Abstract 5217: Genome-wide interactions of processed and red meat intake on colorectal cancer risk
Authors: Mendez Joel Sanchez , Stern Mariana C. , Kim Andre , Morrison John , Lewinger Juan P. , Hsu Li , Kawaguchi Eric , Peters Ulrike , Gauderman William J. ,   on behalf of GECCO, CCFR and CORECT
Published: June 2023

Abstract
Introduction: Colorectal cancer (CRC) is the third most common cancer, and second cause of cancer death worldwide. High red meat and/or processed meat consumption are established risk factors for CRC. Genome-wide association studies have identified over 200 genetic variants that explain ~20% of the variability in CRC risk. However, few large studies have evaluated genome-wide gene by environment (GxE) interactions with meat in CRC. Using the largest CRC pooled dataset available to date we conducted a genome-wide GxE analysis to identify possible interactions between common variants and red meat and/or processed meat intake and CRC risk.
Methods: A pooled sample of 29,912 CRC cases and 39,704 unaffected controls of European (EUR) ancestry from 27 studies was analyzed. Sex- and study-specific quartiles for red meat and processed meat intake were constructed from harmonized questionnaire data on meat consumption. Genotyping arrays were imputated to the Haplotype Reference Consortium. To identify novel CRC interaction loci we used the two-step EDGE method, standard GxE analyses and a 1-3 degrees of freedom (DF) test. We removed previously known GWAS hits and SNPs in high linkage disequilibrium with them.
Results: Our Meta-analyses confirmed a positive association between quartile consumption increase of red meat and processed meat with CRC risk (Red meat OR = 1.30; 95%CI = 1.21-1.41; Processed meat OR = 1.40; 95% CI = 1.20 -1.63). Greater magnitude in point estimates were observed for case-control studies compared to cohort studies, for processed meat consumption among men compared to women, and for red meat consumption and distal colon localization compared to proximal colon or rectum. Two DF GxE tests of red meat consumption revealed two SNPs in chromosome (Chr) 8 (rs4871179 & rs75212442) and a SNP in Chr10 (rs117674361) that map downstream HAS2, COLEC10 and downstream CCSER2. In addition, the two-step EDGE GxE method identified the rs35352860 SNP that maps to the SMAD7 gene in Chr18. Genotype-stratified analyses showed that the red meat and CRC risk association was restricted to homozygous carriers of major alleles for rs4871179, rs75212442 & rs117674361. Moreover, we observed dose-response increase in the red meat and CRC risk association with additional copies of the T allele of the SNP in Chr18, with homozygous carriers of the T allele having 46% higher chance of developing CRC associated with high red meat intake; this in contrast to homozygous carriers of the reference C allele, that had an 18% higher risk of developing CRC. No statistically significant GXE interactions with processed meat intake were found.
Conclusion: In this large-scale genome-wide GxE analysis we identified interactions between 4 SNPs and red meat consumption affecting CRC risk. The interaction with the SMAD7 rs35352860 SNP provides supportive evidence for a role of heme iron in the carcinogenic pathway of red meat intake in CRC development.
Citation Format: Joel Sanchez Mendez, Mariana C. Stern, Andre Kim, John Morrison, Juan P. Lewinger, Li Hsu, Eric Kawaguchi, Ulrike Peters, William J. Gauderman, on behalf of GECCO, CCFR and CORECT. Genome-wide interactions of processed and red meat intake on colorectal cancer risk. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5217.