High Polygenic Risk Scores Positively Associated with Gastric Cancer Risk Interact with Coffee and Polyphenol Intake and Smoking Status in Korean Adults.

Background/objectives: This study investigated the relationship between single nucleotide polymorphisms (SNPs) and gastric cancer (GC) risk, while also examining the interaction of genetic factors with lifestyle variables including the nutrient and bioactive compound intake in Korean adults of a large hospital-based cohort.

Methods: We conducted a genome-wide association study (GWAS) comparing GC patients ( = 312) with healthy controls without cancers ( = 47,994) to identify relevant genetic variants. Generalized multifactor dimensionality reduction (GMDR) was employed to detect SNP interactions between diets and lifestyles. We utilized polygenic risk scores (PRSs) to assess individuals' GC risk based on multiple SNP loci. Among the selected SNPs, since _rs1527482 was a missense mutation, bioactive compounds which decrease the binding energy were found with its wild and mutated proteins by molecular docking analysis.

Results: Individuals with high PRSs exhibited a 4.12-fold increased risk of GC compared to those with low PRSs. Additional factors associated with elevated GC risk included a low white blood cell count (OR = 5.13), smoking (OR = 3.83), and low coffee consumption (OR = 6.30). The _rs1527482 variant showed a positive correlation with GC risk. Molecular docking analyses suggested that certain polyphenols, including theaflavate, rugosin E, vitisifuran B, and plantacyanin, reduced the binding free energy in both wild-type and mutated _rs1527482. However, some polyphenols exhibited differential binding energies between its wild and mutated forms, suggesting they might modulate wild and mutated proteins differently.

Conclusion: High PRSs and _rs1527482 interact with immune function, coffee intake, polyphenol consumption, and smoking status to influence GC risk. These findings could contribute to developing personalized nutrition and lifestyle interventions to reduce GC risk.