BACKGROUND: Leukotrienes (LTs) have been identified as central mediators in asthma and allergy. Pharmacological inhibition of cysteinyl-LT activity improves asthma symptoms and control. Accumulating evidence suggests a role for the dihydroxy leukotriene LTB(4) in airway disease. LTA(4) hydrolase and 5-lipoxygenase activating protein have key roles in LTB(4) production. Single nucleotide polymorphism (SNPs) and haplotypes spanning the LTA4H and ALOX5AP genes have been associated with LTB(4) production and myocardial infarction (MI). OBJECTIVE: To assess the contribution of LTA4H and ALOX5AP polymorphism to asthma and allergy susceptibility. METHODS: Three hundred and forty-one Caucasian families (two asthmatic siblings) were genotyped for eight SNPs spanning ALOX5AP and five SNPs spanning LTA4H. Association analyses of asthma and related phenotypes (total IgE, atopy, bronchial hyper-responsiveness, FEV(1)) were undertaken using the Family Based Association Test. RESULTS: Single point analyses identified association (P < 0.05) between SNPs SG13S114, SG13S89, SG13S41 (ALOX5AP), rs1978331 (LTA4H) and asthma and/or related phenotypes. Haplotype analyses using all LTA4H SNPs identified a single key risk haplotype for the development of asthma (P = 0.006) and related phenotypes (P = 0.042-0.005). Haplotype analyses using all ALOX5AP SNPs identified several asthma and atopy risk and protective haplotypes. There was limited correlation with previously identified MI risk haplotypes in both genes. Carriers of both ALOX5AP SG13S41 and LTA4H rs1978331 alleles had an increased risk of developing asthma (OR 2.17, CI 1.41-3.32). CONCLUSIONS: These data provide evidence for the role of SNPs spanning the ALOX5AP and LTA4H genes in asthma and atopy susceptibility in the Caucasian population and support a role for LTB(4) in disease pathogenesis.
BACKGROUND:Leukotrienes (LTs) have been identified as central mediators in asthma and allergy. Pharmacological inhibition of cysteinyl-LT activity improves asthma symptoms and control. Accumulating evidence suggests a role for the dihydroxy leukotriene LTB(4) in airway disease. LTA(4) hydrolase and 5-lipoxygenase activating protein have key roles in LTB(4) production. Single nucleotide polymorphism (SNPs) and haplotypes spanning the LTA4H and ALOX5AP genes have been associated with LTB(4) production and myocardial infarction (MI). OBJECTIVE: To assess the contribution of LTA4H and ALOX5AP polymorphism to asthma and allergy susceptibility. METHODS: Three hundred and forty-one Caucasian families (two asthmatic siblings) were genotyped for eight SNPs spanning ALOX5AP and five SNPs spanning LTA4H. Association analyses of asthma and related phenotypes (total IgE, atopy, bronchial hyper-responsiveness, FEV(1)) were undertaken using the Family Based Association Test. RESULTS: Single point analyses identified association (P < 0.05) between SNPs SG13S114, SG13S89, SG13S41 (ALOX5AP), rs1978331 (LTA4H) and asthma and/or related phenotypes. Haplotype analyses using all LTA4H SNPs identified a single key risk haplotype for the development of asthma (P = 0.006) and related phenotypes (P = 0.042-0.005). Haplotype analyses using all ALOX5AP SNPs identified several asthma and atopy risk and protective haplotypes. There was limited correlation with previously identified MI risk haplotypes in both genes. Carriers of both ALOX5AP SG13S41 and LTA4Hrs1978331 alleles had an increased risk of developing asthma (OR 2.17, CI 1.41-3.32). CONCLUSIONS: These data provide evidence for the role of SNPs spanning the ALOX5AP and LTA4H genes in asthma and atopy susceptibility in the Caucasian population and support a role for LTB(4) in disease pathogenesis.
Authors: Berran Yucesoy; Michael L Kashon; Victor J Johnson; Zana L Lummus; Kara Fluharty; Denyse Gautrin; André Cartier; Louis-Philippe Boulet; Joaquin Sastre; Santiago Quirce; Susan M Tarlo; Maria-Jesus Cruz; Xavier Munoz; Michael I Luster; David I Bernstein Journal: J Immunotoxicol Date: 2015-09-04 Impact factor: 3.000
Authors: Gretchen Bain; Christopher D King; Kevin Schaab; Melissa Rewolinski; Virginia Norris; Claire Ambery; Jane Bentley; Masanori Yamada; Angelina M Santini; Jeroen van de Wetering de Rooij; Nicholas Stock; Jasmine Zunic; John H Hutchinson; Jilly F Evans Journal: Br J Clin Pharmacol Date: 2013-03 Impact factor: 4.335
Authors: Haig Tcheurekdjian; Marc Via; Anthony De Giacomo; Harriet Corvol; Celeste Eng; Shannon Thyne; Rocio Chapela; William Rodriguez-Cintron; Jose R Rodriguez-Santana; Pedro C Avila; Esteban González Burchard Journal: J Allergy Clin Immunol Date: 2010-10 Impact factor: 10.793
Authors: Chad R Haldeman-Englert; Taiyabah Naeem; Elizabeth A Geiger; Ashley Warnock; Holly Feret; Melissa Ciano; Stefanie L Davidson; Matthew A Deardorff; Elaine H Zackai; Tamim H Shaikh Journal: Am J Med Genet A Date: 2009-08 Impact factor: 2.802
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 Journal: Genes Chromosomes Cancer Date: 2013-02-12 Impact factor: 5.006
Authors: M Via; A De Giacomo; H Corvol; C Eng; M A Seibold; C Gillett; J Galanter; S Sen; H Tcheurekdjian; R Chapela; J R Rodríguez-Santana; W Rodríguez-Cintrón; S Thyne; P C Avila; S Choudhry; E González Burchard Journal: Clin Exp Allergy Date: 2010-01-11 Impact factor: 5.018
Authors: Douglas R Davies; Bjorn Mamat; Olafur T Magnusson; Jeff Christensen; Magnus H Haraldsson; Rama Mishra; Brian Pease; Erik Hansen; Jasbir Singh; David Zembower; Hidong Kim; Alex S Kiselyov; Alex B Burgin; Mark E Gurney; Lance J Stewart Journal: J Med Chem Date: 2009-08-13 Impact factor: 7.446