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.
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Mendez Joel Sanchez, Queme Bryan, Fu Yubo, Morrison John, Lewinger Juan P, Kawaguchi Eric, Mi Huaiyu, 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, Conti David V, Wang Jun, Platz Elizabeth A, 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 Jb, 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 Am, 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, Hsu Li, Peters Ulrike, Gauderman W James, Stern Mariana C
Аннотация
METHODS: A pooled sample of 30,812 cases and 40,504 CRC controls of European ancestry from 27 studies were analyzed. Quantiles for red and processed meat intake were constructed. The 204 GWAS variants were annotated to genes with AnnoQ and assessed for overrepresentation in PANTHER-reported pathways. pPRS's were constructed from significantly overrepresented pathways. Covariate-adjusted logistic regression models evaluated pPRSxE interactions with red or processed meat intake in relation to CRC risk.
RESULTS: A total of 30 variants were overrepresented in four pathways: Alzheimer disease-presenilin, Cadherin/WNT-signaling, Gonadotropin-releasing hormone receptor, and TGF-β signaling. We found a significant interaction between TGF-β-pPRS and red meat intake (p = 0.003). When variants in the TGF-β pathway were assessed, significant interactions with red meat for rs2337113 (intron SMAD7 gene, Chr18), and rs2208603 (intergenic region BMP5, Chr6) (p = 0.013 & 0.011, respectively) were observed. We did not find evidence of pPRS x red meat interactions for other pathways or with processed meat.
CONCLUSIONS: This pathway-based interaction analysis revealed a significant interaction between variants in the TGF-β pathway and red meat consumption that impacts CRC risk.
IMPACT: These findings shed light into the possible mechanistic link between CRC risk and red meat consumption.