Disinfection By-Products in Drinking Water and Bladder Cancer: Evaluation of Risk Modification by Common Genetic Polymorphisms in Two Case-Control Studies

Laura E Beane Freeman, Manolis Kogevinas, Kenneth P Cantor, Cristina M Villanueva, Ludmila Prokunina-Olsson, Oscar Florez-Vargas, Jonine D Figueroa, Mary H Ward, Stella Koutros, Dalsu Baris, Montserrat Garcia-Closas, Molly Schwenn, Allison Johnson, Consol Serra, Adonina Tardon, Reina Garcia-Closas, Alfredo Carrato, Nuria Malats, Margaret R Karagas, Nathaniel RothmanDebra T Silverman

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

BACKGROUND: By-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.

OBJECTIVES: In 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.

METHODS: We 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.

RESULTS: Of 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.

DISCUSSION: We 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.

Original languageEnglish
Pages (from-to)57006
JournalEnvironmental Health Perspectives
Issue number5
Publication statusPublished - 10 May 2022

Keywords / Materials (for Non-textual outputs)

  • Case-Control Studies
  • Disinfectants/analysis
  • Disinfection
  • Drinking Water
  • Female
  • Genome-Wide Association Study
  • Humans
  • Logistic Models
  • Male
  • Polymorphism, Genetic
  • Trihalomethanes/analysis
  • Urinary Bladder Neoplasms/chemically induced
  • Water Pollutants, Chemical/analysis


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