title: Genetic variation in 15-hydroxyprostaglandin dehydrogenase and colon cancer susceptibility.
abstract: BACKGROUND
  15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a metabolic antagonist of COX-2, catalyzing the degradation of inflammation mediator prostaglandin E2 (PGE2) and other prostanoids. Recent studies have established the 15-PGDH gene as a colon cancer suppressor.
  
  
  METHODS
  We evaluated 15-PDGH as a colon cancer susceptibility locus in a three-stage design. We first genotyped 102 single-nucleotide polymorphisms (SNPs) in the 15-PGDH gene, spanning ∼50 kb up and down-stream of the coding region, in 464 colon cancer cases and 393 population controls. We then genotyped the same SNPs, and also assayed the expression levels of 15-PGDH in colon tissues from 69 independent patients for whom colon tissue and paired germline DNA samples were available. In the final stage 3, we genotyped the 9 most promising SNPs from stages 1 and 2 in an independent sample of 525 cases and 816 controls (stage 3).
  
  
  RESULTS
  In the first two stages, three SNPs (rs1365611, rs6844282 and rs2332897) were statistically significant (p<0.05) in combined analysis of association with risk of colon cancer and of association with 15-PGDH expression, after adjustment for multiple testing. For one additional SNP, rs2555639, the T allele showed increased cancer risk and decreased 15-PGDH expression, but just missed statistical significance (p-adjusted = 0.063). In stage 3, rs2555639 alone showed evidence of association with an odds ratio (TT compared to CC) of 1.50 (95% CI = 1.05-2.15, p = 0.026).
  
  
  CONCLUSIONS
  Our data suggest that the rs2555639 T allele is associated with increased risk of colon cancer, and that carriers of this risk allele exhibit decreased expression of 15-PGDH in the colon.
authors.affiliation: Department of Family Medicine and Community Health, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Thompson
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Fink
authors.forename: James D
authors.initials: JD
authors.lastname: Lutterbaugh
authors.forename: Robert C
authors.initials: RC
authors.lastname: Elston
authors.forename: Martina L
authors.initials: ML
authors.lastname: Veigl
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
authors.forename: Li
authors.initials: L
authors.lastname: Li
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012306:Risk
chemical_list: D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase