Protective effect of nonsteroidal anti-inflammatory drugs on colorectal adenomas is modified by a polymorphism in peroxisome proliferator-activated receptor delta.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a decreased risk of colorectal tumors. Single nucleotide polymorphisms (SNPs) in target genes of NSAID action, and their haplotypes, might modulate this protective effect. A case-control study including 724 cases and 682 controls was used to evaluate the effect of NSAIDs on colorectal adenoma risk in The Netherlands, a country in which NSAID use is relatively low. Cases and controls were classified according to presence or absence of endoscopy-proven, pathology-confirmed colorectal adenomas, ever in their lives. Thirteen SNPs in four genes (PPARdelta, PPARgamma, PTGS1 and PTGS2) were genotyped in 787 subjects (384 cases and 403 controls). Compared to non-regular users (< 12 times/year), regular users of NSAIDs (> or = 12 times/year) had a lower risk of colorectal adenomas (odds ratio (OR): 0.75, 95% confidence interval (CI): 0.56-0.99). The results were similar for aspirin only. We found an interaction between SNP c.-789C>T in PPARdelta and NSAID use (P=0.03). The protective effect of NSAIDs was strengthened for regular users with the PPARdelta CT or TT genotypes (OR: 0.35, 95%CI: 0.11-1.13), whereas a positive association was observed for non-regular users with these genotypes (OR: 2.24, 95%CI: 1.06-4.73) as compared to non-regular users with the CC genotype. Also, a statistically significant interaction between a major haplotype containing the minor allele of this SNP and NSAID use was observed. This study confirms the protective effect of NSAIDs and suggests a modulating effect of a SNP in the promoter of PPARdelta.