Gene-gene and gene-environment interactions of colorectal cancer risk : the Korean Cancer Prevention Study-II

Abstract

Background and purpose: Colorectal cancer (CRC) is a complex disease influenced by multi-factorial environmental traits, such as old age, men, personal history of inflammatory bowel disease and adenomatous polyps, obesity, smoking, moderate-to-heavy alcohol consumption, and family history of CRC. To identify the genetic loci that influence CRC risk and interaction effects, we carried out a two stage genome-wide association study (GWAS) in Korean population using multifactor dimensionality reduction (MDR) approach.Materials and Methods: A total of 1,256 individuals were included in the Stage 1 and 589 individuals agreed to participate in Stage 2. Analysis by Genome wide Human Single-nucleotide Polymorphisms Array 5.0 in the Stage 1 and the 48.48 Dynamic Array on the BioMark platform in the Stage 2 were performed by using DNAs derived from venous blood. To evaluate the association between risk for CRC and significant SNPs, multivariate logistic regression model was used with adjustment for age and sex, and gene-gene and gene-environment interactions were detected by the MDR analysis.Results: We identified the three-way gene-gene interaction between rs130275 in TIMP3 region and rs130561 in SYN3 region, and rs1824817 was the best model for predicting the occurrence of the CRC risk (odds ratio (OR): 1.75, 95% confidence interval (CI): 1.42-2.16). Moreover, an interaction between alcohol consumption (OR: 1.90, 95% CI: 1.51-2.38) and smoking status (OR: 3.15, 95% CI: 2.38-4.16) was significantly associated with higher CRC risk.Conclusion: Our findings would be helpful for understand the effect of single gene effect, gene-gene interaction, or gene-environmental interaction on CRC pathogenesis. Furthermore, our findings about gene-gene and geneenvironment combinations using MDR approach might be appropriately applied to CRC prediction model.