title: Genetic variation in prostaglandin E2 synthesis and signaling, prostaglandin dehydrogenase, and the risk of colorectal adenoma.
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.
authors.affiliation: Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Poole
authors.forename: Li
authors.initials: L
authors.lastname: Hsu
authors.forename: Liren
authors.initials: L
authors.lastname: Xiao
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Kulmacz
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Carlson
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.forename: Karen W
authors.initials: KW
authors.lastname: Makar
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004032:Diet; D015232:Dinoprostone / Q000235:genetics* / Q000378:metabolism; D004843:Epistasis, Genetic; D015525:Fatty Acids, Omega-3; D005260:Female; D005395:Fish Oils; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015525:Fatty Acids, Omega-3; D005395:Fish Oils; D015232:Dinoprostone