Yonsei Med J.  2006 Feb;47(1):15-21. 10.3349/ymj.2006.47.1.15.

Genetic Markers for Differentiating Aspirin-Hypersensitivity

• Kim SH
• Park HS

• KMID: 1715869
• DOI: http://doi.org/10.3349/ymj.2006.47.1.15

Abstract

Aspirin-induced asthma (AIA) and aspirin-induced urticaria/ angioedema (AIU) are two major aspirin-related allergies. We summarize recent findings related to their molecular genetic mechanisms in order to identify genetic susceptibility markers for differentiating AIU and AIA. The overproduction of cysteinyl leukotriene has been suggested as a mechanism in both AIU and AIA. Increased expression of CYSLTR1 with CYLSTR1 and CYSLTR2 polymorphisms are new findings in AIA, while the ALOX5 promoter polymorphism has been noted in AIU. An HLA study suggested that DPB1*0301 is a strong genetic marker for AIA, and that HLA DRB1*1302 and DQB1*0609 are markers for AIU susceptibility. Several single nucleotide polymorphisms (SNPs) in the promoters of EP2, TBX21, COX-2, Fc(epsilon)RI(beta), and TBXA2R were associated with AIA, while an Fc(epsilon)RI(alpha) promoter polymorphism was associated with AIU. The functional studies of the key genes involved in AIA and AIU are summarized. The identification and functional study of genetic markers for AIA and AIU susceptibility would further elucidate the pathogenic mechanisms and facilitate the development of early diagnostic markers to establish therapeutic targets.

Keyword

Aspirin-induced asthma; aspirin-induced urticaria/angioedema; gene polymorphism; leukotrienes

Reference

1. Simon RA. Adverse respiratory reactions to aspirin and nonsteroidal anti-inflammatory drugs. Curr Allergy Asthma Rep. 2004; 4:17–24. PMID: 14680616.

2. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol. 2003; 111:913–921. PMID: 12743549.

3. Pierzchalska M, Mastalerz L, Sanak M, Zazula M, Szczeklik A. A moderate and unspecific release of cysteinyl leukotrienes by aspirin from peripheral blood leucocytes precludes its value for aspirin sensitivity testing in asthma. Clin Exp Allergy. 2000; 30:1785–1791. PMID: 11122218.

4. Antczak A, Montuschi P, Kharitonov S, Gorski P, Barnes PJ. Increased exhaled cysteinyl-leukotrienes and 8-isoprostane in aspirin-induced asthma. Am J Respir Crit Care Med. 2002; 166:301–306. PMID: 12153961.

5. Christie PE, Tagari P, Ford-Hutchinson AW, Charlesson S, Chee P, Arm JP, et al. Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects. Am Rev Respir Dis. 1991; 143:1025–1029. PMID: 1850964.

6. Oosaki R, Mizushima Y, Mita H, Shida T, Akiyama K, Kobayashi M. Urinary leukotriene E4 and 11-dehydrothromboxane B2 in patients with aspirin-sensitive asthma. Allergy. 1997; 52:470–473. PMID: 9188934.

7. Grattan CE. Aspirin sensitivity and urticaria. Clin Exp Dermatol. 2003; 28:123–127. PMID: 12653694.

8. Mastalerz L, Setkowicz M, Sanak M, Szczeklik A. Hypersensitivity to aspirin: Common eicosanoid alterations in urticaria and asthma. J Allergy Clin Immunol. 2004; 113:771–775. PMID: 15100686.

9. Sanchez-Borges M, Capriles-Hulett A, Caballero-Fonseca F. Cutaneous reactions to aspirin and nonsteroidal anti-inflammatory drugs. Clin Rev Allergy Immunol. 2003; 24:125–136. PMID: 12668893.

10. 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. PMID: 11028656.

11. Park HS. Early and late onset asthmatic responses following lysine-aspirin inhalation in aspirin-sensitive asthmatic patients. Clin Exp Allergy. 1995; 25:38–40. PMID: 7728622.

12. Nizankowska E, Bestynska-Krypel A, Cmiel A, Szczeklik A. Oral and bronchial provocation tests with aspirin for diagnosis of aspirin-induced asthma. Eur Respir J. 2000; 15:863–869. PMID: 10853850.

13. Ye YM, Kim JE, Kim SH, Suh CH, Nahm DH, Park HS. Clinical characteristics of chronic urticaria with aspirin sensitivity. Korean J Asthma Allergy Clin Immunol. 2005; 25:194–199.

14. Dekker JW, Nizankowska E, Schmitz-Schumann M, Pile K, Bochenek G, Dyczek A, et al. Aspirin-induced asthma and HLA-DRB1 and HLA-DPB1 genotypes. Clin Exp Allergy. 1997; 27:574–577. PMID: 9179433.

15. Choi JH, Lee KW, Oh HB, Lee KJ, Suh YJ, Park CS, et al. HLA association in aspirin-intolerant asthma: DPB1*0301 as a strong marker in a Korean population. J Allergy Clin Immunol. 2004; 113:562–564. PMID: 15007363.

16. Park HS, Kim SH, Sampson AP, Lee KW, Park CS. The HLA-DPB1*0301 marker might predict the requirement for leukotriene receptor antagonist in patients with aspirin-intolerant asthma. J Allergy Clin Immunol. 2004; 114:688–689. PMID: 15446291.

17. Sanak M, Simon HU, Szceklik A. Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet. 1997; 350:1599–1600. PMID: 9393345.

18. Sanak M, Pierzchalska M, Bazan-Socha S, Szczeklik A. Enhanced expression of the leukotriene C4 synthase due to overactive transcription of an allelic variant associated with aspirin-intolerant asthma. Am J Respir Cell Mol Biol. 2000; 23:290–296. PMID: 10970818.

19. Kawagishi Y, Mita H, Taniguchi M, Maruyama M, Oosaki R, Higashi N, et al. Leukotriene C4 synthase promoter polymorphism in Japanese patients with aspirin-induced asthma. J Allergy Clin Immunol. 2002; 109:936–942. PMID: 12063521.

20. Van Sambeek R, Stevenson DD, Baldasaro M, Lam BK, Zhao J, Yoshida S, et al. 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. PMID: 10887308.

21. Choi JH, Park HS, Oh HB, Lee JH, Suh YJ, Park CS, et al. Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase. Hum Genet. 2004; 114:337–344. PMID: 14749922.

22. In KH, Asano K, Beier D, Grobholz J, Finn PW, Silverman EK, et al. 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. PMID: 9062372.

23. Kim SH, Bae JS, Suh CH, Nahm DH, Holloway JW, Park HS. Polymorphism of tandem repeat in promoter of 5-lipoxygenase in ASA-intolerant asthma: a positive association with airway hyperresponsiveness. Allergy. 2005; 60:760–765. PMID: 15876305.

24. Kim SH, Park HS, Choi JH, Oh JM, Suh CH, Nahm DH. A strong association of three genetic variants of CYSLTR1 with ASA-intolerant asthma phenotype. J Allergy Clin Immunol. 2005; 115:S134.

25. Park JS, Chang HS, Park CS, Lee JH, Lee YM, Choi JH, et al. Association analysis of cysteinyl-leukotriene receptor 2 (CYSLTR2) polymorphisms with aspirin intolerance in asthmatics. Pharmacogenet Genomics. 2005; 15:483–492. PMID: 15970796.

26. Jinnai N, Sakagami T, Sekigawa T, Kakihara M, Nakajima T, Yoshida K, et al. 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. PMID: 15496426.

27. Szczeklik W, Sanak M, Szczeklik A. Functional effects and gender association of COX-2 gene polymorphism G-765C in bronchial asthma. J Allergy Clin Immunol. 2004; 114:248–253. PMID: 15316498.

28. Kim SH, Choi JH, Park HS, Holloway JW, Lee SK, Park CS, et al. Association of thromboxane A2 receptor gene polymorphism with the phenotype of acetyl salicylic acid-intolerant asthma. Clin Exp Allergy. 2005; 35:585–590. PMID: 15898979.

29. Tornhamre S, Ehnhage A, Kolbeck KG, Edenius C, Lindgren JA. Uncoupled regulation of leukotriene C4 synthase in platelets from aspirin-intolerant asthmatics and healthy volunteers after aspirin treatment. Clin Exp Allergy. 2002; 32:1566–1573. PMID: 12569976.

30. Kim SH, Bae JS, Oh JM, Suh CH, Nahm DH, Park HS. Genetic polymorphism of FcεR1β-109T > C is associated with a susceptibility to aspirin-intolerant asthma. J Asthma Allergy Immunol. 2005; 25:S248.

31. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000; 100:655–669. PMID: 10761931.

32. Akahoshi M, Obara K, Hirota T, Matsuda A, Hasegawa K, Takahashi N, et al. Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. Hum Genet. 2005; 117:16–26. PMID: 15806396.

33. Kim SH, Choi JH, Lee KW, Kim SH, Shin ES, Oh HB, et al. The HLA-DRB1*1302-DQB1*0609-DPB1*0201 haplotype may be a strong genetic marker for aspirin-induced urticaria. Clin Exp Allergy. 2005; 35:339–344. PMID: 15784113.

34. Mastalerz L, Setkowicz M, Sanak M, Szczeklik A. Hypersensitivity to aspirin: common eicosanoid alterations in urticaria and asthma. J Allergy Clin Immunol. 2004; 113:771–775. PMID: 15100686.

35. Torres-Galvan MJ, Ortega N, Sanchez-Garcia F, Blanco C, Carrillo T, Quiralte J. LTC4-synthase A-444C polymorphism: lack of association with NSAID-induced isolated periorbital angioedema in a Spanish population. Ann Allergy Asthma Immunol. 2001; 87:506–510. PMID: 11770699.

36. Kim SH, Choi JH, Holloway JW, Suh CH, Nahm DH, Park CS, et al. Leukotriene-related gene polymorphisms in patients with ASA-induced urticaria and ASA-intolerant asthma: differing contributions of ALOX5 polymorphism in Korean population. J Korean Med Sci. 2005; (in press).

37. Choi JH, Kim SH, Suh CH, Nahm DH, Park HS. Polymorphisms of high-affinity IgE receptor and histamine-related genes in patients with ASA-induced urticaria/angioedema. J Korean Med Sci. 2005; 20:367–372. PMID: 15953854.

38. Bae JS, Kim SH, Kang YM, Suh CH, Nahm DH, Park HS. Significant association of FcεR1α promoter polymorphism with aspirin-intolerant chronic urticaria. J Asthma Allergy Immunol. 2005; 25:S249.

39. Kowalski ML, Ptasinska A, Jedrzejczak M, Bienkiewicz B, Cieslak M, Grzegorczyk J, et al. Aspirin-triggered 15-HETE generation in peripheral blood leukocytes is a specific and sensitive aspirin-sensitive patients identification test (ASPITest). Allergy. 2005; 60:1139–1145. PMID: 16076298.

40. Park HS. Aspirin-sensitive asthma. BioDrugs. 2000; 13:29–33. PMID: 18034511.

41. Dahlen SE, Malmstrom K, Nizankowska E, Dahlen B, Kuna P, Kowalski M, et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med. 2002; 165:9–14. PMID: 11779723.

42. Obase Y, Shimoda T, Tomari SY, Mitsuta K, Kawano T, Matsuse H, et al. Effects of pranlukast on chemical mediators in induced sputum on provocation tests in atopic and aspirin-intolerant asthmatic patients. Chest. 2002; 121:143–150. PMID: 11796443.

43. Micheletto C, Tognella S, Visconti M, Pomari C, Trevisan F, Dal Negro RW. Montelukast 10 mg improves nasal function and nasal response to aspirin in ASA-sensitive asthmatics: a controlled study vs placebo. Allergy. 2004; 59:289–294. PMID: 14982510.