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


METHODS
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).


RESULTS
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.


CONCLUSIONS
This study confirms the protective effect of NSAIDs and suggests a modulating effect of a SNP in the promoter of PPARdelta.
Siezen
Christine L E
CL
Department of Toxicology Pathology and Genetics, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
Tijhuis
Mariken J
MJ
Kram
Nicolien R
NR
van Soest
Eva M
EM
de Jong
Dirk J
DJ
Fodde
Riccardo
R
van Kranen
Henk J
HJ
Kampman
Ellen
E
D000236:Adenoma / Q000188:drug therapy / Q000235:genetics*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D047494:PPAR delta / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies
D000894:Anti-Inflammatory Agents, Non-Steroidal; D047494:PPAR delta