TGF-β Pathway–Based Polygenic Risk Score Modifies the Association between Red Meat Intake and Colorectal Cancer Risk: Application of a Novel Pathway-Based PRS Method

BACKGROUND: Red and/or processed meat are established colorectal cancer (CRC) risk factors. Genome-wide association studies (GWAS) have reported over 200 variants associated with CRC risk. We used functional annotation data to identify subsets of variants within known pathways to construct pathway-based Polygenic Risk Scores (pPRS) to assess interactions with meat intake. METHODS: A pooled sample of 30,812 cases and 40,504 CRC controls from 27 studies were analyzed. Quantiles for red and processed meat intake were constructed. 204 GWAS variants were annotated to genes with AnnoQ and assessed for overrepresentation in PANTHER-reported pathways. pPRS's were constructed from significantly overrepresented pathways. Covariate-adjusted logistic regression models evaluated interactions between pPRS and red or processed meat intake in relation to CRC risk. RESULTS: A total of 30 variants were overrepresented in four pathways: Presenilin-Alzheimer disease, Cadherin/WNT-signaling, Gonadotropin-releasing hormone receptor, and TGF-β signaling. We found a significant interaction between TGF-β-pPRS and red meat intake (ORint = 0.95; 95% CI = 0.92-0.98; p = 0.003). When variants in the TGF-β pathway were assessed, we observed significant interactions of red meat with rs2337113 (intron SMAD7 gene, Chr18), and rs2208603 (intergenic region BMP5, Chr6) (p = 0.0005 & 0.036, respectively). There was no evidence of pPRS x red meat interactions for other pathways or with processed meat Conclusions:This pathway-based interaction analysis revealed a statistically significant interaction between variants in the TGF-β pathway and red meat consumption that impacts CRC risk. IMPACT: These findings shed light into the possible mechanistic link between red meat consumption and CRC risk.

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Journal
Cancer Epidemiology Biomarkers & Prevention
Published
2026-04-01
DOI
https://doi.org/10.1158/1055-9965.epi-25-1754
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1
Primary Topic
Nutritional Studies and Diet
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article
Field-Weighted Citation Impact
24.86

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article

TGF-β Pathway–Based Polygenic Risk Score Modifies the Association between Red Meat Intake and Colorectal Cancer Risk: Application of a Novel Pathway-Based PRS Method

Bryan Queme, Nikos Papadimitriou, P. A. Newcomb, Ferrán Moratalla-Navarro et al.
1 citations
Cancer Epidemiology Biomarkers & Prevention
Nutritional Studies and Diet
24.86
article

TGF-β Pathway–Based Polygenic Risk Score Modifies the Association between Red Meat Intake and Colorectal Cancer Risk: Application of a Novel Pathway-Based PRS Method

Bryan Queme, Nikos Papadimitriou, P. A. Newcomb, Ferrán Moratalla-Navarro, Christina C. Newton, Mariana Stern, Matthew A.M. Devall, Michael Hoffmeister, Niki L. Dimou, Edward Ruiz-Narváez, A. I. Phipps, Claire Elizabeth Thomas, Jeroen R. Huyghe, Eric S. Kawaguchi, Juan Pablo Lewinger, Marios Giannakis, Andrew J. Pellatt, Daniel D. Buchanan, Anita R. Peoples, L. Hsu, Stephen B. Gruber, Temitope O. Keku, J Hernandez Mendez, Anshul Kundaje, Emmanouil Bouras, Alicja Wolk, Kala Visvanathan, Caroline Y. Um, Robert J. Maclnnis, Conghui Qu, Loïc Le Marchand, Konstantinos K. Tsilidis, Jun Wang, Huaiyu Mi, Marc J. Gunter, D. Timothy Bishop, Cornelia M. Ulrich, Gad Rennert, Demetrius Albanes, Elizabeth A. Platz, Victor Moreno, David A. Drew, Vicente Martín, Sonja I. Berndt, W James Gauderman, Fränzel J.B. van Duijnhoven, Mingyang Song, David V. Conti, Mireia Obón-Santacana, Ulrike Peters, Satu Männistö, Yubo Fu, Hermann Brenner
article en
1 citations

Abstract

BACKGROUND: Red and/or processed meat are established colorectal cancer (CRC) risk factors. Genome-wide association studies (GWAS) have reported over 200 variants associated with CRC risk. We used functional annotation data to identify subsets of variants within known pathways to construct pathway-based Polygenic Risk Scores (pPRS) to assess interactions with meat intake. METHODS: A pooled sample of 30,812 cases and 40,504 CRC controls from 27 studies were analyzed. Quantiles for red and processed meat intake were constructed. 204 GWAS variants were annotated to genes with AnnoQ and assessed for overrepresentation in PANTHER-reported pathways. pPRS's were constructed from significantly overrepresented pathways. Covariate-adjusted logistic regression models evaluated interactions between pPRS and red or processed meat intake in relation to CRC risk. RESULTS: A total of 30 variants were overrepresented in four pathways: Presenilin-Alzheimer disease, Cadherin/WNT-signaling, Gonadotropin-releasing hormone receptor, and TGF-β signaling. We found a significant interaction between TGF-β-pPRS and red meat intake (ORint = 0.95; 95% CI = 0.92-0.98; p = 0.003). When variants in the TGF-β pathway were assessed, we observed significant interactions of red meat with rs2337113 (intron SMAD7 gene, Chr18), and rs2208603 (intergenic region BMP5, Chr6) (p = 0.0005 & 0.036, respectively). There was no evidence of pPRS x red meat interactions for other pathways or with processed meat Conclusions:This pathway-based interaction analysis revealed a statistically significant interaction between variants in the TGF-β pathway and red meat consumption that impacts CRC risk. IMPACT: These findings shed light into the possible mechanistic link between red meat consumption and CRC risk.

Cancer Epidemiology Biomarkers & Prevention
Broad Institute (US), Intermountain Healthcare (US), University of North Carolina at Chapel Hill (US), University of Southern California (US), Brigham and Women's Hospital (US), American Cancer Society (US), City Of Hope National Medical Center (US), University of Leeds (GB), The Royal Melbourne Hospital (AU), Harvard University (US), Johns Hopkins University (US), The University of Melbourne (AU), Technion – Israel Institute of Technology (IL), German Cancer Research Center (DE), Capital Medical University (CN), University of Ioannina (GR), Cancer Council Victoria (AU), University of Washington (US), University of Utah (US), Heidelberg University (DE), University of Michigan (US), Jerusalem Institute for Israel Studies (IL), Huntsman Cancer Institute (US), Bellvitge University Hospital (ES), Karolinska Institutet (SE), Finnish Institute for Health and Welfare (FI), Institut d'Investigació Biomédica de Bellvitge (ES), Massachusetts General Hospital (US), Fred Hutch Cancer Center (US), Cancer Center of Hawaii (US), Cancer Research And Biostatistics (US), Victorian Comprehensive Cancer Centre (AU), Institut Català d'Oncologia (ES), USC Norris Comprehensive Cancer Center (US), Rappaport Family Institute for Research in the Medical Sciences (IL), Dana-Farber Cancer Institute (US), Utah Department of Health (US), National Cancer Institute (US), University of Utah Health Care (US), Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES), Paediatric Integrated Cancer Service (AU), Department of Health and Human Services (US), Centre international de recherche sur le cancer (FR), Imperial College London (GB), University of Virginia (US), Universitat de Barcelona (ES), Universidad de León (ES), Wageningen University & Research (NL), Stanford University (US)
Cancer Research UK, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Fundación Científica Asociación Española Contra el Cáncer, Junta de Castilla y León, National Institutes of Health, Medical Research Council, Cancer Council Victoria, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, National Cancer Institute
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Nutritional Studies and Diet
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