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.
Kim
J-H
JH
Department of Pediatrics, Ulsan University Hospital, Ulsan, Korea.
Lee
S-Y
SY
Kim
H-B
HB
Jin
H-S
HS
Yu
J-H
JH
Kim
B-J
BJ
Kim
B-S
BS
Kang
M-J
MJ
Jang
S-O
SO
Hong
S-J
SJ
D001249:Asthma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D015444:Exercise / Q000502:physiology; D005260:Female; D005838:Genotype; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D020024:Leukotriene Antagonists / Q000627:therapeutic use*; D008297:Male; D016210:Methacholine Chloride / Q000627:therapeutic use*; D011110:Polymorphism, Genetic / Q000235:genetics*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics* / Q000378:metabolism*
D020024:Leukotriene Antagonists; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D016210:Methacholine Chloride; D007073:Immunoglobulin E