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)

Moratalla-Navarro, F.; Obón-Santacana, M.; Rius-Sansalvador, B.; Guinó, E.; Moragas, N.; Donat-Vargas, C.; de Larrea-Baz, N.F.; Molina-Barceló, A.; Guevara, M.; Morón-Duran, F.D.; Dierssen-Sotos, T.; Tardón, A.; Castaño-Vinyals, G.; Cabrera-Castro, N.; Molina, A.J.; Aizpurua, A.; Morales-Suárez-Varela, M.M.; Martín, V.; Fernández-Navarro, P.; Villanueva, C.M.; Moreno, V.

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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Autores:	Moratalla-Navarro, F., Obón-Santacana, M., Rius-Sansalvador, B., Guinó, E., Moragas, N., Donat-Vargas, C., de Larrea-Baz, N.F., Molina-Barceló, A., Guevara, M., Morón-Duran, F.D., Dierssen-Sotos, T., Tardón, A., Castaño-Vinyals, G., Cabrera-Castro, N., Molina, A.J., Aizpurua, A., Morales-Suárez-Varela, M.M., Martín, V., Fernández-Navarro, P., Villanueva, C.M., Moreno, V.
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2026
País:	España
Institución:	Universidad de Málaga
Repositorio:	r-FISABIO. Repositorio Institucional de Producción Científica
OAI Identifier:	oai:dnet:r-fisabio___::f4a5068ede516eed7b6a0abc6a613be2
Acceso en línea:	https://fisabio.portalinvestigacion.com/publicaciones/20347 https://www.scopus.com/inward/record.uri?eid=2-s2.0-105027546033&doi=10.1016%2fj.envint.2026.110059&partnerID=40&md5=5b470a79ce60ff59d1850c8bfdef4ab1
Access Level:	acceso abierto
Palabra clave:	Colorectal Cancer Drinking water Gene-environment interaction Trihalomethanes Aged Case-Control Studies Colorectal Neoplasms Drinking Water Environmental Exposure Female Gene-Environment Interaction Genome-Wide Association Study Humans Male Middle Aged Quantitative Trait Loci Spain Water Pollutants, Chemical Chlorine compounds Diseases Environmental impact Gene expression Proteomics Risk analysis Risk assessment chloroform drinking water nonsteroid antiinflammatory agent trihalomethane Cancer risk Candidate genes Case-control study Colorectal cancer Interaction analysis Interaction modeling Long term exposure Quantitative trait locus cancer comparative study genome guideline health geography health impact health risk quantitative analysis research work threshold volatile organic compound World Health Organization adult Article blood s

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spelling	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)Moratalla-Navarro, F.Obón-Santacana, M.Rius-Sansalvador, B.Guinó, E.Moragas, N.Donat-Vargas, C.de Larrea-Baz, N.F.Molina-Barceló, A.Guevara, M.Morón-Duran, F.D.Dierssen-Sotos, T.Tardón, A.Castaño-Vinyals, G.Cabrera-Castro, N.Molina, A.J.Aizpurua, A.Morales-Suárez-Varela, M.M.Martín, V.Fernández-Navarro, P.Villanueva, C.M.Moreno, V.Colorectal CancerDrinking waterGene-environment interactionTrihalomethanesAgedCase-Control StudiesColorectal NeoplasmsDrinking WaterEnvironmental ExposureFemaleGene-Environment InteractionGenome-Wide Association StudyHumansMaleMiddle AgedQuantitative Trait LociSpainTrihalomethanesWater Pollutants, ChemicalSpainChlorine compoundsDiseasesEnvironmental impactGene expressionProteomicsRisk analysisRisk assessmentchloroformdrinking waternonsteroid antiinflammatory agenttrihalomethanetrihalomethaneCancer riskCandidate genesCase-control studyColorectal cancerGene-environment interactionInteraction analysisInteraction modelingLong term exposureQuantitative trait locusTrihalomethanescancercomparative studydrinking watergenomeguidelinehealth geographyhealth impacthealth riskquantitative analysisresearch workthresholdvolatile organic compoundWorld Health OrganizationadultArticleblood sWe 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. Copyright © 2026. Published by Elsevier Ltd.PERGAMON-ELSEVIER SCIENCE LTD2026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fisabio.portalinvestigacion.com/publicaciones/20347https://www.scopus.com/inward/record.uri?eid=2-s2.0-105027546033&doi=10.1016%2fj.envint.2026.110059&partnerID=40&md5=5b470a79ce60ff59d1850c8bfdef4ab1ENVIRONMENT INTERNATIONALISSN: 01604120ISSNe: 18736750reponame:r-FISABIO. Repositorio Institucional de Producción Científicainstname:Universidad de MálagaInglésinfo:eu-repo/semantics/openAccessoai:dnet:r-fisabio___::f4a5068ede516eed7b6a0abc6a613be22026-06-11T12:45:17Z
dc.title.none.fl_str_mv	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)
title	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)
spellingShingle	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) Moratalla-Navarro, F. Colorectal Cancer Drinking water Gene-environment interaction Trihalomethanes Aged Case-Control Studies Colorectal Neoplasms Drinking Water Environmental Exposure Female Gene-Environment Interaction Genome-Wide Association Study Humans Male Middle Aged Quantitative Trait Loci Spain Trihalomethanes Water Pollutants, Chemical Spain Chlorine compounds Diseases Environmental impact Gene expression Proteomics Risk analysis Risk assessment chloroform drinking water nonsteroid antiinflammatory agent trihalomethane trihalomethane Cancer risk Candidate genes Case-control study Colorectal cancer Gene-environment interaction Interaction analysis Interaction modeling Long term exposure Quantitative trait locus Trihalomethanes cancer comparative study drinking water genome guideline health geography health impact health risk quantitative analysis research work threshold volatile organic compound World Health Organization adult Article blood s
title_short	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)
title_full	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)
title_fullStr	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)
title_full_unstemmed	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)
title_sort	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)
dc.creator.none.fl_str_mv	Moratalla-Navarro, F. Obón-Santacana, M. Rius-Sansalvador, B. Guinó, E. Moragas, N. Donat-Vargas, C. de Larrea-Baz, N.F. Molina-Barceló, A. Guevara, M. Morón-Duran, F.D. Dierssen-Sotos, T. Tardón, A. Castaño-Vinyals, G. Cabrera-Castro, N. Molina, A.J. Aizpurua, A. Morales-Suárez-Varela, M.M. Martín, V. Fernández-Navarro, P. Villanueva, C.M. Moreno, V.
author	Moratalla-Navarro, F.
author_facet	Moratalla-Navarro, F. Obón-Santacana, M. Rius-Sansalvador, B. Guinó, E. Moragas, N. Donat-Vargas, C. de Larrea-Baz, N.F. Molina-Barceló, A. Guevara, M. Morón-Duran, F.D. Dierssen-Sotos, T. Tardón, A. Castaño-Vinyals, G. Cabrera-Castro, N. Molina, A.J. Aizpurua, A. Morales-Suárez-Varela, M.M. Martín, V. Fernández-Navarro, P. Villanueva, C.M. Moreno, V.
author_role	author
author2	Obón-Santacana, M. Rius-Sansalvador, B. Guinó, E. Moragas, N. Donat-Vargas, C. de Larrea-Baz, N.F. Molina-Barceló, A. Guevara, M. Morón-Duran, F.D. Dierssen-Sotos, T. Tardón, A. Castaño-Vinyals, G. Cabrera-Castro, N. Molina, A.J. Aizpurua, A. Morales-Suárez-Varela, M.M. Martín, V. Fernández-Navarro, P. Villanueva, C.M. Moreno, V.
author2_role	author author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Colorectal Cancer Drinking water Gene-environment interaction Trihalomethanes Aged Case-Control Studies Colorectal Neoplasms Drinking Water Environmental Exposure Female Gene-Environment Interaction Genome-Wide Association Study Humans Male Middle Aged Quantitative Trait Loci Spain Trihalomethanes Water Pollutants, Chemical Spain Chlorine compounds Diseases Environmental impact Gene expression Proteomics Risk analysis Risk assessment chloroform drinking water nonsteroid antiinflammatory agent trihalomethane trihalomethane Cancer risk Candidate genes Case-control study Colorectal cancer Gene-environment interaction Interaction analysis Interaction modeling Long term exposure Quantitative trait locus Trihalomethanes cancer comparative study drinking water genome guideline health geography health impact health risk quantitative analysis research work threshold volatile organic compound World Health Organization adult Article blood s
topic	Colorectal Cancer Drinking water Gene-environment interaction Trihalomethanes Aged Case-Control Studies Colorectal Neoplasms Drinking Water Environmental Exposure Female Gene-Environment Interaction Genome-Wide Association Study Humans Male Middle Aged Quantitative Trait Loci Spain Trihalomethanes Water Pollutants, Chemical Spain Chlorine compounds Diseases Environmental impact Gene expression Proteomics Risk analysis Risk assessment chloroform drinking water nonsteroid antiinflammatory agent trihalomethane trihalomethane Cancer risk Candidate genes Case-control study Colorectal cancer Gene-environment interaction Interaction analysis Interaction modeling Long term exposure Quantitative trait locus Trihalomethanes cancer comparative study drinking water genome guideline health geography health impact health risk quantitative analysis research work threshold volatile organic compound World Health Organization adult Article blood s
description	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. Copyright © 2026. Published by Elsevier Ltd.
publishDate	2026
dc.date.none.fl_str_mv	2026
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	https://fisabio.portalinvestigacion.com/publicaciones/20347 https://www.scopus.com/inward/record.uri?eid=2-s2.0-105027546033&doi=10.1016%2fj.envint.2026.110059&partnerID=40&md5=5b470a79ce60ff59d1850c8bfdef4ab1
url	https://fisabio.portalinvestigacion.com/publicaciones/20347 https://www.scopus.com/inward/record.uri?eid=2-s2.0-105027546033&doi=10.1016%2fj.envint.2026.110059&partnerID=40&md5=5b470a79ce60ff59d1850c8bfdef4ab1
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess
eu_rights_str_mv	openAccess
dc.publisher.none.fl_str_mv	PERGAMON-ELSEVIER SCIENCE LTD
publisher.none.fl_str_mv	PERGAMON-ELSEVIER SCIENCE LTD
dc.source.none.fl_str_mv	ENVIRONMENT INTERNATIONAL ISSN: 01604120 ISSNe: 18736750 reponame:r-FISABIO. Repositorio Institucional de Producción Científica instname:Universidad de Málaga
instname_str	Universidad de Málaga
reponame_str	r-FISABIO. Repositorio Institucional de Producción Científica
collection	r-FISABIO. Repositorio Institucional de Producción Científica
repository.name.fl_str_mv
repository.mail.fl_str_mv
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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)

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