Journal of Clinical Immunology

, Volume 28, Issue 4, pp 336–342 | Cite as

Association of Four-locus Gene Interaction with Aspirin-intolerant Asthma in Korean Asthmatics

  • Seung-Hyun Kim
  • Hyun-Hwan Jeong
  • Bo-Young Cho
  • MyoungKi Kim
  • Hyun-Young Lee
  • Jungseob Lee
  • Kyubum Wee
  • Hae-Sim Park



Aspirin-intolerant asthma (AIA), a major clinical presentation of aspirin hypersensitivity, affects 10% of adult asthmatics. The genetic risk factors involved in the susceptibility to AIA have recently been investigated, but multilocus single-nucleotide polymorphisms (SNPs) associated with this susceptibility has not been evaluated.


We examined 246 asthmatic patients: 94 having aspirin intolerance and 152 having aspirin tolerance. We selected 23 SNPs of 13 candidate genes and genotyped each SNP using a primer extension method. Multilocus genetic interactions were examined using multifactor dimensionality reduction (MDR) to test all multilocus SNP combinations to identify a useful SNP set for predicting the AIA phenotype.


We identified the best model using the MDR method, which consisted of a four-locus gene–gene interaction with 65.16% balanced accuracy and a cross-validation consistency of 70% in predicting AIA disease risk among asthmatic patients. This model included four SNPs such as B2ADR 46A>G, CCR3–520T>G, CysLTR1–634C>T, and FCER1B–109T>C.


These results suggest that a multilocus SNP acts in combination to influence the susceptibility to aspirin intolerance in asthmatics and could be a useful genetic marker for the diagnosis of AIA.


Aspirin-intolerant asthma multifactor dimensionality reduction single-nucleotide polymorphism multilocus gene interaction 



aspirin-intolerant asthma


aspirin-tolerant asthma


arachidonate 5-lipoxygenase


adrenergic, beta-2-, receptor, surface


chemokine (C-C motif) receptor 3


cysteinyl leukotriene receptor 1


cysteinyl leukotriene receptor 2


Fc fragment of IgE, high affinity I, receptor for; beta polypeptide


interleukin 10


interleukin 13


interleukin 18


leukotriene C4 synthase


nonsteroidal antiinflammatory drug


single-nucleotide polymorphism


thromboxane A2 receptor


transforming growth factor, beta 1


tumor necrosis factor alpha



This study was supported by grants from the Basic Research Program of the Korea Science and Engineering Foundation (R01-2006-000-10775-0) and the Korea Health 21 R&D Project of the Ministry of Health and Welfare, Republic of Korea (A050571).


  1. 1.
    Simon RA. Adverse respiratory reactions to aspirin and nonsteroidal anti-inflammatory drugs. Curr Allergy Asthma Rep. 2004;4:17–24.PubMedCrossRefGoogle Scholar
  2. 2.
    Hamad AM, Sutcliffe AM, Knox AJ. Aspirin-induced asthma: clinical aspects, pathogenesis and management. Drugs. 2004;64:2417–32.PubMedCrossRefGoogle Scholar
  3. 3.
    Jenkins C, Costello J, Hodge L. Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ. 2004;328:434.PubMedCrossRefGoogle Scholar
  4. 4.
    Szczeklik A, Sanak M, Nizankowska-Mogilnicka E, et al. Aspirin intolerance and the cyclooxygenase–leukotriene pathways. Curr Opin Pulm Med. 2004;10:51–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Picado C. Aspirin-intolerant asthma: role of cyclo-oxygenase enzymes. Allergy. 2002;57:58–60.PubMedCrossRefGoogle Scholar
  6. 6.
    Bisgaard H. Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma. Allergy. 2001;56:7–11.PubMedCrossRefGoogle Scholar
  7. 7.
    Kim SH, Oh JM, Kim YS, et al. Cysteinyl leukotriene receptor 1 promoter polymorphism is associated with aspirin-intolerant asthma in males. Clin Exp Allergy. 2006;36:433–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Kim SH, Choi JH, Park HS, et al. Association of thromboxane A2 receptor gene polymorphism with the phenotype of acetyl salicylic acid-intolerant asthma. Clin Exp Allergy. 2005;35:585–90.PubMedCrossRefGoogle Scholar
  9. 9.
    Kim SH, Bae JS, Suh CH, et al. Polymorphism of tandem repeat in promoter of 5-lipoxygenase in ASA-intolerant asthma: a positive association with airway hyperresponsiveness. Allergy. 2005;60:760–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Kim SH, Ye YM, Lee SK, et al. Association of TNF-alpha genetic polymorphism with HLA DPB1*0301. Clin Exp Allergy. 2006;36:1247–53.PubMedCrossRefGoogle Scholar
  11. 11.
    Kim SH, Park HS, Holloway JW, et al. Association between a TGFbeta1 promoter polymorphism and rhinosinusitis in aspirin-intolerant asthmatic patients. Respir Med. 2007;101:490–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Contopoulos-Ioannidis DG, Manoli EN, Ioannidis JP. Meta-analysis of the association of beta2-adrenergic receptor polymorphisms with asthma phenotypes. J Allergy Clin Immunol. 2005;115:963–72.PubMedCrossRefGoogle Scholar
  13. 13.
    Litonjua AA. The significance of beta2-adrenergic receptor polymorphisms in asthma. Curr Opin Pulm Med. 2006;12:12–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Fukunaga K, Asano K, Mao XQ, et al. Genetic polymorphisms of CC chemokine receptor 3 in Japanese and British asthmatics. Eur Respir J. 2001;17:59–63.PubMedCrossRefGoogle Scholar
  15. 15.
    Chatterjee R, Batra J, Kumar A, et al. Interleukin-10 promoter polymorphisms and atopic asthma in North Indians. Clin Exp Allergy. 2005;35:914–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Howard TD, Whittaker PA, Zaiman AL, et al. Identification and association of polymorphisms in the interleukin-13 gene with asthma and atopy in a Dutch population. Am J Respir Cell Mol Biol. 2001;25:377–84.PubMedGoogle Scholar
  17. 17.
    Higa S, Hirano T, Mayumi M, et al. Association between interleukin-18 gene polymorphism 105A/C and asthma. Clin Exp Allergy. 2003;33:1097–102.PubMedCrossRefGoogle Scholar
  18. 18.
    Hahn LW, Ritchie MD, Moore JH. Multifactor dimensionality reduction software for detecting gene–gene and gene–environment interactions. Bioinformatics. 2003;19:376–82.PubMedCrossRefGoogle Scholar
  19. 19.
    Ritchie MD, Hahn LW, Moore JH. Power of multifactor dimensionality reduction for detecting gene–gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. Genet Epidemiol. 2003;24:150–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Sladek K, Szczeklik A. Cysteinyl leukotrienes overproduction and mast cell activation in aspirin-provoked bronchospasm in asthma. Eur Respir J. 1993;6:391–9.PubMedGoogle Scholar
  21. 21.
    Sladek K, Dworski R, Soja J, et al. Eicosanoids in bronchoalveolar lavage fluid of aspirin-intolerant patients with asthma after aspirin challenge. Am J Respir Crit Care Med. 1994;149:940–6.PubMedGoogle Scholar
  22. 22.
    Szczeklik A, Nizankowska E, Duplaga M. Natural history of aspirin-induced asthma. AIANE Investigators. European Network on Aspirin-induced Asthma. Eur Respir J. 2000;16:432–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Kim SH, Bae JS, Holloway JW, et al. A polymorphism of MS4A2 (–109T>C) encoding the beta-chain of the high-affinity immunoglobulin E receptor (FcepsilonR1beta) is associated with a susceptibility to aspirin-intolerant asthma. Clin Exp Allergy. 2006;36:877–83.PubMedCrossRefGoogle Scholar
  24. 24.
    Szczeklik A, Dworski R, Mastalerz L, et al. Salmeterol prevents aspirin-induced attacks of asthma and interferes with eicosanoid metabolism. Am J Respir Crit Care Med. 1998;158:1168–72.PubMedGoogle Scholar
  25. 25.
    Paganin F, Poubeau P, Yvin JL, et al. The effectiveness of leukotriene antagonists in the treatment of aspirin-intolerant asthmatic patients. Presse Med. 2003;32:978–84. (In French).PubMedGoogle Scholar
  26. 26.
    Park HW, Shin ES, Lee JE, et al. Multilocus analysis of atopy in Korean children using multifactor-dimensionality reduction. Thorax. 2007;62:265–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Semik A, Barczyk A, Pierzchala W. Provocation tests in the diagnosis of acetylsalicylic acid intolerance. Wiad Lek. 2005;58:543–8.PubMedGoogle Scholar
  28. 28.
    Kowalski ML, Ptasinska A, Jedrzejczak M, et al. Aspirin-triggered 15-HETE generation in peripheral blood leukocytes is a specific and sensitive Aspirin-sensitive Patients Identification Test (ASPITest). Allergy. 2005;60:1139–45.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Seung-Hyun Kim
    • 1
  • Hyun-Hwan Jeong
    • 2
  • Bo-Young Cho
    • 1
  • MyoungKi Kim
    • 2
  • Hyun-Young Lee
    • 1
  • Jungseob Lee
    • 3
  • Kyubum Wee
    • 2
  • Hae-Sim Park
    • 1
  1. 1.Department of Allergy and Rheumatology, School of MedicineAjou UniversitySuwonSouth Korea
  2. 2.School of Information and CommunicationAjou UniversitySuwonSouth Korea
  3. 3.Department of MathematicsAjou UniversitySuwonSouth Korea

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