TBXA2R gene polymorphism and responsiveness to leukotriene receptor antagonist in children with asthma.

BACKGROUND: Thromboxane A2 receptor (TBXA2R) gene polymorphism has been associated with atopy and asthma, but few studies have reported the effect of this gene polymorphism on asthma-related phenotype or responsiveness to leukotriene receptor antagonist (LTRA) in asthmatic children. This study investigated associations between asthma-related phenotypes and TBXA2R polymorphism, and also analysed whether the TBXA2R polymorphism has an effect on the efficacy of the LTRA, montelukast, in asthmatic children with exercise-induced bronchoconstriction (EIB).

METHODS: Asthmatic children (n=695) and control children (n=159) were evaluated for asthma-related phenotypes including total IgE, pulmonary function test, and bronchial hyperresponsiveness to methacholine or exercise. Genotypes were detected by PCR-RFLP. In the montelukast study, exercise challenge was performed before and after an 8-week montelukast treatment.

RESULTS: The TBXA2R polymorphism was not associated with asthma susceptibility and the clinical parameters of asthma. However, asthmatic children with combinations of the TBXA2R+795T>C and +924T>C risk alleles had significantly higher total IgE levels (P=0.01), total eosinophil counts (P<0.01) and lower forced expiratory volume in 1 s (FEV(1)) (P=0.02) and forced expiratory rates at 25-75% of vital capacity (P=0.02) than those carrying the common alleles. When compared with individuals with the common alleles, patients with the TBXA2R+924T>C TT homozygote and TBXA2R+795T>C hetero- or homozygote (CT or CC) had a 3.67-fold poor response to 8-week montelukast treatment with respect to maximum percent fall in FEV(1) after exercise (odds ratio, 3.67; 95% confidence interval, 1.15-11.15).

CONCLUSIONS: A combined effect of TBXA2R+795T>C and +924T>C risk alleles may be linked to IgE production, eosinophilic inflammation, and severity of asthma. In addition, the TBXA2R+795T>C genotype may be a predictive marker of a clinical response to the LTRA in Korean asthmatic children with EIB.