Red meat intake interacts with a TGF-β-pathway-based polygenic risk score to impact colorectal cancer risk: Application of a novel approach for polygenic risk score construction.

BackgroundRed 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. MethodsA 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. 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 CRC risk. ResultsA total of 30 variants were overrepresented in four pathways: Presenilin-Alzheimer disease, Cadherin/WNT-signaling, Gonadotropin-releasing hormone receptor, and TGF-{beta} signaling. We found a significant interaction between TGF-{beta}-pPRS and red meat intake (ORint = 0.95; 95% CI = 0.92-0.98; p = 0.003). When variants in the TGF-{beta} 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 ConclusionsThis pathway-based interaction analysis revealed a statistically significant interaction between variants in the TGF-{beta} pathway and red meat consumption that impacts CRC risk. ImpactThese findings shed light into the possible mechanistic link between red meat consumption and CRC risk. Impact statementIn this work, we developed pathway-based Polygenic Risk Scores which, for the first time, suggested that red meat intake interacts with variants overrepresented in TGF-{beta} signaling pathway to impact colorectal cancer risk.