title: Variants downstream of the ornithine decarboxylase gene influence risk of colorectal adenoma and aspirin chemoprevention.
abstract: Increased mucosal polyamine levels and ornithine decarboxylase (ODC) activity are associated with an increased risk of colorectal neoplasia and aspirin treatment reduces risk. Previous studies suggest that a single-nucleotide polymorphism (SNP) in the promoter of the ODC gene (rs2302615) may be associated with adenoma risk and/or response to aspirin chemoprevention. However, a comprehensive investigation of common genetic variation in the region of ODC gene is lacking. Using a tag SNP approach, we investigated associations between genotype or haplotype and adenoma risk among a cohort of 792 non-Hispanic white participants in a randomized trial of aspirin. Generalized linear regression was used to compute relative risks (RR) and 95% confidence intervals (95% CI) adjusted for age and sex. The false discovery rate was used to account for multiple testing. Interactions terms were used to assess whether genotype modified the effect of aspirin treatment. Of 15 SNPs analyzed, seven were statistically significantly associated with adenoma risk. However, in multiple SNP regression models, only two of these, located downstream of the gene, were independently associated with risk: rs11694911 (RR = 1.29; 95% CI, 1.08-1.53; P = 0.005) and rs2430420 (RR = 1.20; 95% CI, 1.03-1.40; P = 0.022). In addition, there was evidence that rs2430420 and rs28362380 modified the effect of aspirin treatment, whereas the previously investigated SNP, rs2302615, had no statistically significant main effect or interaction with aspirin treatment. Our findings suggest that common genetic variants located downstream (3') of the ODC gene influence risk of colorectal adenoma and may also impact the efficacy of aspirin chemoprevention.
authors.affiliation: Department of Community and Family Medicine, Dartmouth Medical School, 46 Centerra Parkway, Suite 300, Lebanon, NH 03766, USA. Elizabeth.L.Barry@dartmouth.edu
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Barry
authors.forename: Leila A
authors.initials: LA
authors.lastname: Mott
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sandler
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Ahnen
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
mesh_terms: D000236:Adenoma / Q000188:drug therapy / Q000235:genetics* / Q000517:prevention & control; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001241:Aspirin / Q000627:therapeutic use*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000517:prevention & control; D005260:Female; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D018570:Risk Assessment; D016037:Single-Blind Method
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin