Skip to main content
SpringerLink
Log in

A possible association of EMID2 polymorphisms with aspirin hypersensitivity in asthma

  • Original Paper
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

Aspirin-intolerant asthma (AIA) is an asthma phenotype characterized by the development of bronchoconstriction following ingestion of aspirin. Despite the well-defined pathological trigger, the underlying mechanisms of AIA are still unclear. With the biophysical characteristics of the human EMI domain-containing protein 2 (EMID2) gene in relation to the extracellular matrix deposition and epithelial-mesenchymal transition as pivotal characteristics of airway remodeling in asthma, we hypothesized that genetic polymorphisms of EMID2 might affect the development of AIA. In this study, the allelic associations of 49 single-nucleotide polymorphisms (SNPs) of the human EMID2 gene were evaluated from 163 AIA patients and 429 aspirin-tolerant asthma (ATA) subjects as controls in a Korean population. Logistic analysis showed that five SNPs (P = 0.01–0.04, but P corr > 0.05) and EMID2_BL2_ht2 haplotype (unique to the minor alleles of rs4727494 and rs13233066; P = 0.02; P corr = 0.02) were significantly associated with AIA. More interestingly, regression analysis of the decline of forced expiratory volume in one second (FEV1) by aspirin provocation revealed that 10 SNPs (P = 0.003–0.04) and four relevant haplotypes (P = 0.002–0.02) were significantly associated with the fall rate of FEV1 by aspirin provocation, indicating that genetic polymorphisms of EMID2 could cause meaningful deficits in the upper and lower airways among AIA patients. These findings provide evidence that EMID2 may be a susceptible genetic factor for aspirin hypersensitivity among asthmatics in Korean population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

AIA:

Aspirin-intolerant asthma

EMID2:

EMI domain-containing protein 2

NSAID:

Non-steroidal inflammatory drugs

ECM:

Extracellular matrix

GINA:

Global Initiative for Asthma

ACE:

Angiotensin converting enzyme

SDS:

Sequence detection system

References

  • Backman KS, Greenberger PA, Patterson R (1997) Airways obstruction in patients with long-term asthma consistent with ‘irreversible asthma’. Chest 112:1234–40

    Article  CAS  PubMed  Google Scholar 

  • Bel EH (2004) Clinical phenotypes of asthma. Curr Opin Pulm Med 10:44–50

    Article  PubMed  Google Scholar 

  • Bressan GM, Daga-Gordini D, Colombatti A, Castellani I, Marigo V, Volpin D (1993) Emilin, a component of elastic fibers preferentially located at the elastin-microfibrils interface. J Cell Biol 121:201–12

    Article  CAS  PubMed  Google Scholar 

  • Chakir J, Shannon J, Molet S, Fukakusa M, Elias J, Laviolette M, Boulet LP, Hamid Q (2003) Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression. J Allergy Clin Immunol 111:1293–8

    Article  CAS  PubMed  Google Scholar 

  • Chetta A, Foresi A, Del Donno M, Bertorelli G, Pesci A, Olivieri D (1997) Airways remodeling is a distinctive feature of asthma and is related to severity of disease. Chest 111:852–7

    Article  CAS  PubMed  Google Scholar 

  • Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, MacIntyre NR, McKay RT, Wanger JS, Anderson SD, Cockcroft DW, Fish JE, Sterk PJ (2000) Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 161:309–29

    CAS  PubMed  Google Scholar 

  • Djukanovic R, Roche WR, Wilson JW, Beasley CR, Twentyman OP, Howarth RH, Holgate ST (1990) Mucosal inflammation in asthma. Am Rev Respir Dis 142:434–57

    CAS  PubMed  Google Scholar 

  • Doliana R, Mongiat M, Bucciotti F, Giacomello E, Deutzmann R, Volpin D, Bressan GM, Colombatti A (1999) EMILIN, a component of the elastic fiber and a new member of the C1q/tumor necrosis factor superfamily of proteins. J Biol Chem 274:16773–81

    Article  CAS  PubMed  Google Scholar 

  • Hackett TL, Warner SM, Stefanowicz D, Shaheen F, Pechkovsky DV, Murray LA, Argentieri R, Kicic A, Stick SM, Bai TR, Knight DA (2009) Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-beta1. Am J Respir Crit Care Med 180:122–33

    Article  CAS  PubMed  Google Scholar 

  • Haitchi HM, Powell RM, Shaw TJ, Howarth PH, Wilson SJ, Wilson DI, Holgate ST, Davies DE (2005) ADAM33 expression in asthmatic airways and human embryonic lungs. Am J Respir Crit Care Med 171:958–65

    Article  PubMed  Google Scholar 

  • Hedman J, Kaprio J, Poussa T, Nieminen MM (1999) Prevalence of asthma, aspirin intolerance, nasal polyposis and chronic obstructive pulmonary disease in a population-based study. Int J Epidemiol 28:717–22

    Article  CAS  PubMed  Google Scholar 

  • Hedrick PW (1987) Gametic disequilibrium measures: proceed with caution. Genetics 117:331–41

    CAS  PubMed  Google Scholar 

  • Holgate ST, Polosa R (2006) The mechanisms, diagnosis, and management of severe asthma in adults. Lancet 368:780–93

    Article  CAS  PubMed  Google Scholar 

  • Jeimy SB, Tasneem S, Cramer EM, Hayward CP (2008) Multimerin 1. Platelets 19:83–95

    Article  CAS  PubMed  Google Scholar 

  • Jenkins HA, Cool C, Szefler SJ, Covar R, Brugman S, Gelfand EW, Spahn JD (2003) Histopathology of severe childhood asthma: a case series. Chest 124:32–41

    Article  PubMed  Google Scholar 

  • Knight DA, Lane CL, Stick SM (2004) Does aberrant activation of the epithelial-mesenchymal trophic unit play a key role in asthma or is it an unimportant sideshow? Curr Opin Pharmacol 4:251–6

    Article  CAS  PubMed  Google Scholar 

  • Leimeister C, Steidl C, Schumacher N, Erhard S, Gessler M (2002) Developmental expression and biochemical characterization of Emu family members. Dev Biol 249:204–18

    Article  CAS  PubMed  Google Scholar 

  • Loren ML, Leung PK, Cooley RL, Chai H, Bell TD, Buck VM (1978) Irreversibility of obstructive changes in severe asthma in childhood. Chest 74:126–9

    Article  CAS  PubMed  Google Scholar 

  • Mauad T, Xavier AC, Saldiva PH, Dolhnikoff M (1999) Elastosis and fragmentation of fibers of the elastic system in fatal asthma. Am J Respir Crit Care Med 160:968–75

    CAS  PubMed  Google Scholar 

  • Mauad T, Silva LF, Santos MA, Grinberg L, Bernardi FD, Martins MA, Saldiva PH, Dolhnikoff M (2004) Abnormal alveolar attachments with decreased elastic fiber content in distal lung in fatal asthma. Am J Respir Crit Care Med 170:857–62

    Article  PubMed  Google Scholar 

  • McDonald JR, Mathison DA, Stevenson DD (1972) Aspirin intolerance in asthma. Detection by oral challenge. J Allergy Clin Immunol 50:198–207

    Article  CAS  PubMed  Google Scholar 

  • Minshall EM, Leung DY, Martin RJ, Song YL, Cameron L, Ernst P, Hamid Q (1997) Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma. Am J Respir Cell Mol Biol 17:326–33

    CAS  PubMed  Google Scholar 

  • Nomura A, Uchida Y, Sakamoto T, Ishii Y, Masuyama K, Morishima Y, Hirano K, Sekizawa K (2002) Increases in collagen type I synthesis in asthma: the role of eosinophils and transforming growth factor-beta. Clin Exp Allergy 32:860–5

    Article  CAS  PubMed  Google Scholar 

  • Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74:765–9

    Article  CAS  PubMed  Google Scholar 

  • Pagani F, Baralle FE (2004) Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 5:389–96

    Article  CAS  PubMed  Google Scholar 

  • Sakagami T, Jinnai N, Nakajima T, Sekigawa T, Hasegawa T, Suzuki E, Inoue I, Gejyo F (2007) ADAM33 polymorphisms are associated with aspirin-intolerant asthma in the Japanese population. J Hum Genet 52:66–72

    Article  CAS  PubMed  Google Scholar 

  • Song T, Li G, Jing G, Jiao X, Shi J, Zhang B, Wang L, Ye X, Cao F (2008) SUMO1 polymorphisms are associated with non-syndromic cleft lip with or without cleft palate. Biochem Biophys Res Commun 377:1265–8

    Article  CAS  PubMed  Google Scholar 

  • Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–89

    Article  CAS  PubMed  Google Scholar 

  • Szczeklik A, Nizankowska E, Duplaga M (2000) Natural history of aspirin-induced asthma. AIANE investigators. European network on aspirin-induced asthma. Eur Respir J 16:432–6

    Article  CAS  PubMed  Google Scholar 

  • Tagaya E, Tamaoki J (2007) Mechanisms of airway remodeling in asthma. Allergol Int 56:331–40

    Article  CAS  PubMed  Google Scholar 

  • Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, Torrey D, Pandit S, McKenny J, Braunschweiger K, Walsh A, Liu Z, Hayward B, Folz C, Manning SP, Bawa A, Saracino L, Thackston M, Benchekroun Y, Capparell N, Wang M, Adair R, Feng Y, Dubois J, FitzGerald MG, Huang H, Gibson R, Allen KM, Pedan A, Danzig MR, Umland SP, Egan RW, Cuss FM, Rorke S, Clough JB, Holloway JW, Holgate ST, Keith TP (2002) Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 418:426–30

    Article  PubMed  Google Scholar 

  • Ward C, Pais M, Bish R, Reid D, Feltis B, Johns D, Walters EH (2002) Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma. Thorax 57:309–16

    Article  CAS  PubMed  Google Scholar 

  • Warner JO, Marguet C, Rao R, Roche WR, Pohunek P (1998) Inflammatory mechanisms in childhood asthma. Clin Exp Allergy 28(Suppl 5):71–5, discussion 90-1

    Article  PubMed  Google Scholar 

  • Yang Y, Haitchi HM, Cakebread J, Sammut D, Harvey A, Powell RM, Holloway JW, Howarth P, Holgate ST, Davies DE (2008) Epigenetic mechanisms silence a disintegrin and metalloprotease 33 expression in bronchial epithelial cells. J Allergy Clin Immunol 121:1393–9, 1399 e1-14

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the Korea Health 21 R&D Project (A010249); a grant number M1-0302-00-0073 from Korea Science and Engineering Foundation (KOSEF) funded by the Korea government (MEST) (No. 2009-0080157); an Intramural Research Grant of the Korea National Institute of Health (grant number 4800-4845-300-260-00); an Intramural Research Grant from Sogang University (grant number 200810021.01); and a Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0093822). The DNA samples were generously provided by Soonchunhyang University, Bucheon Hospital Biobank, a member of the National Biobank of Korea, supported by the Ministry of Health, Welfare and Family Affairs, Republic of Korea.

Conflicts of interest

The authors declare no conflict of interests.

Author information

Authors and Affiliations

  1. Department of Life Science, Sogang University, 1 Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea

    Charisse Flerida A. Pasaje, Jeong-Hyun Kim, Tae-Joon Park, Jin-Sol Lee, Yongha Kim, Joon Seol Bae & Hyoung Doo Shin

  2. Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, 153-803, Republic of Korea

    Byung-Lae Park, Hyun Sub Cheong & Hyoung Doo Shin

  3. Division of Internal Medicine, Chungbuk National University, College of Medicine, Cheongju, 361-711, Republic of Korea

    Mi-Kyeong Kim

  4. Department of Allergy, Chonnam National University Medical School and Research Institute of Medical Sciences, Gwangju, 501-757, Republic of Korea

    Inseon S. Choi

  5. Department of Internal Medicine and Institute of Allergy and Clinical Immunology, Seoul National University College of Medicine, Seoul, 110-744, Republic of Korea

    Sang Heon Cho

  6. Division of Allergy and Immunology, Institute of Allergy, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 120-752, Republic of Korea

    Chein-Soo Hong & Yong Won Lee

  7. Pulmonary, Allergy and Critical Care Medicine, Hallym University College of Medicine, Chuncheon, 200-702, Republic of Korea

    Jae-Young Lee

  8. Department of Physiology, College of Medicine, Hanyang University, Seoul, 133-791, Republic of Korea

    In Song Koh

  9. Division of Allergy and Respiratory Medicine, Genome Research Center for Allergy and Respiratory Diseases, Soonchunhyang University Bucheon Hospital, Bucheon, 420-767, Republic of Korea

    Choon-Sik Park

  10. Genome Research Center for Allergy and Respiratory Diseases, Soonchunhyang University Hospital, Bucheon, 420-767, Republic of Korea

    Choon-Sik Park

Authors
  1. Charisse Flerida A. Pasaje
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeong-Hyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Byung-Lae Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyun Sub Cheong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mi-Kyeong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Inseon S. Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sang Heon Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chein-Soo Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yong Won Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jae-Young Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. In Song Koh
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tae-Joon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jin-Sol Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yongha Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Joon Seol Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Choon-Sik Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Hyoung Doo Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Choon-Sik Park or Hyoung Doo Shin.

Electronic supplementary materials

Below is the link to the electronic supplementary material.

Supplementary Table 1

Variants of EMID2 included in this study (DOC 67 kb)

Supplementary Table 2

Logistic analysis of the SNPs in EMID2 between AIA and ATA patients (DOC 122 kb)

Supplementary Table 3

Logistic analysis of the haplotypes in EMID2 between AIA and ATA patients (DOC 50 kb)

Supplementary Table 4

Association analysis between SNPs of EMID2 gene and the fall of FEV1 by aspirin provocation (DOC 79 kb)

Supplementary Table 5

Association analysis between haplotypes of EMID2 gene and the fall of FEV1 by aspirin provocation (DOC 47 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pasaje, C.F.A., Kim, JH., Park, BL. et al. A possible association of EMID2 polymorphisms with aspirin hypersensitivity in asthma. Immunogenetics 63, 13–21 (2011). https://doi.org/10.1007/s00251-010-0490-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-010-0490-8

Keywords

Search

Navigation