THM level and GSTT1 and GSTZ1 polymorphisms, considered individually. No interaction was found between THM and either GSTM1 or NAT2 polymorphisms.

Conclusion: This large bladder cancer study suggests that polymorphisms in key metabolizing enzymes for two major chemical families of DBP may modify the risk associated with this common exposure.