TGF-β Pathway-Based Polygenic Risk Score Modifies the Association between Red Meat Intake and Colorectal Cancer Risk:...

Area of Science:

• Genetics
• Cancer Epidemiology
• Molecular Biology

Background:

• Red and processed meat consumption are known risk factors for colorectal cancer (CRC).
• Genome-wide association studies (GWAS) have identified over 200 CRC risk variants.
• Pathway-based polygenic risk scores (pPRS) can refine genetic risk assessment by integrating functional annotation data.

Purpose of the Study:

• To construct pathway-based polygenic risk scores (pPRS) using functional annotation data.
• To investigate interactions between pPRS and meat intake in relation to CRC risk.
• To identify specific genetic pathways and variants involved in the meat-CRC association.

Main Methods:

• Analyzed pooled data from 30,812 CRC cases and 40,504 controls across 27 studies.
• Annotated 204 GWAS variants to genes and assessed pathway overrepresentation using AnnoQ and PANTHER.
• Constructed pPRS from significantly overrepresented pathways and evaluated interactions with red/processed meat intake via logistic regression.

Main Results:

• Identified 30 variants in four pathways: Presenilin-Alzheimer disease, Cadherin/WNT-signaling, Gonadotropin-releasing hormone receptor, and TGF-β signaling.
• Found a significant interaction between TGF-β pathway pPRS and red meat intake (ORint = 0.95, p = 0.003).
• Specific variants (rs2337113 in SMAD7, rs2208603 near BMP5) within the TGF-β pathway showed significant interaction with red meat intake.

Conclusions:

• A statistically significant interaction exists between genetic variants in the TGF-β pathway and red meat consumption impacting CRC risk.
• These findings provide mechanistic insights into the link between red meat intake and colorectal cancer development.