Abstract 3761: ALOX5 and FLAP tagSNPs, NSAID use and colorectal neoplasia risk
Authors: Kleinstein Sarah E. , Poole Elizabeth M. , Slattery Martha L. , Xiao Liren , Duggan David , Hsu Li , Makar Karen W. , Curtin Karen , Koepl Lisel , Muehling Jill , Taverna Darin , Caan Bette J. , Carlson Christopher S. , Potter John D. , Ulrich Cornelia M. 
Published: June 2012

Introduction: 5-Lipoxygenase-activating protein (FLAP) binds to arachidonic acid (AA) and activates arachidonate 5-lipoxygenase (ALOX5). ALOX5 is upregulated in colon cancer and is involved in the synthesis of leukotriene A4, which plays an important role in immunity and inflammation. ALOX5 also competes with the prostaglandin H synthases PTGS1 and PTGS2, which convert AA into prostaglandins. NSAIDs reduce the risk of colorectal neoplasia and inhibit PTGS1 and PTGS2. We investigated associations between ALOX5 and FLAP and risk of colorectal neoplasia, as well as potential NSAID interactions in three independent study populations that capture the range of colorectal carcinogenesis by including both adenoma and cancer cases.

Methods: A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r2=0.90, MAF=4%) identified 32 tagSNPs in FLAP, representing common genetic variation in Europeans. ALOX5 lacked resequencing data, and we were only able to look at candidate polymorphisms. We used an identical Illumina platform to investigate FLAP SNPs and 1 ALOX5 candidate SNP in three US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). VNTR polymorphisms in both genes were also genotyped. Multiple logistic regression analysis was used, adjusting for age, sex, center and restricted to Caucasians (&gt;90% of all study participants). A p value &lt; 0.05 without multiple comparison adjustment was considered statistically significant.

Results: The variant ALOX5 allele of rs4986832 G&gt;A showed a significant trend towards decreased risk of rectal cancer (ORhzv=0.65; 95% CI 0.43-0.98; p-trend=0.04). For FLAP, several SNPs showed increased risk of colorectal neoplasia across all three studies, with the strongest associations for: rs12429692 A&gt;T ORhzv=2.05, 95% CI 1.20-3.53 in adenoma (global p=0.01); rs17239025 G&gt;C ORhet/hzv=1.43, 95% CI 1.01-2.04 in rectal cancer (global p=0.05, p-trend=0.04); rs17222919 A&gt;C ORhzv=1.55, 95% CI 1.00-2.42 in rectal cancer (p-trend=0.05). The inverse association with NSAID use was stronger among those with the wildtype genotype for rs9551960 A&gt;G (rectal cancer p-interaction=0.05) and rs17239025 G&gt;C (colon cancer p-int=0.02), whereas those with variant genotypes had greater NSAID risk reduction of rectal cancer for rs9315053 A&gt;C (p-int=0.03), rs9508832 G&gt;A (p-int=0.02), and rs9506352 G&gt;A (p-int=0.04).

Conclusion: We show evidence that genetic variability in ALOX5 and FLAP may affect risk of colorectal neoplasia. These results suggest that, in ALOX5, rs4986832 is associated with a decreased risk of rectal cancer, whereas FLAP SNPs rs12429692, rs17239025 and rs17222919 increase colorectal neoplasia risk. Additionally, we provide evidence that genetic variability in FLAP may modify the protective association of NSAID use against colorectal neoplasia.

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 3761. doi:10.1158/1538-7445.AM2011-3761