Abstract 3756: ALOX12 and ALOX15 tagSNPs, NSAID use, and the risk of colorectal neoplasia
Authors: Karen W. Makar, Elizabeth M. Poole, Liren Xiao, Li Hsu, Karen Curtin, David Duggan, Sarah E. Kleinstein, Jill Muehling, Darin Taverna, Bette J. Caan, Christopher S. Carlson, John D. Potter, Martha L. Slattery, Cornelia M. Ulrich
Journal: Cancer Research (2011)

Abstract Introduction: Arachidonate lipoxygenase (ALOX) enzymes generate potent inflammatory mediators via the metabolism of arachidonic acid. Genetic polymorphisms in the lipoxygenase gene family have been implicated in cancer and inflammatory diseases such as asthma, bone loss, and atherosclerosis. NSAIDs, which reduce colorectal cancer risk, induce apoptosis in colon cancer cells via upregulation of ALOX15. We hypothesize that polymorphisms in lipoxygenases ALOX12 and ALOX15 may influence colorectal neoplasia risk and protective NSAIDs effects. Methods: A linkage-disequilibrium (LD)-based tagSNP-selection algorithm (r2=0.90, MAF=4%) identified tagSNPs in ALOX12 and ALOX15 representing common genetic variation in Europeans. We genotyped 17 SNPs in ALOX12 and 21 SNPs in ALOX15 in three independent study populations that capture the range of colorectal carcinogenesis by including adenoma, colon, and rectal cancer cases. We investigated these SNPs in relation to colorectal neoplasia risk and potential interactions with NSAID use in three US population-based case-control studies of colon cancer (n=1424/1780 cases/controls), rectal cancer (n=583/775), and colorectal adenoma (n=485/578). Multiple logistic regression analysis was used, adjusting for age, sex, and study site, and restricted to Caucasians (&amp;gt;90% of all study participants). A p value &amp;lt; 0.05 without multiple comparison adjustment was considered statistically significant. Results: In ALOX12, rs11571364 was associated with a modestly increased risk of colon cancer among variant allele carriers (OR: 1.23, 95% CI: 1.01-1.51). A risk increase was also seen in rectal cancer, but was not statistically significant (OR: 1.26, 95% CI: 0.92-1.71). The homozygous variant genotype of another SNP in ALOX12 showed a possible reduced risk of rectal cancer (rs2073438, OR: 0.66, 95% CI: 0.42-1.04), but not colon cancer or adenomas. No significant interactions between SNPs in ALOX12 and NSAID use were observed in any of the three studies. In ALOX15, rs2619112 showed a suggested increase in rectal cancer risk. However, the risk was more elevated among those with a heterozygous genotype (OR: 1.37; 95% CI: 1.06-1.77) than among those with a homozygous variant genotype (OR: 1.13, 95% CI: 0.83-1.55). We detected a significant interaction between this SNP and NSAID use. Among NSAID non-users, the homozygous genotype was associated with increased rectal cancer risk (OR: 1.24). Among NSAID users, the homozygous wildtype and homozygous variant genotypes were associated with decreased risk, but there was no association among heterozygous NSAID users (p-interaction=0.04). Conclusion: Polymorphisms in ALOX12 and ALOX15 are associated with risk of rectal and colon cancer, but not colorectal adenomas. An ALOX15 SNP previously associated with bone mineral density levels and coronary artery disease risk was associated with rectal cancer risk and showed possible interaction with NSAID use. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3756. doi:10.1158/1538-7445.AM2011-3756