Aspirin and
eicosapentaenoic acid (EPA) reduce colorectal
adenomatous polyp risk and affect synthesis of
oxylipins including
prostaglandin E2. We investigated whether 35 SNPs in
oxylipin metabolism genes such as
cyclooxygenase (PTGS) and
lipoxygenase (ALOX), as well as 7 SNPs already associated with
colorectal cancer risk reduction by
aspirin (e.g., TP53; rs104522), modified the effects of
aspirin and EPA on colorectal
polyp recurrence in the randomized 2 × 2 factorial seAFOod trial. Treatment effects were reported as the incidence rate ratio (
IRR) and 95% confidence interval (CI) by stratifying negative binomial and Poisson regression analyses of colorectal
polyp risk on SNP genotype. Statistical significance was reported with adjustment for the false discovery rate as the P and q value. 542 (of 707) trial participants had both genotype and colonoscopy outcome data. Reduction in colorectal
polyp risk in
aspirin users compared with nonaspirin users was restricted to rs4837960 (PTGS1) common homozygotes [
IRR, 0.69; 95% confidence interval (CI), 0.53-0.90); q = 0.06], rs2745557 (
PTGS2) compound heterozygote-rare homozygotes [
IRR, 0.60 (0.41-0.88); q = 0.06], rs7090328 (ALOX5) rare homozygotes [
IRR 0.27 (0.11-0.64); q = 0.05], rs2073438 (ALOX12) common homozygotes [
IRR, 0.57 (0.41-0.80); q = 0.05], and rs104522 (TP53) rare homozygotes [
IRR, 0.37 (0.17-0.79); q = 0.06]. No modification of colorectal
polyp risk in EPA users was observed. In conclusion, genetic variants relevant to the proposed mechanism of action on
oxylipins are associated with differential colorectal
polyp risk reduction by
aspirin in individuals who develop multiple colorectal
polyps. SNP genotypes should be considered during development of personalized, predictive models of
colorectal cancer chemoprevention by
aspirin.
PREVENTION RELEVANCE: Single-nucleotide polymorphisms in genes controlling
lipid mediator signaling may modify the colorectal
polyp prevention activity of
aspirin. Further investigation is required to determine whether testing for genetic variants can be used to target
cancer chemoprevention by
aspirin to those who will benefit most.