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Association of angiotensin I-converting enzyme gene polymorphisms with aspirin intolerance in asthmatics.

Authors
Kim, TH; Chang, HS; Park, SM; Nam, BY; Park, JS; Rhim, T; Park, HS; Kim, MK; Choi, IS; Cho, SH; Chung, IY; Park, BL; Park, CS; Shin, HD
Citation
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 38(11):1727-1737, 2008
Journal Title
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
ISSN
0954-78941365-2222
Abstract
BACKGROUND: Aspirin-intolerant asthma (AIA) refers to the development of bronchoconstriction in asthmatic individuals following the ingestion of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). Angiotensin I-converting enzyme (ACE), a membrane-bound peptidase present in the lung, plays a pivotal role in the metabolism of the endogenous peptides involved in the pathogenesis of asthma. METHODS: We screened a Korean asthma cohort (581 asthmatics including 81 aspirin-intolerant asthmatics and 231 aspirin-tolerant asthmatics, and 181 normal controls) for four single nucleotide polymorphisms (SNPs; -262 A>T and -115 T>C in the 5'-flanking region and +5467 T>C [Pro450Pro] and+11860 A>G [Thr776Thr] in the coding region) and one ins/del (+21288 CT) in the ACE gene. RESULTS: None of the SNPs or haplotypes showed any association with the development of asthma, but they were significantly associated with the risk of AIA. Logistic regression indicated that the frequency of the rare alleles of -262 A>T and -115 T>C was higher in subjects with AIA than in subjects with aspirin-tolerant asthma (ATA) (P=0.003-0.01, P( corr)=0.015-0.05). Subjects homozygous for the rare alleles of -262 A>T and -115 T>C showed a greater decline in forced expiratory volume in 1 s (FEV(1)) after aspirin provocation than those homozygous for the common alleles (P<0.05). A luciferase reporter assay indicated that ACE promoters containing the rare -262 A>T allele possessed lower activity than did those containing the common allele (P=0.009). In addition, ACE promoters bearing the rare -115 T>C allele had no luciferase activity. DNA-protein binding assays revealed a band containing the ACE promoter region (including -262 A) and a protein complex. CONCLUSION: The -262 A>T polymorphism in the promoter of the ACE gene is associated with AIA, and the rare allele of -262 A>T may confer aspirin hypersensitivity via the down-regulation of ACE expression.
MeSH terms
AdolescentAdultAgedAged, 80 and overAspirin/administration & dosageAspirin/adverse effects*Asthma/complicationsAsthma/genetics*Asthma/physiopathology*Binding Sites/geneticsChildDrug Hypersensitivity/complicationsDrug Hypersensitivity/genetics*Drug Hypersensitivity/physiopathologyFemaleForced Expiratory Volume/physiologyGene Expression/geneticsGene Frequency/geneticsHaplotypes/geneticsHumansLogistic ModelsMaleMiddle AgedPeptidyl-Dipeptidase A/genetics*Polymorphism, Genetic/geneticsPolymorphism, Single Nucleotide/geneticsPolymorphism, Single Nucleotide/immunologyPromoter Regions, Genetic/geneticsTranscription Factors/metabolismYoung Adult
DOI
10.1111/j.1365-2222.2008.03082.x
PMID
18727619
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Journal Papers > School of Medicine / Graduate School of Medicine > Allergy
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