Allergy Asthma Immunol Res.  2013 Sep;5(5):258-276. 10.4168/aair.2013.5.5.258.

Unraveling the Genetic Basis of Aspirin Hypersensitivity in Asthma Beyond Arachidonate Pathways

• Park SM
• Park JS
• Park HS
• Park CS

• KMID: 2260806
• DOI: http://doi.org/10.4168/aair.2013.5.5.258

Abstract

Although aspirin-exacerbated respiratory disease (AERD) has attracted a great deal of attention because of its association with severe asthma, it remains widely under-diagnosed in the asthmatic population. Oral aspirin challenge is the best method of diagnosing AERD, but this is a time-consuming procedure with serious complications in some cases. Thus, development of non-invasive methods for easy diagnosis is necessary to prevent unexpected complications of aspirin use in susceptible patients. For the past decade, many studies have attempted to elucidate the genetic variants responsible for risk of AERD. Several approaches have been applied in these genetic studies. To date, a limited number of biologically plausible candidate genes in the arachidonate and immune and inflammatory pathways have been studied. Recently, a genome-wide association study was performed. In this review, the results of these studies are summarized, and their limitations discussed. In addition to the genetic variants, changes in methylation patterns on CpG sites have recently been identified in a target tissue of aspirin hypersensitivity. Finally, perspectives on application of new genomic technologies are introduced; these will aid our understanding of the genetic pathogenesis of aspirin hypersensitivity in asthma.

Keyword

Aspirin; hypersensitivity; asthma; single nucleotide polymorphism; genome-wide association study; methylation

MeSH Terms

Aspirin
Asthma
Genome-Wide Association Study
Humans
Hypersensitivity
Methylation
Polymorphism, Single Nucleotide
Aspirin

Figure

• 

  Fig. 1 Summary of AERD associated single nucleotide polymorphisms in the genes of immune response and arachidonate pathway. OR, odds ratio; Ref, reference. (A) HLA DQ, Major histocompatibility complex, class II, DQ; HLA-DPB1, Major histocompatibility complex, class II, DP beta 1; IL4, INTERLEUKIN 4; IL 13, INTERLEUKIN 13; TBET, T-BOX EXPRESSED IN T CELLS; IL-10, Interleukin 10; TGF-beta 1, transforming growth factor, beta 1. (B) MS4A2, MEMBRANE-SPANNING 4-DOMAINS, SUBFAMILY A, MEMBER 7; FCER1γ, Fc fragment of IgE, high affinity I, receptor for; gamma polypeptide; FCER1α, Fc fragment of IgE, high affinity I, receptor for; alpha polypeptide. (C) LTC4S, Leukotriene C4 syntrhase; CACNG6, Calcium channel, voltage-dependent gamma-6 subunit; ALOX5, Arachidonate 5-lipoxygenase; NAT2, N-Acytyltransferase 2; CysLTR1, Cysteinyl leukotriene receptor 1; CysLTR2, Cysteinyl leukotriene receptor 2. (D) TLR3, TOLL-LIKE RECEPTOR 3. (E) NLRP3, NLR FAMILY, PYRIN DOMAIN-CONTAINING 3; PPARG, Peroxisome proliferator-activated receptor-gamma; ACE, Angiotensin 1-converting enzyme; ADAM33, A distegrin and metalloproteinase domain 33; FSIP1, Fibrous sheath interacting protein 1; EMID2, Emilin/multimerin domain-containing protein 2; SMOC2, Sparc-related modular calcium-binding protein 2; SLC6A12, Solute carrier family 6 (neurotransmitter transporter, betaine/gaba), member 12; SLC22A2, Solute carreier familyY 22 (organic cation transporter), member 2; KIF3A, Kinesin family member 3A. (F) ADORA1, adenosine A1 receptor; ADORA2A, adenosine A2a receptor; GPR44, G protein-coupled receptor 44; PTGER2, Prostaglandin E Receptor 2; PTGER3, Prostaglandin E Receptor 3; PTGER4, Prostaglandin E Receptor 4; PTGIR, Prostaglandin I2 receptor; TBXAS1, Thromboxane A synthase 1; TBXA2R, Thromboxane A2 receptor; RGS7BP, Regulator of G protein signaling 7-binding protein.

• 

  Fig. 2 Summary of DNA methylation data. (A) Volcano plot of differential methylation level between AIA and ATA in nasal polyp tissues (A-1) and buffy coat samples (A-2). Red dots: Deltabeta≥0.5 and P value≤0.01, blue dots: Deltabeta ≤-0.5 and P value≤0.01, grey dots: -0.5≤Deltabeta≤0.5 and P value>0.01. Delta-Beta: difference of DNA methylation level (subtracting the DNA methylation level of ATA from AIA). -log (P): log-transformed t-test P values. (B) Distribution of the DNA methylation level of AIA and ATA in buffy coat and nasal polyp. Average Beta: DNA methylation level (0 to 1). (C) Heatmap of 490 differentially methylated CpGs between AIA and ATA in buffy coat and nasal polyp (modified from reference 125).

Reference

1. Lee RU, Stevenson DD. Aspirin-exacerbated respiratory disease: evlauation and management. Allergy Asthma Immunol Res. 2011; 3:3–10.

2. Mascia K, Haselkorn T, Deniz YM, Miller DP, Bleecker ER, Borish L. TENOR Study Group. Aspirin sensitivity and severity of asthma: evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma. J Allergy Clin Immunol. 2005; 116:970–975.

3. Szczeklik A, Nizankowska E, Duplaga M. Natural history of aspirin-induced asthma. AIANE Investigators. European Network on Aspirin-Induced Asthma. Eur Respir J. 2000; 16:432–436.

4. Hedman J, Kaprio J, Poussa T, Nieminen MM. Prevalence of asthma, aspirin intolerance, nasal polyposis and chronic obstructive pulmonary disease in a population-based study. Int J Epidemiol. 1999; 28:717–722.

5. Kalyoncu AF, Karakaya G, Sahin AA, Bariş YI. Occurrence of allergic conditions in asthmatics with analgesic intolerance. Allergy. 1999; 54:428–435.

6. Zielenski J, Tsui LC. Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet. 1995; 29:777–807.

7. Sousa AR, Parikh A, Scadding G, Corrigan CJ, Lee TH. Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. N Engl J Med. 2002; 347:1493–1499.

8. Picado C. Aspirin-intolerant asthma: role of cyclo-oxygenase enzymes. Allergy. 2002; 57:Suppl 72. 58–60.

9. Cowburn AS, Sladek K, Soja J, Adamek L, Nizankowska E, Szczeklik A, Lam BK, Penrose JF, Austen FK, Holgate ST, Sampson AP. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest. 1998; 101:834–846.

10. Sanak M, Pierzchalska M, Bazan-Socha S, Szczeklik A. Enhanced expression of the leukotriene C(4) synthase due to overactive transcription of an allelic variant associated with aspirin-intolerant asthma. Am J Respir Cell Mol Biol. 2000; 23:290–296.

11. Kawagishi Y, Mita H, Taniguchi M, Maruyama M, Oosaki R, Higashi N, Kashii T, Kobayashi M, Akiyama K. Leukotriene C4 synthase promoter polymorphism in Japanese patients with aspirin-induced asthma. J Allergy Clin Immunol. 2002; 109:936–942.

12. Van Sambeek R, Stevenson DD, Baldasaro M, Lam BK, Zhao J, Yoshida S, Yandora C, Drazen JM, Penrose JF. 5' flanking region polymorphism of the gene encoding leukotriene C4 synthase does not correlate with the aspirin-intolerant asthma phenotype in the United States. J Allergy Clin Immunol. 2000; 106:72–76.

13. Choi JH, Park HS, Oh HB, Lee JH, Suh YJ, Park CS, Shin HD. Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase. Hum Genet. 2004; 114:337–344.

14. In KH, Asano K, Beier D, Grobholz J, Finn PW, Silverman EK, Silverman ES, Collins T, Fischer AR, Keith TP, Serino K, Kim SW, De Sanctis GT, Yandava C, Pillari A, Rubin P, Kemp J, Israel E, Busse W, Ledford D, Murray JJ, Segal A, Tinkleman D, Drazen JM. Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. J Clin Invest. 1997; 99:1130–1137.

15. Orning L. Omega-oxidation of cysteine-containing leukotrienes by rat-liver microsomes. Isolation and characterization of omega-hydroxy and omega-carboxy metabolites of leukotriene E4 and N-acetylleukotriene E4. Eur J Biochem. 1987; 170:77–85.

16. Kim JM, Park BL, Park SM, Lee SH, Kim MO, Jung S, Lee EH, Uh ST, Park JS, Choi JS, Kim YH, Kim MK, Choi IS, Cho SH, Choi BW, Park HS, Chang HS, Shin HD, Park CS. Association analysis of N-acetyl transferase-2 polymorphisms with aspirin intolerance among asthmatics. Pharmacogenomics. 2010; 11:951–958.

17. Metters KM. Leukotriene receptors. J Lipid Mediat Cell Signal. 1995; 12:413–427.

18. Kim SH, Oh JM, Kim YS, Palmer LJ, Suh CH, Nahm DH, Park HS. Cysteinyl leukotriene receptor 1 promoter polymorphism is associated with aspirin-intolerant asthma in males. Clin Exp Allergy. 2006; 36:433–439.

19. Hao L, Sayers I, Cakebread JA, Barton SJ, Beghé B, Holgate ST, Sampson AP, Holloway JW. The cysteinyl-leukotriene type 1 receptor polymorphism 927T/C is associated with atopy severity but not with asthma. Clin Exp Allergy. 2006; 36:735–741.

20. Arriba-Mendez S, Sanz C, Isidoro-Garcia M, Davild I, Laffond E, Horeno E, Avila C, Lorente F. 927T>C polymorphism of the cysteinyl-leukotriene type-1 receptor (CYSLTR1) gene in children with asthma and atopic dermatitis. Pediatr Allergy Immunol. 2006; 17:323–328.

21. Thompson MD, Capra V, Takasaki J, Maresca G, Rovati GE, Slutsky AS, Lilly C, Zamel N, McIntyre Burnham W, Cole DE, Siminovitch KA. A functional G300S variant of the cysteinyl leukotriene 1 receptor is associated with atopy in a Tristan da Cunha isolate. Pharmacogenet Genomics. 2007; 17:539–549.

22. Daniels SE, Bhattacharrya S, James A, Leaves NI, Young A, Hill MR, Faux JA, Ryan GF, le Söuef PN, Lathrop GM, Musk AW, Cookson WO. A genome-wide search for quantitative trait loci underlying asthma. Nature. 1996; 383:247–250.

23. Pillai SG, Cousens DJ, Barnes AA, Buckley PT, Chiano MN, Hosking LK, Cameron LA, Fling ME, Foley JJ, Green A, Sarau HM, Schmidt DB, Sprankle CS, Blumenthal MN, Vestbo J, Kennedy-Wilson K, Wixted WE, Wagner MJ, Anderson WH, Ignar DM. Investigators of the GAIN Network. A coding polymorphism in the CYSLT2 receptor with reduced affinity to LTD4 is associated with asthma. Pharmacogenetics. 2004; 14:627–633.

24. Fukai H, Ogasawara Y, Migita O, Koga M, Ichikawa K, Shibasaki M, Arinami T, Noguchi E. Association between a polymorphism in cysteinyl leukotriene receptor 2 on chromosome 13q14 and atopic asthma. Pharmacogenetics. 2004; 14:683–690.

25. Park JS, Chang HS, Park CS, Lee JH, Lee YM, Choi JH, Park HS, Kim LH, Park BL, Choi YH, Shin HD. Association analysis of cysteinyl-leukotriene receptor 2 (CYSLTR2) polymorphisms with aspirin intolerance in asthmatics. Pharmacogenet Genomics. 2005; 15:483–492.

26. Shin JA, Chang HS, Park SM, Jang AS, Park SW, Park JS, Uh ST, Lim GI, Rhim T, Kim MK, Choi IS, Chung IY, Park BL, Shin HD, Park CS. Genetic effect of CysLTR2 polymorphisms on its mRNA synthesis and stabilization. BMC Med Genet. 2009; 10:106.

27. Coleman RA, Smith WL, Narumiya S. International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev. 1994; 46:205–229.

28. Jinnai N, Sakagami T, Sekigawa T, Kakihara M, Nakajima T, Yoshida K, Goto S, Hasegawa T, Koshino T, Hasegawa Y, Inoue H, Suzuki N, Sano Y, Inoue I. Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin-intolerant asthma: a candidate gene approach. Hum Mol Genet. 2004; 13:3203–3217.

29. Kim SH, Kim YK, Park HW, Jee YK, Kim SH, Bahn JW, Chang YS, Kim SH, Ye YM, Shin ES, Lee JE, Park HS, Min KU. Association between polymorphisms in prostanoid receptor genes and aspirin-intolerant asthma. Pharmacogenet Genomics. 2007; 17:295–304.

30. Park BL, Park SM, Park JS, Uh ST, Choi JS, Kim YH, Kim MK, Choi IS, Choi BW, Cho SH, Hong CS, Lee YW, Lee JY, Park CS, Shin HD. Association of PTGER gene family polymorphisms with aspirin intolerant asthma in Korean asthmatics. BMB Rep. 2010; 43:445–449.

31. Capra V, Habib A, Accomazzo MR, Ravasi S, Citro S, Levy-Toledano S, Nicosia S, Rovati GE. Thromboxane prostanoid receptor in human airway smooth muscle cells: a relevant role in proliferation. Eur J Pharmacol. 2003; 474:149–159.

32. Kumlin M, Dahlén B, Björck T, Zetterström O, Granström E, Dahlén SE. Urinary excretion of leukotriene E4 and 11-dehydro-thromboxane B2 in response to bronchial provocations with allergen, aspirin, leukotriene D4, and histamine in asthmatics. Am Rev Respir Dis. 1992; 146:96–103.

33. Oh SH, Kim YH, Park SM, Cho SH, Park JS, Jang AS, Park SW, Uh ST, Lee YM, Kim MK, Choi IS, Cho SH, Hong CS, Lee YW, Lee JY, Choi BW, Park BL, Shin HD, Park CS. Association analysis of thromboxane A synthase 1 gene polymorphisms with aspirin intolerance in asthmatic patients. Pharmacogenomics. 2011; 12:351–363.

34. Leung TF, Tang NL, Lam CW, Li AM, Chan IH, Ha G. Thromboxane A2 receptor gene polymorphism is associated with the serum concentration of cat-specific immunoglobulin E as well as the development and severity of asthma in Chinese children. Pediatr Allergy Immunol. 2002; 13:10–17.

35. Shin HD, Park BL, Jung JH, Wang HJ, Park HS, Choi BW, Hong SJ, Lee YM, Kim YH, Park CS. Association of thromboxane A2 receptor (TBXA2R) with atopy and asthma. J Allergy Clin Immunol. 2003; 112:454–457.

36. Kim SH, Choi JH, Park HS, Holloway JW, Lee SK, Park CS, Shin HD. Association of thromboxane A2 receptor gene polymorphism with the phenotype of acetyl salicylic acid-intolerant asthma. Clin Exp Allergy. 2005; 35:585–590.

37. De Vries L, Gist Farquhar M. RGS proteins: more than just GAPs for heterotrimeric G proteins. Trends Cell Biol. 1999; 9:138–144.

38. Martemyanov KA, Yoo PJ, Skiba NP, Arshavsky VY. R7BP, a novel neuronal protein interacting with RGS proteins of the R7 family. J Biol Chem. 2005; 280:5133–5136.

39. Lee EH, Park BL, Park SM, Lee SH, Park SW, Park JS, Uh ST, Kim MK, Choi IS, Cho SH, Hong CS, Lee JY, Choi BW, Shin HD, Park CS. Association analysis of RGS7BP gene polymorphisms with aspirin intolerance in asthmatic patients. Ann Allergy Asthma Immunol. 2011; 106:292–300.e6.

40. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol. 2003; 111:913–921. quiz 922.

41. Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Fernández-Viña M, Geraghty DE, Holdsworth R, Hurley CK, Lau M, Lee KW, Mach B, Maiers M, Mayr WR, Müller CR, Parham P, Petersdorf EW, Sasazuki T, Strominger JL, Svejgaard A, Terasaki PI, Tiercy JM, Trowsdale J. Nomenclature for factors of the HLA system, 2010. Tissue Antigens. 2010; 75:291–455.

42. Mullarkey MF, Thomas PS, Hansen JA, Webb DR, Nisperos B. Association of aspirin-sensitive asthma with HLA-DQw2. Am Rev Respir Dis. 1986; 133:261–263.

43. Lympany PA, Welsh KI, Christie PE, Schmitz-Schumann M, Kemeny DM, Lee TH. An analysis with sequence-specific oligonucleotide probes of the association between aspirin-induced asthma and antigens of the HLA system. J Allergy Clin Immunol. 1993; 92:114–123.

44. Dekker JW, Nizankowska E, Schmitz-Schumann M, Pile K, Bochenek G, Dyczek A, Cookson WO, Szczeklik A. Aspirin-induced asthma and HLA-DRB1 and HLA-DPB1 genotypes. Clin Exp Allergy. 1997; 27:574–577.

45. Adjers K, Karjalainen J, Pessi T, Eklund C, Hurme M. Epistatic effect of TLR4 and IL4 genes on the risk of asthma in females. Int Arch Allergy Immunol. 2005; 138:251–256.

46. Burchard EG, Silverman EK, Rosenwasser LJ, Borish L, Yandava C, Pillari A, Weiss ST, Hasday J, Lilly CM, Ford JG, Drazen JM. Association between a sequence variant in the IL-4 gene promoter and FEV(1) in asthma. Am J Respir Crit Care Med. 1999; 160:919–922.

47. Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science. 1994; 265:956–959.

48. Kim BS, Park SM, Uhm TG, Kang JH, Park JS, Jang AS, Uh ST, Kim MK, Choi IS, Cho SH, Hong CS, Lee YW, Lee JY, Choi BW, Park HS, Park BL, Shin HD, Chung IY, Park CS. Effect of single nucleotide polymorphisms within the interleukin-4 promoter on aspirin intolerance in asthmatics and interleukin-4 promoter activity. Pharmacogenet Genomics. 2010; 20:748–758.

49. Palikhe NS, Kim SH, Cho BY, Choi GS, Kim JH, Ye YM, Park HS. IL-13 Gene Polymorphisms are Associated With Rhinosinusitis and Eosinophilic Inflammation in Aspirin Intolerant Asthma. Allergy Asthma Immunol Res. 2010; 2:134–140.

50. Akahoshi M, Obara K, Hirota T, Matsuda A, Hasegawa K, Takahashi N, Shimizu M, Nakashima K, Cheng L, Doi S, Fujiwara H, Miyatake A, Fujita K, Higashi N, Taniguchi M, Enomoto T, Mao XQ, Nakashima H, Adra CN, Nakamura Y, Tamari M, Shirakawa T. Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. Hum Genet. 2005; 117:16–26.

51. Kim SH, Bae JS, Holloway JW, Lee JT, Suh CH, Nahm DH, Park HS. 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; 36:877–883.

52. Palikhe NS, Kim SH, Cho BY, Ye YM, Hur GY, Park HS. Association of three sets of high-affinity IgE receptor (FcepsilonR1) polymorphisms with aspirin-intolerant asthma. Respir Med. 2008; 102:1132–1139.

53. Yoshida S, Sakamoto H, Yamawaki Y, Shoji T, Akahori K, Onuma K, Nakagawa H, Hasegawa H, Amayasu H. Effect of acyclovir on bronchoconstriction and urinary leukotriene E4 excretion in aspirin-induced asthma. J Allergy Clin Immunol. 1998; 102:909–914.

54. Palikhe NS, Kim SH, Kim JH, Losol P, Ye YM, Park HS. Role of toll-like receptor 3 variants in aspirin-exacerbated respiratory disease. Allergy Asthma Immunol Res. 2011; 3:123–127.

55. Pétrilli V, Dostert C, Muruve DA, Tschopp J. The inflammasome: a danger sensing complex triggering innate immunity. Curr Opin Immunol. 2007; 19:615–622.

56. Hitomi Y, Ebisawa M, Tomikawa M, Imai T, Komata T, Hirota T, Harada M, Sakashita M, Suzuki Y, Shimojo N, Kohno Y, Fujita K, Miyatake A, Doi S, Enomoto T, Taniguchi M, Higashi N, Nakamura Y, Tamari M. Associations of functional NLRP3 polymorphisms with susceptibility to food-induced anaphylaxis and aspirin-induced asthma. J Allergy Clin Immunol. 2009; 124:779–785.e6.

57. Lee JY, Park SW, Chang HK, Kim HY, Rhim T, Lee JH, Jang AS, Koh ES, Park CS. A disintegrin and metalloproteinase 33 protein in patients with asthma: Relevance to airflow limitation. Am J Respir Crit Care Med. 2006; 173:729–735.

58. 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. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature. 2002; 418:426–430.

59. Lee JH, Park HS, Park SW, Jang AS, Uh ST, Rhim T, Park CS, Hong SJ, Holgate ST, Holloway JW, Shin HD. ADAM33 polymorphism: association with bronchial hyper-responsiveness in Korean asthmatics. Clin Exp Allergy. 2004; 34:860–865.

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

61. Wen GY, Yang SY, Kaczmarski W, He XY, Pappas KS. Presence of hydroxysteroid dehydrogenase type 10 in amyloid plaques (APs) of Hsiao's APP-Sw transgenic mouse brains, but absence in APs of Alzheimer's disease brains. Brain Res. 2002; 954:115–122.

62. Kim JY, Kim JH, Park TJ, Bae JS, Lee JS, Pasaje CF, Park BL, Cheong HS, Park JS, Park SW, Uh ST, Kim MK, Choi IS, Cho SH, Choi BW, Park CS, Shin HD. Positive association between aspirin-intolerant asthma and genetic polymorphisms of FSIP1: a case-case study. BMC Pulm Med. 2010; 10:34.

63. Freishtat RJ, Benton AS, Watson AM, Wang Z, Rose MC, Hoffman EP. Delineation of a gene network underlying the pulmonary response to oxidative stress in asthma. J Investig Med. 2009; 57:756–764.

64. Fouladkou F, Lu C, Jiang C, Zhou L, She Y, Walls JR, Kawabe H, Brose N, Henkelman RM, Huang A, Bruneau BG, Rotin D. The ubiquitin ligase Nedd4-1 is required for heart development and is a suppressor of thrombospondin-1. J Biol Chem. 2010; 285:6770–6780.

65. Ward C, Pais M, Bish R, Reid D, Feltis B, Johns D, Walters EH. Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma. Thorax. 2002; 57:309–316.

66. Leimeister C, Steidl C, Schumacher N, Erhard S, Gessler M. Developmental expression and biochemical characterization of Emu family members. Dev Biol. 2002; 249:204–218.

67. Pasaje CF, Kim JH, Park BL, Cheong HS, Kim MK, Choi IS, Cho SH, Hong CS, Lee YW, Lee JY, Koh IS, Park TJ, Lee JS, Kim Y, Bae JS, Park CS, Shin HD. A possible association of EMID2 polymorphisms with aspirin hypersensitivity in asthma. Immunogenetics. 2011; 63:13–21.

68. Christiansen SC, Proud D, Cochrane CG. Detection of tissue kallikrein in the bronchoalveolar lavage fluid of asthmatic subjects. J Clin Invest. 1987; 79:188–197.

69. Roisman GL, Danel CJ, Lacronique JG, Alhenc-Gelas F, Dusser DJ. Decreased expression of angiotensin-converting enzyme in the airway epithelium of asthmatic subjects is associated with eosinophil inflammation. J Allergy Clin Immunol. 1999; 104:402–410.

70. 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. Association of angiotensin I-converting enzyme gene polymorphisms with aspirin intolerance in asthmatics. Clin Exp Allergy. 2008; 38:1727–1737.

71. Fredholm BB, Ijzerman AP, Jacobson KA, Klotz KN, Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev. 2001; 53:527–552.

72. Fozard JR, Ellis KM, Villela Dantas MF, Tigani B, Mazzoni L. Effects of CGS 21680, a selective adenosine A2A receptor agonist, on allergic airways inflammation in the rat. Eur J Pharmacol. 2002; 438:183–188.

73. Kim SH, Kim YK, Park HW, Kim SH, Kim SH, Ye YM, Min KU, Park HS. Adenosine deaminase and adenosine receptor polymorphisms in aspirin-intolerant asthma. Respir Med. 2009; 103:356–363.

74. Hirai H, Tanaka K, Yoshie O, Ogawa K, Kenmotsu K, Takamori Y, Ichimasa M, Sugamura K, Nakamura M, Takano S, Nagata K. Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J Exp Med. 2001; 193:255–261.

75. Huang JL, Gao PS, Mathias RA, Yao TC, Chen LC, Kuo ML, Hsu SC, Plunkett B, Togias A, Barnes KC, Stellato C, Beaty TH, Huang SK. Sequence variants of the gene encoding chemoattractant receptor expressed on Th2 cells (CRTH2) are associated with asthma and differentially influence mRNA stability. Hum Mol Genet. 2004; 13:2691–2697.

76. Palikhe NS, Kim SH, Cho BY, Ye YM, Choi GS, Park HS. Genetic variability in CRTH2 polymorphism increases eotaxin-2 levels in patients with aspirin exacerbated respiratory disease. Allergy. 2010; 65:338–346.

77. Ueki S, Matsuwaki Y, Kayaba H, Oyamada H, Kanda A, Usami A, Saito N, Chihara J. Peroxisome proliferator-activated receptor gamma regulates eosinophil functions: a new therapeutic target for allergic airway inflammation. Int Arch Allergy Immunol. 2004; 134:Suppl 1. 30–36.

78. Min JW, Jang AS, Park SM, Lee SH, Lee JH, Park SW, Park CS. Comparison of plasma eotaxin family level in aspirin-induced and aspirin-tolerant asthma patients. Chest. 2005; 128:3127–3132.

79. Palmer CN, Doney AS, Ismail T, Lee SP, Murrie I, Macgregor DF, Mukhopadhyay S. PPARG locus haplotype variation and exacerbations in asthma. Clin Pharmacol Ther. 2007; 81:713–718.

80. Oh SH, Park SM, Park JS, Jang AS, Lee YM, Uh ST, Kim YH, Choi IS, Kim MK, Park BL, Shin HD, Park CS. Association analysis of peroxisome proliferator-activated receptors gamma gene polymorphisms with asprin hypersensitivity in asthmatics. Allergy Asthma Immunol Res. 2009; 1:30–35.

81. Shah AS, Farmen SL, Moninger TO, Businga TR, Andrews MP, Bugge K, Searby CC, Nishimura D, Brogden KA, Kline JN, Sheffield VC, Welsh MJ. Loss of Bardet-Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia. Proc Natl Acad Sci U S A. 2008; 105:3380–3385.

82. Sivaprasad U, Gibson AM, Wang N, Khurana Hershey GK. Expression of cilia structural genes is downregulated in asthma and single nucleotide polymorphisms in these genes correlate with asthma. J Allergy Clin Immunol. 2009; 123:S81.

83. Kim JH, Cha JY, Cheong HS, Park JS, Jang AS, Uh ST, Kim MK, Choi IS, Cho SH, Park BL, Bae JS, Park CS, Shin HD. KIF3A, a cilia structural gene on chromosome 5q31, and its polymorphisms show an association with aspirin hypersensitivity in asthma. J Clin Immunol. 2011; 31:112–121.

84. Picado C, Bioque G, Roca-Ferrer J, Pujols L, Mullol J, Benitez P, Bulbena O. Nuclear factor-kappaB activity is down-regulated in nasal polyps from aspirin-sensitive asthmatics. Allergy. 2003; 58:122–126.

85. Liu M, Wang L, Holm BA, Enhorning G. Dysfunction of guinea-pig pulmonary surfactant and type II pneumocytes after repetitive challenge with aerosolized ovalbumin. Clin Exp Allergy. 1997; 27:802–807.

86. Rückert P, Bates SR, Fisher AB. Role of clathrin- and actin-dependent endocytotic pathways in lung phospholipid uptake. Am J Physiol Lung Cell Mol Physiol. 2003; 284:L981–L989.

87. Natsume W, Tanabe K, Kon S, Yoshida N, Watanabe T, Torii T, Satake M. SMAP2, a novel ARF GTPase-activating protein, interacts with clathrin and clathrin assembly protein and functions on the AP-1-positive early endosome/trans-Golgi network. Mol Biol Cell. 2006; 17:2592–2603.

88. Kim JY, Kim JH, Park BL, Cheong HS, Park JS, Jang AS, Uh ST, Choi JS, Kim YH, Kim MK, Choi IS, Cho SH, Choi BW, Park CS, Shin HD. Putative association of SMAPIL polymorphisms with risk of aspirin intolerance in asthmatics. J Asthma. 2010; 47:959–965.

89. Rasola A, Galietta LJ, Barone V, Romeo G, Bagnasco S. Molecular cloning and functional characterization of a GABA/betaine transporter from human kidney. FEBS Lett. 1995; 373:229–233.

90. Xiang YY, Wang S, Liu M, Hirota JA, Li J, Ju W, Fan Y, Kelly MM, Ye B, Orser B, O'Byrne PM, Inman MD, Yang X, Lu WY. A GABAergic system in airway epithelium is essential for mucus overproduction in asthma. Nat Med. 2007; 13:862–867.

91. Golovko AI, Sofronov GA, Kliuntina TV. The effect of salicylates on the toxicity of GABAlytics for mice. Biull Eksp Biol Med. 1995; 119:619–620.

92. Pasaje CF, Kim JH, Park BL, Cheong HS, Chun JY, Park TJ, Lee JS, Kim Y, Bae JS, Park JS, Yoon SH, Uh ST, Choi JS, Kim YH, Kim MK, Choi IS, Cho SH, Choi BW, Park CS, Shin HD. Association of SLC6A12 variants with aspirin-intolerant asthma in a Korean population. Ann Hum Genet. 2010; 74:326–334.

93. Kimura H, Takeda M, Narikawa S, Enomoto A, Ichida K, Endou H. Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins. J Pharmacol Exp Ther. 2002; 301:293–298.

94. Gosens R, Zaagsma J, Grootte Bromhaar M, Nelemans A, Meurs H. Acetylcholine: a novel regulator of airway smooth muscle remodelling? Eur J Pharmacol. 2004; 500:193–201.

95. Kang HJ, Song IS, Shin HJ, Kim WY, Lee CH, Shim JC, Zhou HH, Lee SS, Shin JG. Identification and functional characterization of genetic variants of human organic cation transporters in a Korean population. Drug Metab Dispos. 2007; 35:667–675.

96. Park TJ, Kim JH, Bae JS, Park BL, Cheong HS, Chun JY, Lee JS, Kim JY, Pasaje CF, Cho SH, Uh ST, Kim MK, Choi IS, Koh IS, Park CS, Shin HD. Possible association of SLC22A2 polymorphisms with aspirin-intolerant asthma. Int Arch Allergy Immunol. 2011; 155:395–402.

97. Brueggemann LI, Mani BK, Mackie AR, Cribbs LL, Byron KL. Novel actions of nonsteroidal anti-inflammatory drugs on vascular ion channels: accounting for cardiovascular side effects and identifying new therapeutic applications. Mol Cell Pharmacol. 2010; 2:15–19.

98. Wang IM, Stepaniants S, Boie Y, Mortimer JR, Kennedy B, Elliott M, Hayashi S, Loy L, Coulter S, Cervino S, Harris J, Thornton M, Raubertas R, Roberts C, Hogg JC, Crackower M, O'Neill G, Paré PD. Gene expression profiling in patients with chronic obstructive pulmonary disease and lung cancer. Am J Respir Crit Care Med. 2008; 177:402–411.

99. Lee JS, Kim JH, Bae JS, Kim JY, Park TJ, Pasaje CF, Park BL, Cheong HS, Uh ST, Park JS, Jang AS, Kim MK, Choi IS, Park CS, Shin HD. Association of CACNG6 polymorphisms with aspirin-intolerance asthmatics in a Korean population. BMC Med Genet. 2010; 11:138.

100. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, Depner M, von Berg A, Bufe A, Rietschel E, Heinzmann A, Simma B, Frischer T, Willis-Owen SA, Wong KC, Illig T, Vogelberg C, Weiland SK, von Mutius E, Abecasis GR, Farrall M, Gut IG, Lathrop GM, Cookson WO. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature. 2007; 448:470–473.

101. Himes BE, Hunninghake GM, Baurley JW, Rafaels NM, Sleiman P, Strachan DP, Wilk JB, Willis-Owen SA, Klanderman B, Lasky-Su J, Lazarus R, Murphy AJ, Soto-Quiros ME, Avila L, Beaty T, Mathias RA, Ruczinski I, Barnes KC, Celedón JC, Cookson WO, Gauderman WJ, Gilliland FD, Hakonarson H, Lange C, Moffatt MF, O'Connor GT, Raby BA, Silverman EK, Weiss ST. Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene. Am J Hum Genet. 2009; 84:581–593.

102. Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM, Thorleifsson G, Helgadottir H, Steinthorsdottir V, Stefansson H, Williams C, Hui J, Beilby J, Warrington NM, James A, Palmer LJ, Koppelman GH, Heinzmann A, Krueger M, Boezen HM, Wheatley A, Altmuller J, Shin HD, Uh ST, Cheong HS, Jonsdottir B, Gislason D, Park CS, Rasmussen LM, Porsbjerg C, Hansen JW, Backer V, Werge T, Janson C, Jönsson UB, Ng MC, Chan J, So WY, Ma R, Shah SH, Granger CB, Quyyumi AA, Levey AI, Vaccarino V, Reilly MP, Rader DJ, Williams MJ, van Rij AM, Jones GT, Trabetti E, Malerba G, Pignatti PF, Boner A, Pescollderungg L, Girelli D, Olivieri O, Martinelli N, Ludviksson BR, Ludviksdottir D, Eyjolfsson GI, Arnar D, Thorgeirsson G, Deichmann K, Thompson PJ, Wjst M, Hall IP, Postma DS, Gislason T, Gulcher J, Kong A, Jonsdottir I, Thorsteinsdottir U, Stefansson K. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet. 2009; 41:342–347.

103. Kim JH, Park BL, Cheong HS, Bae JS, Park JS, Jang AS, Uh ST, Choi JS, Kim YH, Kim MK, Choi IS, Cho SH, Choi BW, Park CS, Shin HD. Genome-wide and follow-up studies identify CEP68 gene variants associated with risk of aspirin-intolerant asthma. PLoS One. 2010; 5:e13818.

104. Goldstein DB. Common genetic variation and human traits. N Engl J Med. 2009; 360:1696–1698.

105. Kraft P, Hunter DJ. Genetic risk prediction--are we there yet? N Engl J Med. 2009; 360:1701–1703.

106. Holloway JW, Barton SJ, Holgate ST, Rose-Zerilli MJ, Sayers I. The role of LTA4H and ALOX5AP polymorphism in asthma and allergy susceptibility. Allergy. 2008; 63:1046–1053.

107. Higuchi T, Seki N, Kamizono S, Yamada A, Kimura A, Kato H, Itoh K. Polymorphism of the 5'-flanking region of the human tumor necrosis factor (TNF)-alpha gene in Japanese. Tissue Antigens. 1998; 51:605–612.

108. Shin HD, Park BL, Kim LH, Jung JH, Wang HJ, Kim YJ, Park HS, Hong SJ, Choi BW, Kim DJ, Park CS. Association of tumor necrosis factor polymorphisms with asthma and serum total IgE. Hum Mol Genet. 2004; 13:397–403.

109. Hong SJ, Kim HB, Kang MJ, Lee SY, Kim JH, Kim BS, Jang SO, Shin HD, Park CS. TNF-alpha (-308 G/A) and CD14 (-159T/C) polymorphisms in the bronchial responsiveness of Korean children with asthma. J Allergy Clin Immunol. 2007; 119:398–404.

110. Kim SH, Ye YM, Lee SK, Choi JH, Holloway JW, Park CS, Park HS. Association of TNF-alpha genetic polymorphism with HLA DPB1*0301. Clin Exp Allergy. 2006; 36:1247–1253.

111. Kim SH, Park HS, Holloway JW, Shin HD, Park CS. Association between a TGFbeta1 promoter polymorphism and rhinosinusitis in aspirin-intolerant asthmatic patients. Respir Med. 2007; 101:490–495.

112. Fuss IJ, Boirivant M, Lacy B, Strober W. The interrelated roles of TGF-beta and IL-10 in the regulation of experimental colitis. J Immunol. 2002; 168:900–908.

113. Hobbs K, Negri J, Klinnert M, Rosenwasser LJ, Borish L. Interleukin-10 and transforming growth factor-beta promoter polymorphisms in allergies and asthma. Am J Respir Crit Care Med. 1998; 158:1958–1962.

114. Chatterjee R, Batra J, Kumar A, Mabalirajan U, Nahid S, Niphadkar PV, Ghosh B. Interleukin-10 promoter polymorphisms and atopic asthma in North Indians. Clin Exp Allergy. 2005; 35:914–919.

115. Lim S, Crawley E, Woo P, Barnes PJ. Haplotype associated with low interleukin-10 production in patients with severe asthma. Lancet. 1998; 352:113.

116. Kim SH, Yang EM, Lee HN, Cho BY, Ye YM, Park HS. Combined effect of IL-10 and TGF-beta1 promoter polymorphisms as a risk factor for aspirin-intolerant asthma and rhinosinusitis. Allergy. 2009; 64:1221–1225.

117. Szczeklik A. The cyclooxygenase theory of aspirin-induced asthma. Eur Respir J. 1990; 3:588–593.

118. Szefler SJ, Phillips BR, Martinez FD, Chinchilli VM, Lemanske RF, Strunk RC, Zeiger RS, Larsen G, Spahn JD, Bacharier LB, Bloomberg GR, Guilbert TW, Heldt G, Morgan WJ, Moss MH, Sorkness CA, Taussig LM. Characterization of within-subject responses to fluticasone and montelukast in childhood asthma. J Allergy Clin Immunol. 2005; 115:233–242.

119. Park JS, Jang AS, Park SW, Lee YM, Uh ST, Kim YH, Cha JY, Park SM, Park CS. Protection of leukotriene receptor antagonist against aspirin-induced bronchospasm in asthmatics. Allergy Asthma Immunol Res. 2010; 2:48–54.

120. Choi JH, Lee KW, Oh HB, Lee KJ, Suh YJ, Park CS, Park HS. HLA association in aspirin-intolerant asthma: DPB1*0301 as a strong marker in a Korean population. J Allergy Clin Immunol. 2004; 113:562–564.

121. Kim SH, Ye YM, Hur GY, Lee SK, Sampson AP, Lee HY, Park HS. CysLTR1 promoter polymorphism and requirement for leukotriene receptor antagonist in aspirin-intolerant asthma patients. Pharmacogenomics. 2007; 8:1143–1150.

122. Pasaje CF, Kim JH, Park BL, Cheong HS, Park TJ, Lee JS, Kim Y, Bae JS, Kim JM, Park JS, Park CS, Shin HD. Association of the variants in AGT gene with modified drug response in Korean aspirin-intolerant asthma patients. Pulm Pharmacol Ther. 2011; 24:595–601.

123. Thomsen SF, van der, Kyvik KO, Skytthe A, Backer V. Estimates of asthma heritability in a large twin sample. Clin Exp Allergy. 2010; 40:1054–1061.

124. Miller RL. Prenatal maternal diet affects asthma risk in offspring. J Clin Invest. 2008; 118:3265–3268.

125. Cheong HS, Park SM, Kim MO, Park JS, Lee JY, Byun JY, Park BL, Shin HD, Park CS. Genome-wide methylation profile of nasal polyps: relation to aspirin hypersensitivity in asthmatics. Allergy. 2011; 66:637–644.

126. Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet. 2010; 11:415–425.

127. Wheeler DA, Srinivasan M, Egholm M, Shen Y, Chen L, McGuire A, He W, Chen YJ, Makhijani V, Roth GT, Gomes X, Tartaro K, Niazi F, Turcotte CL, Irzyk GP, Lupski JR, Chinault C, Song XZ, Liu Y, Yuan Y, Nazareth L, Qin X, Muzny DM, Margulies M, Weinstock GM, Gibbs RA, Rothberg JM. The complete genome of an individual by massively parallel DNA sequencing. Nature. 2008; 452:872–876.

128. Wellcome Trust Case Control Consortium. Craddock N, Hurles ME, Cardin N, Pearson RD, Plagnol V, Robson S, Vukcevic D, Barnes C, Conrad DF, Giannoulatou E, Holmes C, Marchini JL, Stirrups K, Tobin MD, Wain LV, Yau C, Aerts J, Ahmad T, Andrews TD, Arbury H, Attwood A, Auton A, Ball SG, Balmforth AJ, Barrett JC, Barroso I, Barton A, Bennett AJ, Bhaskar S, Blaszczyk K, Bowes J, Brand OJ, Braund PS, Bredin F, Breen G, Brown MJ, Bruce IN, Bull J, Burren OS, Burton J, Byrnes J, Caesar S, Clee CM, Coffey AJ, Connell JM, Cooper JD, Dominiczak AF, Downes K, Drummond HE, Dudakia D, Dunham A, Ebbs B, Eccles D, Edkins S, Edwards C, Elliot A, Emery P, Evans DM, Evans G, Eyre S, Farmer A, Ferrier IN, Feuk L, Fitzgerald T, Flynn E, Forbes A, Forty L, Franklyn JA, Freathy RM, Gibbs P, Gilbert P, Gokumen O, Gordon-Smith K, Gray E, Green E, Groves CJ, Grozeva D, Gwilliam R, Hall A, Hammond N, Hardy M, Harrison P, Hassanali N, Hebaishi H, Hines S, Hinks A, Hitman GA, Hocking L, Howard E, Howard P, Howson JM, Hughes D, Hunt S, Isaacs JD, Jain M, Jewell DP, Johnson T, Jolley JD, Jones IR, Jones LA, Kirov G, Langford CF, Lango-Allen H, Lathrop GM, Lee J, Lee KL, Lees C, Lewis K, Lindgren CM, Maisuria-Armer M, Maller J, Mansfield J, Martin P, Massey DC, McArdle WL, McGuffin P, McLay KE, Mentzer A, Mimmack ML, Morgan AE, Morris AP, Mowat C, Myers S, Newman W, Nimmo ER, O'Donovan MC, Onipinla A, Onyiah I, Ovington NR, Owen MJ, Palin K, Parnell K, Pernet D, Perry JR, Phillips A, Pinto D, Prescott NJ, Prokopenko I, Quail MA, Rafelt S, Rayner NW, Redon R, Reid DM, Renwick , Ring SM, Robertson N, Russell E, St Clair D, Sambrook JG, Sanderson JD, Schuilenburg H, Scott CE, Scott R, Seal S, Shaw-Hawkins S, Shields BM, Simmonds MJ, Smyth DJ, Somaskantharajah E, Spanova K, Steer S, Stephens J, Stevens HE, Stone MA, Su Z, Symmons DP, Thompson JR, Thomson W, Travers ME, Turnbull C, Valsesia A, Walker M, Walker NM, Wallace C, Warren-Perry M, Watkins NA, Webster J, Weedon MN, Wilson AG, Woodburn M, Wordsworth BP, Young AH, Zeggini E, Carter NP, Frayling TM, Lee C, McVean G, Munroe PB, Palotie A, Sawcer SJ, Scherer SW, Strachan DP, Tyler-Smith C, Brown MA, Burton PR, Caulfield MJ, Compston A, Farrall M, Gough SC, Hall AS, Hattersley AT, Hill AV, Mathew CG, Pembrey M, Satsangi J, Stratton MR, Worthington J, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand W, Parkes M, Rahman N, Todd JA, Samani NJ, Donnelly P. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature. 2010; 464:713–720.

129. Toft M, Ross OA. Copy number variation in Parkinson's disease. Genome Med. 2010; 2:62.