Allergy Asthma Immunol Res.  2009 Oct;1(1):30-35. 10.4168/aair.2009.1.1.30.

Association analysis of peroxisome proliferator-activated receptors gamma gene polymorphisms with asprin hypersensitivity in asthmatics

• Oh SH
• Park SM
• Park JS
• Jang AS
• Lee YM
• Uh ST
• Kim YH
• Choi IS
• Kim MK
• Park BL
• Shin HD
• Park CS

• KMID: 2133796
• DOI: http://doi.org/10.4168/aair.2009.1.1.30

Abstract

PURPOSE
Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors activated by ligands of the nuclear hormone receptor superfamily. The activation of PPARgamma regulates inflammation by downregulating the production of Th2 type cytokines and eosinophil function. In addition, a range of natural substances, including arachidonate pathway metabolites such as 15-hydroxyeicosatetranoic acid (15-HETE), strongly promote PPARG expression. Therefore, genetic variants of the PPARG gene may be associated with the development of aspirin-intolerant asthma (AIA). We investigated the relationship between single nucleotide polymorphism (SNP) of the PPARG gene and AIA.
METHODS
Based on the results of an oral aspirin challenge, asthmatics (n=403) were categorized into two groups: those with a decrease in FEV1 of 15% or greater (AIA) or less than 15% (aspirin-tolerant asthma, ATA). We genotyped two single nucleotide polymorphisms in the PPARG gene from Korean asthmatics and normal controls (n=449): +34C>G (Pro12Ala) and +82466C>T (His449His).
RESULTS
Logistic regression analysis showed that +82466C>T and haplotype 1 (CC) were associated with the development of aspirin hypersensitivity in asthmatics (P=0.04). The frequency of the rare allele of +82466C>T was significantly higher in AIA patients than in ATA patients in the recessive model [P=0.04, OR=3.97 (1.08-14.53)]. In addition, the frequency of PPARG haplotype 1 was significantly lower in AIA patients than in ATA patients in the dominant model (OR=0.25, P=0.04).
CONCLUSIONS
The +82466C>T polymorphism and haplotype 1 of the PPARG gene may be linked to increased risk for aspirin hypersensitivity in asthma.

Keyword

peroxisome proliferator-activated receptors gamma; aspirin; asthma; gene; polymorphism

MeSH Terms

Alleles
Aspirin
Asthma
Cytokines
Eosinophils
Haplotypes
Humans
Hypersensitivity
Inflammation
Ligands
Logistic Models
Peroxisome Proliferator-Activated Receptors
Peroxisomes
Polymorphism, Single Nucleotide
PPAR gamma
Aspirin
Cytokines
Ligands
PPAR gamma
Peroxisome Proliferator-Activated Receptors

Figure

• 

  Fig. 1 The comparison of the rate of fall (%) of FEV1 with aspirin provocation between subjects possessing the rare and common alleles by (A) +82466C>T and (B) haplotype 1 of PPARG gene. The P values were obtained by linear regression analysis, controlled for age (continuous value), gender (male=0, female=1), atopy status (non-atopy=0, atopy=1), smoking status (non-smoker=0, ex-smoker=1, smoker=2), and BMI (continuous value) as covariates.

Reference

1. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM. The nuclear receptor superfamily: the second decade. Cell. 1995. 83:835–839.

2. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994. 79:1147–1156.

3. Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, Fruchart JC, Chapman J, Najib J, Staels B. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem. 1998. 273:25573–25580.

4. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998. 391:82–86.

5. Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum JL, Funk CD, Conrad D, Glass CK. Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature. 1999. 400:378–382.

6. 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.

7. Benayoun L, Letuve S, Druilhe A, Boczkowski J, Dombret MC, Mechighel P, Megret J, Leseche G, Aubier M, Pretolani M. Regulation of peroxisome proliferator-activated receptor gamma expression in human asthmatic airways: relationship with proliferation, apoptosis, and airway remodeling. Am J Respir Crit Care Med. 2001. 164:1487–1494.

8. Samter M, Beers RF Jr. Concerning the nature of intolerance to aspirin. J Allergy. 1967. 40:281–293.

9. Stevenson DD, Sanchez-Borges M, Szczeklik A. Classification of allergic and pseudoallergic reactions to drugs that inhibit cyclooxygenase enzymes. Ann Allergy Asthma Immunol. 2001. 87:177–180.

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

11. Bachert C, Wagenmann M, Hauser U, Rudack C. IL-5 synthesis is upregulated in human nasal polyp tissue. J Allergy Clin Immunol. 1997. 99:837–842.

12. 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.

13. 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.

14. National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma update on selected topics. J Allergy Clin Immunol. 2002. 110:S141–S219.

15. 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.

16. Cormican LJ, Farooque S, Altmann DR, Lee TH. Improvements in an oral aspirin challenge protocol for the diagnosis of aspirin hypersensitivity. Clin Exp Allergy. 2005. 35:717–722.

17. Ferris BG. Epidemiology Standardization Project (American Thoracic Society). Am Rev Respir Dis. 1978. 118:1–120.

18. Moon MK, Cho YM, Jung HS, Park YJ, Yoon KH, Sung YA, Park BL, Lee HK, Park KS, Shin HD. Genetic polymorphisms in peroxisome proliferator-activated receptor gamma are associated with Type 2 diabetes mellitus and obesity in the Korean population. Diabet Med. 2005. 22:1161–1166.

19. Oh SH, Park SM, Lee YH, Cha JY, Lee JY, Shin EK, Park JS, Park BL, Shin HD, Park CS. Association of peroxisome proliferator-activated receptor-gamma gene polymorphisms with the development of asthma. Respir Med. 2009. 103:1020–1024.

20. Hedrick PW. Gametic disequilibrium measures: proceed with caution. Genetics. 1987. 117:331–341.

21. Kim KS, Choi SM, Shin SU, Yang HS, Yoon Y. Effects of peroxisome proliferator-activated receptor-gamma 2 Pro12Ala polymorphism on body fat distribution in female Korean subjects. Metabolism. 2004. 53:1538–1543.

22. Rhee EJ, Oh KW, Lee WY, Kim SY, Oh ES, Baek KH, Kang MI, Kim SW. Effects of two common polymorphisms of peroxisome proliferator-activated receptor-gamma gene on metabolic syndrome. Arch Med Res. 2006. 37:86–94.

23. Doney AS, Fischer B, Cecil JE, Boylan K, McGuigan FE, Ralston SH, Morris AD, Palmer CN. Association of the Pro12Ala and C1431T variants of PPARG and their haplotypes with susceptibility to Type 2 diabetes. Diabetologia. 2004. 47:555–558.

24. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000. 26:76–80.

25. Ardlie KG, Lunetta KL, Seielstad M. Testing for population subdivision and association in four case-control studies. Am J Hum Genet. 2002. 71:304–311.

26. Buzzetti R, Petrone A, Ribaudo MC, Alemanno I, Zavarella S, Mein CA, Maiani F, Tiberti C, Baroni MG, Vecci E, Arca M, Leonetti F, Di Mario U. The common PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity. Eur J Hum Genet. 2004. 12:1050–1054.

27. Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell. 1998. 93:229–240.

28. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 1995. 83:803–812.

29. Kowalski ML, Ptasinska A, Bienkiewicz B, Pawliczak R, DuBuske L. Differential effects of aspirin and misoprostol on 15-hydroxyeicosatetraenoic acid generation by leukocytes from aspirin-sensitive asthmatic patients. J Allergy Clin Immunol. 2003. 112:505–512.

30. Limor R, Sharon O, Knoll E, Many A, Weisinger G, Stern N. Lipoxygenase-derived metabolites are regulators of peroxisome proliferator-activated receptor gamma-2 expression in human vascular smooth muscle cells. Am J Hypertens. 2008. 21:219–223.

31. 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.