Genetic variation in the lipoxygenase pathway and risk of colorectal neoplasia |
| |
Authors: | Sarah E Kleinstein Laura Heath Karen W Makar Elizabeth M Poole Brenna L Seufert Martha L Slattery Liren Xiao David J Duggan Li Hsu Karen Curtin Lisel Koepl Jill Muehling Darin Taverna Bette J Caan Christopher S Carlson John D Potter Cornelia M Ulrich |
| |
Institution: | 1. Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;2. Department of Epidemiology, University of Washington, Seattle, WA 98195;3. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;4. Department of Medicine, School of Medicine, University of Utah, Salt Lake City, UT 84108;5. The Translational Genomics Research Institute, Phoenix, AZ 85004;6. Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA 94612;7. Centre for Public Health Research, Massey University, Wellington, New Zealand 6140;8. National Center for Tumor Diseases and German Cancer Research Center, Heidelberg D‐69120, Germany |
| |
Abstract: | Arachidonate lipoxygenase (ALOX) enzymes metabolize arachidonic acid to generate potent inflammatory mediators and play an important role in inflammation‐associated diseases. We investigated associations between colorectal cancer risk and polymorphisms in ALOX5, FLAP, ALOX12, and ALOX15, and their interactions with nonsteroidal anti‐inflammatory drug (NSAID) use. We genotyped fifty tagSNPs, one candidate SNP, and two functional promoter variable nucleotide tandem repeat (VNTR) polymorphisms in three US population‐based case‐control studies of colon cancer (1,424 cases/1,780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). Individuals with variant genotypes of the ALOX5 VNTR had a decreased risk of rectal cancer, with the strongest association seen for individuals with one or more alleles of >5 repeats (wild type = 5, OR>5/≥5 = 0.42, 95% CI 0.20–0.92; P = 0.01). Four SNPs in FLAP (rs17239025), ALOX12 (rs2073438), and ALOX15 (rs4796535 and rs2619112) were associated with rectal cancer risk at P ≤ 0.05. One SNP in FLAP (rs12429692) was associated with adenoma risk. A false discovery rate (FDR) was applied to account for false positives due to multiple testing; the ALOX15 associations were noteworthy at 25% FDR. Colorectal neoplasia risk appeared to be modified by NSAID use in individuals with variant alleles in FLAP and ALOX15. One noteworthy interaction (25% FDR) was observed for rectal cancer. Genetic variability in ALOXs may affect risk of colorectal neoplasia, particularly for rectal cancer. Additionally, genetic variability in FLAP and ALOX15 may modify the protective effect of NSAID use against colorectal neoplasia. © 2013 Wiley Periodicals, Inc. |
| |
Keywords: | |
|
|