title: Genetic variation in the lipoxygenase pathway and risk of colorectal neoplasia.
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.
authors: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Sarah E
authors: SE
authors: Kleinstein
authors: Laura
authors: L
authors: Heath
authors: Karen W
authors: KW
authors: Makar
authors: Elizabeth M
authors: EM
authors: Poole
authors: Brenna L
authors: BL
authors: Seufert
authors: Martha L
authors: ML
authors: Slattery
authors: Liren
authors: L
authors: Xiao
authors: David J
authors: DJ
authors: Duggan
authors: Li
authors: L
authors: Hsu
authors: Karen
authors: K
authors: Curtin
authors: Lisel
authors: L
authors: Koepl
authors: Jill
authors: J
authors: Muehling
authors: Darin
authors: D
authors: Taverna
authors: Bette J
authors: BJ
authors: Caan
authors: Christopher S
authors: CS
authors: Carlson
authors: John D
authors: JD
authors: Potter
authors: Cornelia M
authors: CM
authors: Ulrich
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins / Q000235:genetics; D000236:Adenoma / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D017422:Sequence Analysis, DNA
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D001092:Arachidonate 12-Lipoxygenase; C476558:ALOX12 protein, human; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase
references: Cerebrovasc Dis. 2010;29(6):528-37
references: 20357438
references: Hum Hered. 2008;65(1):1-8
references: 17652958
references: Nat Rev Cancer. 2006 Feb;6(2):130-40
references: 16491072
references: Cancer Epidemiol Biomarkers Prev. 1999 Aug;8(8):659-68
references: 10744125
references: N Engl J Med. 2003 Mar 6;348(10):883-90
references: 12621132
references: Cancer Res. 1997 Jan 1;57(1):75-80
references: 8988044
references: Genes Chromosomes Cancer. 2012 Jun;51(6):598-605
references: 22371331
references: Chest. 2011 Jul;140(1):16-18
references: 21729890
references: Hum Mutat. 2006 Jan;27(1):78-87
references: 16320347
references: J Natl Cancer Inst. 2000 Jul 19;92(14):1136-42
references: 10904086
references: Cancer Epidemiol Biomarkers Prev. 2006 Mar;15(3):502-8
references: 16537708
references: Biomed Pharmacother. 1999 Aug;53(7):303-8
references: 10472428
references: Cancer Epidemiol Biomarkers Prev. 2010 Jan;19(1):89-100
references: 20056627
references: Tumour Biol. 2009;30(4):185-99
references: 19752603
references: Br J Cancer. 2004 May 4;90(9):1760-4
references: 15150618
references: Cancer Epidemiol Biomarkers Prev. 2002 Nov;11(11):1305-15
references: 12433707
references: Cancer Epidemiol Biomarkers Prev. 1996 Oct;5(10):779-84
references: 8896888
references: Genet Test Mol Biomarkers. 2009 Jun;13(3):361-5
references: 19473080
references: Science. 2001 Nov 30;294(5548):1871-5
references: 11729303
references: Am J Pathol. 2002 Aug;161(2):421-8
references: 12163367
references: Pharmacogenomics J. 2008 Aug;8(4):237-47
references: 18195728
references: Obesity (Silver Spring). 2009 Sep;17(9):1657-63
references: 19521344
references: Am J Epidemiol. 2003 Aug 1;158(3):214-24
references: 12882943
references: Cell Mol Life Sci. 2002 May;59(5):799-807
references: 12088280
references: Am J Hum Genet. 2004 Jan;74(1):106-20
references: 14681826
references: Allergy. 2006 Jan;61(1):97-103
references: 16364163
references: Cancer Epidemiol Biomarkers Prev. 2004 Apr;13(4):538-45
references: 15066917
references: Atherosclerosis. 2011 Apr;215(2):411-6
references: 21316676
references: Proc Natl Acad Sci U S A. 1996 May 28;93(11):5241-6
references: 8643560
references: Autoimmunity. 2009 May;42(4):383-5
references: 19811308
references: Prostate. 1998 Nov 1;37(3):161-73
references: 9792133
references: Heart Vessels. 2010 Sep;25(5):368-73
references: 20676957
references: J Biol Chem. 2011 Jul 8;286(27):23920-7
references: 21558275
references: Calcif Tissue Int. 2007 Jul;81(1):10-7
references: 17520163
references: Calcif Tissue Int. 2008 Sep;83(3):155-66
references: 18787887
references: Br J Pharmacol. 2010 Aug;160(8):1963-72
references: 20649594
references: FASEB J. 2001 Sep;15(11):2007-9
references: 11511519
references: Nutr Cancer. 2003;46(2):166-71
references: 14690792
references: Int J Cancer. 2004 Sep 20;111(5):750-6
references: 15252846
references: Mol Cancer Ther. 2002 Sep;1(11):929-35
references: 12481414
references: Behav Brain Res. 2001 Nov 1;125(1-2):279-84
references: 11682119
references: Cancer Res. 2002 Jun 15;62(12):3361-4
references: 12067974
references: Am J Respir Crit Care Med. 2000 Feb;161(2 Pt 2):S77-80
references: 10673232
references: Carcinogenesis. 2012 Jan;33(1):108-12
references: 22045029
references: Pharmacogenomics J. 2011 Oct;11(5):337-47
references: 20548327
references: Inflamm Bowel Dis. 2007 Apr;13(4):416-23
references: 17206686
references: FASEB J. 2003 Nov;17(14):1986-95
references: 14597668
references: Cancer Epidemiol Biomarkers Prev. 2010 Feb;19(2):547-57
references: 20086108
references: J Lipid Res. 2011 May;52(5):991-1003
references: 21296957
references: Cancer Prev Res (Phila). 2012 Feb;5(2):164-78
references: 22084361
references: Carcinogenesis. 2005 Apr;26(4):785-91
references: 15661803
references: Cancer Res. 2001 Sep 1;61(17):6307-12
references: 11522616
references: Int J Oncol. 2010 Jun;36(6):1541-9
references: 20428779
references: Carcinogenesis. 2007 Jun;28(6):1259-63
references: 17277229
references: N Engl J Med. 2004 Jan 1;350(1):29-37
references: 14702425
references: Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):616-9
references: 15767339
references: Carcinogenesis. 2011 Nov;32(11):1660-7
references: 21859832
references: Cancer. 2007 Mar 1;109(5):849-57
references: 17236225
references: J Clin Invest. 1997 Mar 1;99(5):1130-7
references: 9062372
references: Clin Cancer Res. 2011 Nov 15;17(22):7139-47
references: 21976545
references: Stroke. 2009 Nov;40(11):3436-42
references: 19729601
references: Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):4015-21
references: 15217933
references: Mediators Inflamm. 2010;2010:
references: 20953328
references: Nat New Biol. 1971 Jun 23;231(25):232-5
references: 5284360
references: Adv Exp Med Biol. 2003;525:201-4
references: 12751768
references: Epidemiology. 1990 Jan;1(1):43-6
references: 2081237
references: Clin Exp Allergy. 2010 Apr;40(4):582-9
references: 20067482
references: N Engl J Med. 2003 Mar 6;348(10):891-9
references: 12621133
references: Cancer Epidemiol Biomarkers Prev. 2004 May;13(5):889-93
references: 15159324
references: Clin Exp Allergy. 2003 Aug;33(8):1103-10
references: 12911785
references: J Natl Cancer Inst. 1998 Nov 4;90(21):1609-20
references: 9811310
references: Allergy. 2008 Aug;63(8):1046-53
references: 18547289
references: J Bone Miner Res. 2006 Apr;21(4):556-64
references: 16598376
references: Cancer Res. 2001 May 1;61(9):3566-9
references: 11325819
references: Int J Obes Relat Metab Disord. 1998 Feb;22(2):178-84
references: 9504326
references: Prostaglandins Leukot Essent Fatty Acids. 2006 Feb;74(2):125-34
references: 16364620
references: Arch Med Res. 2010 Nov;41(8):634-41
references: 21199733
references: Carcinogenesis. 2007 Jun;28(6):1197-201
references: 17151091
references: Int J Cancer. 1991 Nov 11;49(5):774-86
references: 1937964
references: J Zhejiang Univ Sci B. 2009 Mar;10(3):219-29
references: 19283877
references: Carcinogenesis. 2004 Dec;25(12):2467-72
references: 15308583