Interactions between Diet, Lifestyle and IL10, IL1B, and PTGS2/COX-2 Gene Polymorphisms in Relation to Risk of Colorectal Cancer in a Prospective Danish Case-Cohort Study

Background & Aims: Diet contributes to colorectal cancer development and may be potentially modified. We wanted to identify the biological mechanisms underlying colorectal carcinogenesis by assessment of diet-gene interactions. Methods: The polymorphisms IL10 C-592A (rs1800872), C-rs3024505-T, IL1b C-3737T (rs4848306), G-1464C (rs1143623), T-31C (rs1143627) and PTGS2 (encoding COX-2) A-1195G (rs689466), G-765C (rs20417), and T8473C (rs5275) were assessed in relation to risk of colorectal cancer (CRC) and interaction with diet (red meat, fish, fibre, cereals, fruit and vegetables) and lifestyle (non-steroid-anti-inflammatory drug use and smoking status) was assessed in a nested case-cohort study of nine hundred and seventy CRC cases and 1789 randomly selected participants from a prospective study of 57,053 persons. Results: IL1b C-3737T, G-1464C and PTGS2 T8473C variant genotypes were associated with risk of CRC compared to the homozygous wildtype genotype (IRR=0.81, 95% CI: 0.68-0.97, p=0.02, and IRR=1.22, 95% CI: 1.04-1.44, p=0.02, IRR=0.75, 95% CI: 0.57-0.99, p=0.04, respectively). Interactions were found between diet and IL10 rs3024505 (P-value for interaction (P-int); meat=0.04, fish=0.007, fibre=0.0008, vegetables=0.0005), C-592A (P-int; fibre=0.025), IL1b C-3737T (P-int; vegetables=0.030, NSAID use=0.040) and PTGS2 genotypes G-765C (P-int; meat=0.006, fibre=0.0003, fruit 0.004), and T8473C (P-int; meat 0.049, fruit=0.03) and A-1195G (P-int; meat 0.038, fibre 0.040, fruit=0.059, vegetables=0.025, and current smoking=0.046). Conclusions: Genetically determined low COX-2 and high IL-1 beta activity were associated with increased risk of CRC in this northern Caucasian cohort. Furthermore, interactions were found between IL10, IL1b, and PTGS2 and diet and lifestyle factors in relation to CRC. The present study demonstrates that gene-environment interactions may identify genes and environmental factors involved in colorectal carcinogenesis.