title: Cyclooxygenase-2 polymorphisms, aspirin treatment, and risk for colorectal adenoma recurrence--data from a randomized clinical trial.
abstract: Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in the production of prostaglandins, potent mediators of inflammation. Chronic inflammation plays an important role in the development and progression of colorectal cancer. Aspirin inhibits COX-2 activity and lowers the risk for colorectal adenomas and cancer. We investigated whether common genetic variation in COX-2 influenced risk for colorectal adenoma recurrence among 979 participants in the Aspirin/Folate Polyp Prevention Study who were randomly assigned to placebo or aspirin and followed for 3 years for the occurrence of new adenomas. Of these participants, 44.2% developed at least one new adenoma during follow-up. Adjusted relative risks and 95% confidence intervals (95% CI) were calculated to test the association between genetic variation at six COX-2 single-nucleotide polymorphisms and adenoma occurrence and interaction with aspirin treatment. Two single-nucleotide polymorphisms were significantly associated with increased adenoma recurrence: for rs5277, homozygous carriers of the minor C allele had a 51% increased risk compared with GG homozygotes (relative risk, 1.51; 95% CI, 1.01-2.25), and for rs4648310, heterozygous carriers of the minor G allele had a 37% increased risk compared with AA homozygotes (relative risk, 1.37; 95% CI, 1.05-1.79). (There were no minor allele homozygotes.) In stratified analyses, there was suggestive evidence that rs4648319 modified the effect of aspirin. These results support the hypothesis that COX-2 plays a role in the etiology of colon cancer and may be a target for aspirin chemoprevention and warrant further investigation in other colorectal adenoma and cancer populations.
authors.affiliation: Department of Community and Family Medicine, Dartmouth Medical School, Suite 300, Evergreen Center, 46 Centerra Parkway, Lebanon, NH 03756, USA. Elizabeth.L.Barry@Dartmouth.edu
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Barry
authors.forename: Leah B
authors.initials: LB
authors.lastname: Sansbury
authors.forename: Maria V
authors.initials: MV
authors.lastname: Grau
authors.forename: Iqbal U
authors.initials: IU
authors.lastname: Ali
authors.forename: Shirley
authors.initials: S
authors.lastname: Tsang
authors.forename: David J
authors.initials: DJ
authors.lastname: Munroe
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Ahnen
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sandler
authors.forename: Fred
authors.initials: F
authors.lastname: Saibil
authors.forename: Jiang
authors.initials: J
authors.lastname: Gui
authors.forename: Robert S
authors.initials: RS
authors.lastname: Bresalier
authors.forename: Gail E
authors.initials: GE
authors.lastname: McKeown-Eyssen
authors.forename: Carol
authors.initials: C
authors.lastname: Burke
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
mesh_terms: D000236:Adenoma / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D000368:Aged; D001241:Aspirin / Q000008:administration & dosage*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D005260:Female; D005492:Folic Acid / Q000235:genetics / Q000627:therapeutic use; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D005492:Folic Acid; D051546:Cyclooxygenase 2; D001241:Aspirin