Expression of Leukotriene C 4 Synthase and Plasminogen Activator Inhibitor 1 Gene Promoter Polymorphisms in Sinusitis

Abstract

Background

Studies have described polymorphisms in genes involved with both leukotriene synthesis and remodeling. Leukotriene C₄ synthase (LTC₄S) is the critical terminal pathway enzyme involved in regulation of cysteinyl leukotriene (CysLT) synthesis. An A-to-C base exchange in the promoter region of the LTC₄S gene influences its expression. The plasminogen activator inhibitor (PAI) 1 gene is associated with tissue fibrosis. The presence of either 4G or 5G residues in the promoter region has been associated with altered transcription. The role of these polymorphisms was investigated in patients with sinusitis and polyps. We performed a prospective study of patients undergoing endoscopic sinus surgery at a university hospital between 1996 and 2004.

Methods

Demographic data and sinus tissue were collected from patients. Patients were classified into four groups: controls, chronic hyperplastic eosinophilic sinusitis (CHES), aspirin exacerbated respiratory disease (AERD), and chronic inflammatory sinusitis (CIS). DNA was analyzed for the LTC₄S and the PAI-1 promoter polymorphisms using standard PCR techniques.

Results

There were 133 patients with 76 women and 57 men (mean age, 42 years). Sixty-six people were in the control group, 16 people were in the CIS group, 51 people were in the CHES group, and 22 people were in the AERD group. The LTC₄S allelic frequencies were controls, A = 0.81 and C = 0.19; CIS, A = 0.73 and C = 0.27; CHES, A = 0.69 and C = 0.31; AERD, A = 0.67 and C = 0.33. The C allele was more frequent in CHES versus controls (p = 0.04). The PAI-1 allele frequencies were controls, 5G = 0.55 and 4G = 0.45; CIS, 5G = 0.47 and 4G = 0.53; CHES, 5G = 0.56 and 4G = 0.44; AERD, 5G = 0.54 and 4G = 0.46. Increased expression of the 4G allele of the PAI-1 gene was observed in CIS; however, this genetic variance between the four groups was not statistically different (p > 0.05).

Conclusion

There appears to be a genetic component that contributes to nasal polyp formation in sinusitis. Although the LTC₄S polymorphism has previously been associated with aspirin-sensitive asthma, this is the first demonstration that the polymorphism is associated with CHES and this is independent of aspirin sensitivity.

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References

Slavin

R.G.

Nasal polyps and sinusitis.

JAMA 278: 1849–1854, 1997.

Ray

N.F.

, Baraniuk

J.N.

, Thamer

Healthcare expenditures for sinusitis in 1996: Contributions of asthma, rhinitis, and other airway disorders.

J Allergy Clin Immunol 103: 408–414, 1999.

Sanak

, Pierzchalska

, Bazan-Socha

, and Szceklik

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 23: 290–296, 2000.

Sanak

, Simon

, and Szczeklik

Leukotriene C₄ synthase promoter polymorphism and risk of aspirin-induced asthma.

Lancet 350: 1599–1600, 1997.

Sanak

, and Szczeklik

Leukotriene C₄ synthase polymorphism and aspirin-induced asthma.

J Allergy Clin Immunol 107: 561, 2001.

Kawagishi

, Mita

, Taniguchi

Leukotriene C₄ synthase promoter polymorphism in Japanese patients with aspirin-induced asthma.

J Allergy Clin Immunol 109: 936–942, 2002.

Van Sambeek

, Stevenson

D.D.

, Baldasaro

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 106: 72–76, 2000.

Kedda

M.A.

, Shi

, Duffy

Characterization of two polymorphisms in the leukotriene C₄ synthase gene in an Australian population of subjects with mild, moderate, and severe asthma.

J Allergy Clin Immunol 113: 889–895, 2004.

Sampson

A.P.

, Siddiqui

, Buchanan

Variant LTC₄ synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast.

Thorax 55(suppl 2): S28–S31, 2000.

10.

Torres-Galvan

M.J.

, Ortega

, Sanchez-Garcia

LTC4 synthase A-444C polymorphism: Lack of association with NSAID-induced isolated periorbital angioedema in a Spanish population.

Ann Allergy Asthma Immunol 87: 506–510, 2001.

11.

Sayers

, Barton

, Rorke

Allelic association and functional studies of promoter polymorphism in the leukotriene C₄ synthase gene (LTC4S) in asthma.

Thorax 58: 417–424, 2003.

12.

Cho

S.H.

, Hall

I.P.

, Wheatley

Possible role of 4G/5G polymorphism of the plasminogen activator inhibitor 1 gene in the development of asthma.

J Allergy Clin Immunol 108: 212–214, 2001.

13.

Cho

S.H.

, Ryu

C.H.

, and Oh

C.K.

Plasminogen activator inhibitor-1 in the pathogenesis of asthma.

Exp Biol Med 229: 138–146, 2004.

14.

Steinke

J.W.

, Bradley

, Arango

Cysteinyl leukotriene expression in chronic hyperplastic sinusitis-nasal polyposis: Importance to eosinophilia and asthma.

J Allergy Clin Immunol 111: 342–349, 2003.

15.

Szczeklik

, and Stevenson

D.D.

Aspirin-induced asthma: Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management.

J Allergy Clin Immunol 111: 913–921, 2003.

16.

Szczeklik

, and Nizankowska

Clinical features and diagnosis of aspirin induced asthma.

Thorax 55 Suppl 2: S42–S44, 2000.

17.

Berges-Gimeno

M.P.

, Simon

R.A.

, and Stevenson

D.D.

The natural history and clinical characteristics of aspirin-exacerbated respiratory disease.

Ann Allergy Asthma Immunol 89: 474–478, 2002.

18.

Buckova

, Holla

L.I.

, and Vacha

Polymorphism 4G/5G in the plasminogen activator inhibitor-1 (PAI-1) gene is associated with IgE-mediated allergic diseases and asthma in the Czech population.

Allergy 57: 446–448, 2002.