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BACKGROUND: Red meat and/or processed meat are established colorectal cancer risk factors. Genome-wide association studies (GWAS) have reported more than 200 variants associated with colorectal cancer 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 colorectal cancer controls from 27 studies was analyzed. Quantiles for red and processed meat intake were constructed. A total of 204 GWAS variants were annotated to genes with Annotation Query (AnnoQ) and assessed for overrepresentation in PANTHER-reported pathways. pPRSs were constructed from significantly overrepresented pathways. Covariate-adjusted logistic regression models evaluated interactions between pPRS and red or processed meat intake in relation to colorectal cancer risk.RESULTS: A total of 30 variants were overrepresented in four pathways: presenilin/Alzheimer disease, cadherin/WNT signaling, gonadotropin-releasing hormone receptor, and transforming growth factor-β (TGF-β) signaling. We found a significant interaction between TGF-β pPRS and red meat intake [ORint = 0.95; 95% confidence interval (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 SMAD family member 7 (SMAD7) gene, Chr18] and rs2208603 [intergenic region bone morphogenetic protein 5 (BMP5), Chr6; P = 0.0005 and 0.036, respectively]. There was no evidence of pPRS × 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 influences colorectal cancer risk.IMPACT: These findings shed light on the possible mechanistic link between red meat consumption and colorectal cancer risk.