TGF-β Pathway-Based Polygenic Risk Score Modifies the Association between Red Meat Intake and Colorectal Cancer Risk: Application of a Novel Pathway-Based PRS Method.
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Sanchez Mendez Joel, Queme Bryan, Fu Yubo, Morrison John L, Lewinger Juan Pablo, Kawaguchi Eric S, Mi Huaiyu, Obón-Santacana Mireia, Moratalla-Navarro Ferran, Martín Vicente, Moreno Victor, Qu Conghui, Huyghe Jeroen R, Newcomb Polly A, Phipps Amanda I, Thomas Claire E, Conti David V, Wang Jun, Platz Elizabeth A, Visvanathan Kala, Keku Temitope O, Newton Christina C, Um Caroline Y, Kundaje Anshul, Gunter Marc J, Dimou Niki, Papadimitriou Nikos, van Duijnhoven Fränzel J B, Männistö Satu, Rennert Gad, Wolk Alicja, Hoffmeister Michael, Brenner Hermann, Tian Yu, Le Marchand Loïc, Bouras Emmanouil, Tsilidis Konstantinos K, Bishop D Timothy, Maclnnis Robert J, Buchanan Daniel D, Ulrich Cornelia M, Peoples Anita R, Pellatt Andrew, Li Li, Devall Matthew A, Albanes Demetrius, Berndt Sonja I, Gruber Stephen B, Ruiz-Narvaez Edward, Song Mingyang, Drew David A, Chan Andrew T, Giannakis Marios, Hsu Li, Peters Ulrike, Stern Mariana C, Gauderman W James
Аннотация
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.