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

Authors

  • T-H. Kim,

    1. Genome Research Center for Allergy and Respiratory Disease, Soonchunhyang University Bucheon Hospital, 1174 Jung-dong, Wonmi-gu, Bucheon, Gyeonggi-do 420-767, Korea,
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    • 1Tae-Hoon Kim and Hun-Soo Chang equally contributed as the first authors.

  • H-S. Chang,

    1. Genome Research Center for Allergy and Respiratory Disease, Soonchunhyang University Bucheon Hospital, 1174 Jung-dong, Wonmi-gu, Bucheon, Gyeonggi-do 420-767, Korea,
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    • 1Tae-Hoon Kim and Hun-Soo Chang equally contributed as the first authors.

  • S-M. Park,

    1. Genome Research Center for Allergy and Respiratory Disease, Soonchunhyang University Bucheon Hospital, 1174 Jung-dong, Wonmi-gu, Bucheon, Gyeonggi-do 420-767, Korea,
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  • B-Y. Nam,

    1. Genome Research Center for Allergy and Respiratory Disease, Soonchunhyang University Bucheon Hospital, 1174 Jung-dong, Wonmi-gu, Bucheon, Gyeonggi-do 420-767, Korea,
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  • J-S. Park,

    1. Genome Research Center for Allergy and Respiratory Disease, Soonchunhyang University Bucheon Hospital, 1174 Jung-dong, Wonmi-gu, Bucheon, Gyeonggi-do 420-767, Korea,
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  • T. Rhim,

    1. Genome Research Center for Allergy and Respiratory Disease, Soonchunhyang University Bucheon Hospital, 1174 Jung-dong, Wonmi-gu, Bucheon, Gyeonggi-do 420-767, Korea,
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  • H-S. Park,

    1. Department of Allergy and Rheumatology, Ajou University School of Medicine, Suwon, Korea,
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  • M-K. Kim,

    1. Department of Internal Medicine, Chungbuk National University, College of Medicine, 62 Gaesin-dong, Heungduk-gu, Cheongju, Chungcheongbuk-do 361-711, Korea,
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  • I. S. Choi,

    1. Department of Allergy, Chonnam National University Medical School and Research Institute of Medical Sciences, 8 Hakdong, Dong-gu, Gwangju 501-757, Korea,
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  • S. H. Cho,

    1. Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, 28 Yongon-dong, Chongno-ku, Seoul 110-744, Korea,
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  • I. Y. Chung,

    1. Division of Molecular and Life Science, Hanyang University, Ansan, Gyeonggi-do, Korea,
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  • B-L. Park,

    1. Department of Genetic Epidemiology, SNP Genetics, Inc., 1407 14th Floor, Woolim-rall'ey B, Gasan-dong, Geumcheon-gu, Seoul 153-803, Korea
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  • C-S. Park,

    1. Genome Research Center for Allergy and Respiratory Disease, Soonchunhyang University Bucheon Hospital, 1174 Jung-dong, Wonmi-gu, Bucheon, Gyeonggi-do 420-767, Korea,
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  • H-D. Shin

    1. Department of Genetic Epidemiology, SNP Genetics, Inc., 1407 14th Floor, Woolim-rall'ey B, Gasan-dong, Geumcheon-gu, Seoul 153-803, Korea
    2. Department of Life Science, Sogang University, Shinsu-dong, Mapo-gu, Seoul 121-742, Korea
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Correspondence:
Dr Choon-Sik Park, Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, 1174 Jung-dong, Wonmi-gu, Bucheon, Gyeonggi-do 420-021, Korea. E-mail: mdcspark@unitel.co.kr

Summary

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 (FEV1) 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.

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