Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk.
In the human colon, arachidonic acid is metabolized primarily by cyclooxygenase (COX) and arachidonate lipoxygenase (ALOX) to bioactive lipids, which are implicated in colon cancer risk. Several polymorphisms in ALOX and COX genes have been identified, including G-1752A, G-1699A and Glu254Lys in ALOX5; Gln261Arg in ALOX12; Leu237Met and Val481Ile in COX1; and C-645T and Val511Ala in COX2. Because of the significant role of arachidonic acid metabolism in colon cancer, we hypothesized that these polymorphisms could influence susceptibility to colon cancer. We addressed this hypothesis in African-Americans and Caucasians using colon cancer cases (n = 293) and hospital- (n = 229) and population-based (n = 304) control groups. Polymorphisms did not differ between the control groups (P > 0.05); thus, they are combined for all analyses presented. ALOX5 Glu254Lys and COX2 C-645T and Val511Ala allele frequencies differed between Caucasians and African-American controls (P < 0.001). The ALOX5 -1752 and -1699 polymorphisms were in linkage disequilibrium (P < 0.001) and associated with a decreased risk in Caucasians in ALOX5 haplotype analyses (P = 0.03). Furthermore, an inverse association was observed between A alleles at positions -1752 and -1699 of ALOX5 and colon cancer risk in Caucasians, but not in African-Americans. Caucasians with A alleles at ALOX5 -1752 had a reduced odds of colon cancer versus those with G alleles [odds ratio (OR) (GA versus GG), 0.63; 95% confidence interval (CI), 0.39-1.01; OR (AA versus GG), 0.33; 95% CI, 0.07-1.65, P(trend) = 0.02]. Similar results were observed for ALOX5 G-1699A [OR (GA versus GG), 0.59, 95% CI, 0.37-0.94; OR (AA versus GG), 0.27, 95% CI, 0.06-1.32, P(trend) = 0.01]. Statistically significant associations with colon cancer were not observed for the other polymorphisms investigated. We have shown for the first time that a haplotype containing ALOX5 G-1752A and G-1699A in a negative regulatory region of the promoter may influence colon cancer risk in Caucasians.
Laboratory of Human Carcinogensis, Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892, USA.
Julie E
JE
Goodman
Elise D
ED
Bowman
Stephen J
SJ
Chanock
Anthony J
AJ
Alberg
Curtis C
CC
Harris
D001741:Black or African American; D000368:Aged; D001091:Arachidonate Lipoxygenases / Q000235:genetics*; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012307:Risk Factors; D044465:White People
D007527:Isoenzymes; D008565:Membrane Proteins; D001091:Arachidonate Lipoxygenases; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases