Genome-wide interaction analysis of long-term trihalomethane exposure in drinking water and colorectal cancer risk in a Spanish Multicenter Case-Control Study (MCC-Spain)

We conducted a genome-wide interaction analysis between long-term exposure to trihalomethanes in drinking water and colorectal cancer (CRC) risk in a multicenter case-control study in Spain, including 1037 CRC cases and 2100 controls. Exposure categories were estimated based on sex-specific median a...

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Bibliographic Details
Authors: Moratalla Navarro, Ferran, Obón Santacana, Mireia, Rius Sansalvador, Blanca, Guinó, Elisabet, Moragas, Núria, Donat Vargas, Carolina, Fernández de Larrea-Baz, Nerea, Molina Barceló, Ana, Guevara, Marcela, Morón-Duran, Francisco D, Dierssen Sotos, Trinidad, Tardón, Adonina, Castaño-Vinyals, Gemma, Cabrera Castro, Natalia, Molina, Antonio J., Aizpurua Atxega, Amaia, Morales Suárez Varela, María M., Martín, Vicente, Fernández Navarro, Pablo, Villanueva, Cristina M., Moreno Aguado, Víctor
Format: article
Status:Published version
Publication Date:2026
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:dnet:ubarcelona__::360c159c0f19f6264b48037c6f3e2875
Online Access:https://hdl.handle.net/2445/228965
Access Level:Open access
Keyword:Aigua potable
Contaminants orgànics de l'aigua
Càncer colorectal
Drinking water
Organic water pollutants
Colorectal cancer
Description
Summary:We conducted a genome-wide interaction analysis between long-term exposure to trihalomethanes in drinking water and colorectal cancer (CRC) risk in a multicenter case-control study in Spain, including 1037 CRC cases and 2100 controls. Exposure categories were estimated based on sex-specific median and quartile values of total trihalomethanes (TTHM), chloroform (CHCl3), and brominated trihalomethanes (Br-THMs) among controls. In addition, TTHM exposure was assessed relative to the WHO guideline thresholds. Gene-environment interaction models were computed with the GxEScanR package. To explore biological plausibility, relevant results were inspected in search of expression quantitative trait loci (eQTLs) in two independent resources: BarcUVaSeq and the Genome Tissue Expression (GTEx) v8. Finally, we searched the Comparative Toxicogenomics Database to identify candidate genes previously linked to trihalomethane exposure, retrieved their eQTLs, and evaluated gene-environment interactions with TTHM levels. We found three variants that modulated CRC risk in relation to CHCl3 and TTHM exposure: rs77985109 near LRRC8B, chr15:28997737 near WHAMMP2, and rs7890183 near MAGEB2. Two additional variants were specifically found for women and one for rectal cancer. Functional assessment suggested a regulatory role of rs77985109 in LRRC8B expression. Moreover, eQTL analysis of candidate genes revealed an additional variant associated with CCL2 which could modulate CRC risk under different TTHM exposure levels. The present study identified novel loci potentially influencing CRC susceptibility under THM exposure, highlighting the importance of integrating environmental and genetic data to better understand environmental driven cancer risks. Further research is needed to confirm these results and clarify underlying mechanisms.

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