Genome-Wide Gene–Environment Interaction Analyses to Understand the Relationship between Red Meat and Processed Meat Intake and Colorectal Cancer Risk

Mariana C. Stern*, Joel Sanchez Mendez, Andre E. Kim, Mireia Obón-Santacana, Ferran Moratalla-Navarro, Vicente Martín, Victor Moreno, Yi Lin, Stephanie A. Bien, Conghui Qu, Yu-Ru Su, Emily White, Tabitha A. Harrison, Jeroen R. Huyghe, Catherine M. Tangen, Polly A. Newcomb, Amanda I. Phipps, Claire E. Thomas, Eric S. Kawaguchi, Juan Pablo LewingerJohn L. Morrison, David V. Conti, Jun Wang, Duncan C. Thomas, Elizabeth A. Platz, Kala Visvanathan, Temitope O. Keku, Christina C. Newton, Caroline Y. Um, Anshul Kundaje, Anna Shcherbina, Neil Murphy, Marc J. Gunter, Niki Dimou, Nikos Papadimitriou, Stéphane Bézieau, Franzel J.B. van Duijnhoven, Satu Männistö, Gad Rennert, Alicja Wolk, Michael Hoffmeister, Hermann Brenner, Jenny Chang-Claude, Yu Tian, Loïc Le Marchand, Michelle Cotterchio, Konstantinos K. Tsilidis, D.T. Bishop, Yohannes Adama Melaku, Brigid M. Lynch, Daniel D. Buchanan, Cornelia M. Ulrich, Jennifer Ose, Anita R. Peoples, Andrew J. Pellatt, Li Li, Matthew A.M. Devall, Peter T. Campbell, Demetrius Albanes, Stephanie J. Weinstein, Sonja I. Berndt, Stephen B. Gruber, Edward Ruiz-Narvaez, Mingyang Song, Amit D. Joshi, David A. Drew, Jessica L. Petrick, Andrew T. Chan, Marios Giannakis, Ulrike Peters*, Li Hsu, W.J. Gauderman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Background: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene–environment (GxE) interaction analysis to identify genetic variants that may modify these associations.
Methods: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan.
Results: Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk [per quartile red meat OR = 1.30; 95% confidence interval (CI) = 1.21–1.41; processed meat OR = 1.40; 95% CI = 1.20–1.63]. Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95% CI = 1.29–1.46), 1.20 (95% CI = 1.12–1.27), and 1.07 (95% CI = 0.95–1.19) for CC, CG, and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95% CI = 1.11–1.24), 1.35 (95% CI = 1.26–1.44), and 1.46 (95% CI = 1.26–1.69) for CC, CT, and TT, respectively.
Conclusions: We propose two novel biomarkers that support the role of meat consumption with an increased risk of colorectal cancer.
Impact: The reported GxE interactions may explain the increased risk of colorectal cancer in certain population subgroups.
Original languageEnglish
Pages (from-to)400-410
JournalCancer Epidemiology Biomarkers & Prevention
Issue number3
Publication statusPublished - 1 Mar 2024


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