Abstract
B192
Observational and interventional trials have demonstrated that nonsteroidal anti-inflammatory medication (NSAID) reduce colorectal neoplasm risk. Prior studies have suggested this effect may be modified by functional variants in NSAID metabolizing enzymes, such as cytochrome P450 (CYP) 2C9 and uridine diphosphate glucuronosyltransferase (UGT) 1A6. We investigated this hypothesis in participants enrolled within the Tennessee Colorectal Polyp Study, a large, colonoscopy-based case-control study. Function polymorphisms in the CYP2C9 (rs1057910, rs1799853) and UGT1A6 (rs1105879, rs2070959) genes were determined for 831 adenoma cases and 1722 controls. Regular NSAID use was associated with a reduced risk of colorectal adenoma, and the adjusted odds ratios (OR) were 0.80 (95% confidence interval (CI) 0.66 - 0.98) for aspirin and 0.68 (0.49-0.93) for non-aspirin NSAIDs. No apparent association with adenoma risk was found for any of the CYP2C9 and UGT1A6 genotypes evaluated in the study. However, CYP2C9 genotype appears to modify the association between NSAID use and adenoma risk. The association with NSAIDs use was stronger among subjects carrying the variant CYP2C9 allele than those carrying only the common allele. When stratified by gender, women with a CYP2C9 variant who were regular aspirin users had an OR of 0.21 (0.06-0.66) for colorectal adenoma compared to non-regular aspirin users. Women with the CYP2C9 wild-type genotype who were regular aspirin users had an OR of 1.13 (0.74-1.74) compared to non-regular aspirin users. In men with a CYP2C9 variant, regular aspirin use did not seem to impact adenoma risk with an OR of 1.01 (0.62-1.63) compared to non-regular aspirin users. This modifying effect was also more apparent among non-smokers. UGT1A6 polymorphism was found to modify the association of aspirin use and adenoma risk but not non-aspirin NSAID use and adenoma risk. The results from this study provide additional support that the protective effect of NSAID may be modified by certain genetic factors, such as CYP2C9 functional variants.
[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]