Genetic Variation in Prostaglandin E2 Synthesis and Signaling, Prostaglandin Dehydrogenase, and the Risk of Colorectal Adenoma

Background: Prostaglandins are important inflammatory mediators; prostaglandin E-2 (PGE(2)) is the predominant prostaglandin in colorectal neoplasia and affects colorectal carcinogenesis. Prostaglandins are metabolites of omega-6 and omega-3 polyunsaturated fatty acids; their biosynthesis is the primary target of nonsteroidal anti-inflammatory drugs (NSAID), which reduce colorectal neoplasia risk. Methods: We investigated candidate and tagSNPs in PGE(2) synthase (PGES), PGE(2) receptors (EP2 and EP4), and prostaglandin dehydrogenase (PGDH) in a case-control study of adenomas (n = 483) versus polyp-free controls (n = 582) and examined interactions with NSAID use or fish intake, a source of omega-3 fatty acids. Results: A 30% adenoma risk reduction was observed for EP2 4950G>A (intron 1; ORGA/AA vs. (GG), 0.71; 95% confidence interval, 0.52-0.99). For the candidate polymorphism EP4 Val294Ile, increasing fish intake was associated with increased adenoma risk among those with variant genotypes, but not among those with the Val/Val genotype (P-interaction = 0.02). An interaction with fish intake was also observed for PGES -664A>T (5' untranslated region; P-interaction = 0.01). Decreased risk with increasing fish intake was only seen among those with the AT or TT genotypes (OR>2 t/wk vs. <1 t/wk, 0.56; 95% confidence interval, 0.28-1.13). We also detected interactions between NSAIDs and EP2 9814C>A (intron 1) and PGDH 343C>A (intron 1). However, none of the observed associations was statistically significant after adjustment for multiple testing. We investigated potential gene-gene interactions using the Chatterjee 1 degree of freedom Tukey test and logic regression; neither method detected significant interactions. Conclusions: These data provide little support for associations between adenoma risk and genetic variability related to PGE(2), yet suggest gene-environment interactions with anti-inflammatory exposures. Cancer Epidemiol Biomarkers Prev; 19(2); 547-57. (C) 2010 AACR.