Genome-Wide Gene–Environment Interaction Analyses to Understand the Relationship between Red Meat and Processed Meat Intake and Colorectal Cancer Risk
Authors: Stern Mariana C. , Sanchez Mendez Joel , Kim Andre E. , Obón-Santacana Mireia , Moratalla-Navarro Ferran , Martín Vicente , Moreno Victor , Lin Yi , Bien Stephanie A. , Qu Conghui , Su Yu-Ru , White Emily , Harrison Tabitha A. , Huyghe Jeroen R. , Tangen Catherine M. , Newcomb Polly A. , Phipps Amanda I. , Thomas Claire E. , Kawaguchi Eric S. , Lewinger Juan Pablo , Morrison John L. , Conti David V. , Wang Jun , Thomas Duncan C. , Platz Elizabeth A. , Visvanathan Kala , Keku Temitope O. , Newton Christina C. , Um Caroline Y. , Kundaje Anshul , Shcherbina Anna , Murphy Neil , Gunter Marc J. , Dimou Niki , Papadimitriou Nikos , Bézieau Stéphane , van Duijnhoven Franzel J.B. , Männistö Satu , Rennert Gad , Wolk Alicja , Hoffmeister Michael , Brenner Hermann , Chang-Claude Jenny , Tian Yu , Le Marchand Loïc , Cotterchio Michelle , Tsilidis Konstantinos K. , Bishop D. Timothy , Melaku Yohannes Adama , Lynch Brigid M. , Buchanan Daniel D. , Ulrich Cornelia M. , Ose Jennifer , Peoples Anita R. , Pellatt Andrew J. , Li Li , Devall Matthew A.M. , Campbell Peter T. , Albanes Demetrius , Weinstein Stephanie J. , Berndt Sonja I. , Gruber Stephen B. , Ruiz-Narvaez Edward , Song Mingyang , Joshi Amit D. , Drew David A. , Petrick Jessica L. , Chan Andrew T. , Giannakis Marios , Peters Ulrike , Hsu Li , Gauderman W. James 
Published: December 2023

Abstract

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.