Poole, Elizabeth M and Hsu, Li and Xiao, Liren and Kulmacz, Richard J and Carlson, Christopher S and Rabinovitch, Peter S and Makar, Karen W and Potter, John D and Ulrich, Cornelia M (2010) Genetic variation in prostaglandin E2 synthesis and signaling, prostaglandin dehydrogenase, and the risk of colorectal adenoma. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 19 (2). pp. 547-557. ISSN 1538-7755
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Abstract
BACKGROUND: Prostaglandins are important inflammatory mediators; prostaglandin E2 (PGE2) 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 PGE2 synthase (PGES), PGE2 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; OR(GA/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.
| Item Type: | Article or Abstract |
|---|---|
| Additional Information: | This article is available to subscribers only for the first 12 months following publication. |
| DOI: | 10.1158/1055-9965.EPI-09-0869 |
| PubMed ID: | 20086108 |
| NIHMSID: | NIHMS157592 |
| PMCID: | PMC2849740 |
| Grant Numbers: | R01 CA112516, R01 CA112516, R03 CA123577 |
| Keywords or MeSH Headings: | Adenoma/genetics* Adenoma/metabolism* Adult Aged Animals Anti-Inflammatory Agents, Non-Steroidal/pharmacology Case-Control Studies Colorectal Neoplasms/genetics* Colorectal Neoplasms/metabolism* Diet Dinoprostone/genetics* Dinoprostone/metabolism Epistasis, Genetic Fatty Acids, Omega-3 Female Fish Oils Genetic Predisposition to Disease* Genetic Variation Humans Male Middle Aged Polymorphism, Single Nucleotide Risk Factors Signal Transduction/physiology |
| Subjects: | Diseases > Solid tumors > Digestive system cancer Cellular and Organismal Processes > Genetic processes > Mutation Research Methodologies > Epidemiology > Risk assessment |
| Depositing User: | Library Staff |
| Date Deposited: | 12 Mar 2010 22:23 |
| Last Modified: | 14 Feb 2012 14:43 |
| URI: | http://authors.fhcrc.org/id/eprint/405 |
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