Cyclooxygenase-2 polymorphisms, aspirin treatment, and risk for colorectal adenoma recurrence--data from a randomized clinical trial.
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.
Barry
Elizabeth L
EL
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
Sansbury
Leah B
LB
Grau
Maria V
MV
Ali
Iqbal U
IU
Tsang
Shirley
S
Munroe
David J
DJ
Ahnen
Dennis J
DJ
Sandler
Robert S
RS
Saibil
Fred
F
Gui
Jiang
J
Bresalier
Robert S
RS
McKeown-Eyssen
Gail E
GE
Burke
Carol
C
Baron
John A
JA
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
D052246:Cyclooxygenase 2 Inhibitors; D005492:Folic Acid; D051546:Cyclooxygenase 2; D001241:Aspirin