Prostacyclin synthase and arachidonate 5-lipoxygenase polymorphisms and risk of colorectal polyps.
Prostacyclin synthase (PGIS) and arachidonate 5-lipoxygenase (ALOX5) are enzymes relevant to prostaglandin and leukotriene synthesis, both important pathways for colon cancer risk. We hypothesized that genetic variation altering the function of these enzymes would modify risk of colorectal polyps. In a Minnesota-based case-control study of adenomatous (n = 517) or hyperplastic (n = 192) polyps versus polyp-free controls (n = 618), we investigated the role of promoter repeat polymorphisms in PGIS and ALOX5 as well as ALOX5 -1700 G>A. Having fewer than six repeats on both PGIS alleles (<6R/<6R) was associated with an increased risk of adenomas compared with the 6R/6R (wild-type) genotype (OR, 1.90; 95% CI, 1.09-3.30). Having more repeats (>6R/> or =6R) reduced risk (OR, 0.73; 95% CI, 0.40-1.35; P(trend) = 0.03). In allele-based analyses, fewer repeats were associated with a modestly increased risk of adenomas and perhaps hyperplastic polyps. There were no risk differences for either the ALOX5 VNTR or -1700 G>A polymorphisms. Associations with regular use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) differed by PGIS genotype. Among individuals with at least one wild-type allele, NSAID use was associated with a decreased risk; however, those with fewer PGIS repeats (<6R/<6R) did not benefit (P(interaction) = 0.06). There was also evidence of an interaction between the COX-2 -765 G>C and ALOX5 -1700 G>A genotypes (P(interaction) = 0.07). The PGIS promoter polymorphism may affect risk of colorectal polyps and modify the effects of NSAID use on polyp risk. A more comprehensive investigation of genetic variability in prostaglandin synthesis in relation to risk of colorectal neoplasia and NSAID pharmacogenetics is warranted.
Poole
Elizabeth M
EM
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M4-B402, Seattle, WA 98109-1024, USA.
Bigler
Jeannette
J
Whitton
John
J
Sibert
Justin G
JG
Potter
John D
JD
Ulrich
Cornelia M
CM
D018256:Adenomatous Polyps / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D000328:Adult; D017677:Age Distribution; D000368:Aged; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics*; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000032:analysis; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005838:Genotype; D006801:Humans; D015994:Incidence; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011379:Prognosis; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D017678:Sex Distribution; D015996:Survival Rate
D014408:Biomarkers, Tumor; D003577:Cytochrome P-450 Enzyme System; D001094:Arachidonate 5-Lipoxygenase; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase