BACKGROUND: 5-Lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FLAP) are essential for cysteinyl-leukotriene (cys-LT) production, critical mediators in asthma. OBJECTIVE: We sought to identify novel promoter polymorphisms within the FLAP (ALOX5AP) gene promoter and test the role of these and the previously identified 5-LO (ALOX5) Sp1 promoter polymorphism in asthma susceptibility. METHODS: To assess genetic association with asthma phenotypes, we genotyped 341 Caucasian families (containing two asthmatic siblings) and non-asthmatic control subjects (n=184). Genetic association was determined by case-control and transmission disequilibrium test (TDT) analyses. To determine the functional role of polymorphisms on basal transcription, we generated ALOX5AP-promoter-luciferase constructs and transiently transfected human HeLa cells. RESULTS: A novel G/A substitution at -336 bp and a poly(A) repeat (n=19 or 23) at position -169 to -146 bp were identified in the ALOX5AP promoter. Genotyping found the -336 A and poly(A19) alleles at frequencies of q=0.06 and 0.12, respectively. No ALOX5AP allele was associated with asthma or asthma-related phenotypes in case-control or TDT analyses. ALOX5AP-promoter-luciferase analyses did not support a functional role of the -336 or poly(A) polymorphism in determining basal transcription. The ALOX5 Sp1 polymorphism was predominantly homozygous wild-type 5/5 (frequency q=0.70) and heterozygous 4/5 (q=0.23) genotypes and no allele was associated with asthma or asthma-related phenotypes. CONCLUSION: Taken together, these data do not support a significant role for these polymorphisms in genetic susceptibility to asthma in the Caucasian population.
BACKGROUND:5-Lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FLAP) are essential for cysteinyl-leukotriene (cys-LT) production, critical mediators in asthma. OBJECTIVE: We sought to identify novel promoter polymorphisms within the FLAP (ALOX5AP) gene promoter and test the role of these and the previously identified 5-LO (ALOX5) Sp1 promoter polymorphism in asthma susceptibility. METHODS: To assess genetic association with asthma phenotypes, we genotyped 341 Caucasian families (containing two asthmatic siblings) and non-asthmatic control subjects (n=184). Genetic association was determined by case-control and transmission disequilibrium test (TDT) analyses. To determine the functional role of polymorphisms on basal transcription, we generated ALOX5AP-promoter-luciferase constructs and transiently transfected human HeLa cells. RESULTS: A novel G/A substitution at -336 bp and a poly(A) repeat (n=19 or 23) at position -169 to -146 bp were identified in the ALOX5AP promoter. Genotyping found the -336 A and poly(A19) alleles at frequencies of q=0.06 and 0.12, respectively. No ALOX5AP allele was associated with asthma or asthma-related phenotypes in case-control or TDT analyses. ALOX5AP-promoter-luciferase analyses did not support a functional role of the -336 or poly(A) polymorphism in determining basal transcription. The ALOX5 Sp1 polymorphism was predominantly homozygous wild-type 5/5 (frequency q=0.70) and heterozygous 4/5 (q=0.23) genotypes and no allele was associated with asthma or asthma-related phenotypes. CONCLUSION: Taken together, these data do not support a significant role for these polymorphisms in genetic susceptibility to asthma in the Caucasian population.
Authors: John J Lima; Shu Zhang; Audrey Grant; Lianhe Shao; Kelan G Tantisira; Hooman Allayee; Jianwei Wang; James Sylvester; Janet Holbrook; Robert Wise; Scott T Weiss; Kathleen Barnes Journal: Am J Respir Crit Care Med Date: 2005-11-17 Impact factor: 21.405
Authors: Alexa J Resler; Karen W Makar; Laura Heath; John Whitton; John D Potter; Elizabeth M Poole; Nina Habermann; Dominique Scherer; David Duggan; Hansong Wang; Noralane M Lindor; Michael N Passarelli; John A Baron; Polly A Newcomb; Loic Le Marchand; Cornelia M Ulrich Journal: Carcinogenesis Date: 2014-06-07 Impact factor: 4.944
Authors: Miles D Thompson; Jun Takasaki; Valérie Capra; G Enrico Rovati; Kathy A Siminovitch; W McIntyre Burnham; Thomas J Hudson; Yohan Bossé; David E C Cole Journal: Mol Diagn Ther Date: 2006 Impact factor: 4.074
Authors: Nina Habermann; Cornelia M Ulrich; Abbie Lundgreen; Karen W Makar; Elizabeth M Poole; Bette Caan; Richard Kulmacz; John Whitton; Rachel Galbraith; John D Potter; Martha L Slattery Journal: Genes Nutr Date: 2012-06-08 Impact factor: 5.523
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