title: Polymorphisms in PTGS1 (=COX-1) and risk of colorectal polyps.
abstract: Two isoforms of prostaglandin H synthase (PTGS = COX) are key enzymes in prostaglandin synthesis and primary targets for aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). Use of aspirin or other NSAIDs is associated with a lower risk and reduced recurrence of colorectal adenomas, established precursors of adenocarcinoma. This study investigated risk of colorectal adenomatous and hyperplastic polyps associated with several polymorphisms in the coding region of PTGS1. Within the Minnesota polyp case-control study, patients with colorectal adenomatous (n = 521) or hyperplastic (n = 194) polyps and n = 621 polyp-free controls were genotyped for four PTGS1 polymorphisms (R8W, L15-L16del, P17L, L237M); these had been predicted to affect protein function based on sequence-homology software. Age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed. Whereas there was no appreciable difference in adenoma or hyperplastic polyp risk associated with R8W, P17L, and L237M, an increased risk was observed for individuals heterozygous for the L15-L16del polymorphism (OR = 3.6, 95% CI 1.2-11.2). The variant L15-L16del allele appeared to be associated with a stronger increase in adenoma risk among nonusers of aspirin/other NSAIDs. The reduced risk observed with aspirin/other NSAID use was limited to those wild type for P17L [PP users: OR = 0.6 (0.5-0.8) versus PP nonusers: 1.0 (referent) (P interaction = 0.03)]. To our knowledge, this study represents the first investigation of polymorphisms in PTGS1 and risk of colorectal polyps. The L15-L16del variant allele may result in an increased risk of colorectal adenomas, whereas P17L may be relevant to the pharmacogenetics of aspirin. These preliminary findings require confirmation in larger studies of colorectal neoplasia.
authors.affiliation: Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, M4-B402, Seattle, WA 98109-1024, USA. nulrich@fhcrc.org
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
authors.forename: Jeannette
authors.initials: J
authors.lastname: Bigler
authors.forename: Rachel
authors.initials: R
authors.lastname: Sparks
authors.forename: John
authors.initials: J
authors.lastname: Whitton
authors.forename: Justin G
authors.initials: JG
authors.lastname: Sibert
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yasui
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
mesh_terms: D018256:Adenomatous Polyps / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000328:Adult; D017677:Age Distribution; D000368:Aged; D016022:Case-Control Studies; D003111:Colonic Polyps / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D003113:Colonoscopy; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D016001:Confidence Intervals; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015994:Incidence; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011379:Prognosis; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012016:Reference Values; D018570:Risk Assessment; D017678:Sex Distribution
chemical_list: D011451:Prostaglandin-Endoperoxide Synthases