Sayers, I., Barton, S., Rorke, S., Sawyer, J., Peng, Q., Beghe, B., Ye, S., Keith, T., Clough, J.B., Holloway, J.W., Sampson, A.P. and Holgate, S.T.
Promoter polymorphism in the 5-lipoxygenase (ALOX5) and 5-lipoxygenase-activating protein (ALOX5AP) genes and asthma susceptibility in a Caucasian population
Clinical & Experimental Allergy, 33, (8), . (doi:10.1046/j.1365-2222.2003.01733.x).
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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.
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