IL-5 and thromboxane A2 receptor gene polymorphisms are associated with decreased pulmonary function in Korean children with atopic asthma

doi:10.1016/j.jaci.2004.10.047

Journal of Allergy and Clinical Immunology

Volume 115, Issue 4, April 2005, Pages 758-763

https://doi.org/10.1016/j.jaci.2004.10.047 Get rights and content

Background

Asthmatic airways undergo chronic inflammatory cell infiltration by T cells and eosinophils, which results in sustained airway hyperresponsiveness. IL-5 is important for eosinophil-induced airway inflammation and airway hyperresponsiveness. Thromboxane A2 and its receptor, TBXA2R, are involved in constriction of respiratory smooth muscles and may play a role in thickening and remodeling of airways, which contributes to the severity of asthma. The relationship between IL-5 and TBXA2R gene polymorphisms and pulmonary function in children with asthma has rarely been examined.

Objective

To determine whether IL-5 (T−746C) and TBXA2R (T924C) gene polymorphisms are associated with asthma phenotype and pulmonary function in Korean children with atopic and nonatopic asthma.

Methods

We conducted an association study between known polymorphisms of IL-5 (T−746C) and TBXA2R (T924C) and asthma phenotype and the parameters of atopy and pulmonary function in atopic and nonatopic Korean children with asthma. The subjects were 240 atopic children with asthma, 70 nonatopic children with asthma, and 106 nonatopic healthy children. Asthma phenotypes and bronchial responsiveness to methacholine were determined by a physician. IL-5 and TBXA2R gene polymorphisms were determined by genotyping by using PCR-RFLP assays.

Results

The genotype frequencies of IL-5 and TBXA2R polymorphisms did not differ between healthy controls and atopic or nonatopic children with asthma. A significant association was observed between the IL-5 polymorphism and forced expiratory flow at 25% to 75% of forced vital capacity (FEF_25-75%; %; P = .002), and between the TBXA2R polymorphism and FEV₁ (%; P = .035) and FEF_25-75% (%; P = .042) in children with atopic asthma, whereas no such association between the polymorphisms and lung function was observed in nonatopic or control children. In atopic children with asthma, we identified a significant gene-gene interaction in that the combination of the IL-5 (T−746C) and TBXA2R (T924C) mutant alleles was shown to be associated with reduced pulmonary function as determined by FEF_25-75% (%) measurement.

Conclusion

The current study indicates that IL-5 (T−746C) and TBXA2R (T924C) polymorphisms alone are associated with spirometric markers of asthma severity, whereas they are not associated with presence of asthma per se. In addition, the data suggest that an interaction between IL-5 and TBXA2R genes may contribute to the severity of asthma, especially atopic asthma. These results suggest that IL-5 and TBXA2R genes may be disease-modifying genes in Korean children with atopic asthma.

Section snippets

Subjects

Two hundred forty atopic children with asthma, 70 nonatopic children with asthma, and 106 nonatopic healthy children were enrolled at the Asthma and Allergy Clinics of the Asan Medical Center. As shown in Table I, all patients with asthma and controls (healthy subjects) were appropriately matched for age and sex (P > .05). There were significant differences in FEV₁, PC₂₀, total IgE, total eosinophil counts (TECs), and eosinophil fraction among the 3 groups (P < .01; Table I).

Asthma phenotypes and

Genotyping of IL-5 (T−746C) and TBXA2R (T924C)

The association between asthma and IL-5 (T−746C) or TBXA2R (T924C) polymorphisms was investigated by comparing the occurrence of polymorphisms in children with asthma and healthy children. The frequencies of the IL-5 CC homozygote (11.2%) and CT heterozygote (41.7%) in children with atopic asthma were not significantly different from the frequencies in healthy control children (13.2% and 36.8%, respectively; Table II). Similarly, the frequencies of the TBXA2R CC homozygote (5.4%) and CT

Discussion

Although IL-5 is important in allergic inflammation, no studies have proven the association between IL-5 polymorphism and asthma per se or the clinical parameters of asthma. IL-5 polymorphism was not associated with development of asthma per se in this study. However, FEF_25-75% (%) was lower in atopic children with asthma carrying homozygous and heterozygous mutant alleles of the IL-5 gene compared with those carrying the homozygous wild-type allele. These findings suggest a possibility of IL-5

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View full text

Mechanisms of asthma and allergic inflammationIL-5 and thromboxane A2 receptor gene polymorphisms are associated with decreased pulmonary function in Korean children with atopic asthma

Background

Objective

Methods

Results

Conclusion

Section snippets

Subjects

Genotyping of IL-5 (T−746C) and TBXA2R (T924C)

Discussion

J Allergy Clin Immunol

Am J Hum Genet

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Prostglandins Leukot Essent Fatty Acids

Chest

Am J Hum Genet

J Allergy Clin Immunol

J Allergy Clin Immunol

Eosinophilia

N Engl J Med

Predominant Th2-like bronchoalveolar T-lymphocyte population in atopic asthma

N Engl J Med

Late response to allergen is associated with increased concentrations of tumor necrosis factor-alpha and IL-5 in induced sputum

J Allergy Clin Immunol

Expression of mRNA for interleukin-5 in mucosal bronchial biopsies from asthma

J Clin Invest

Effect of inhaled interleukin-5 on airway hyperreactivity and eosinophilia in asthmatics

Am J Respir Crit Care Med

Mechanisms of acute eosinophil mobilization from the bone marrow stimulated by interleukin 5: the role of specific adhesion molecules and phosphadylinositol 3-kinase

J Exp Med

Mechanisms of asthma and allergic inflammation
IL-5 and thromboxane A2 receptor gene polymorphisms are associated with decreased pulmonary function in Korean children with atopic asthma