β2 Adrenoceptor Polymorphisms Predict Response to β2-Agonists in Children With Acute Asthma

Abstract

Martin AC, Zhang G, Rueter K, et al. J Asthma. 2008;45(5):383–388 PURPOSE OF THE STUDY. To evaluate the influence of single-nucleotide polymorphisms in the β2-adrenoceptor gene on the response to inhaled β2 agonists in children with acute asthma exacerbations. STUDY POPULATION. There were 148 children aged 2 to 16 years presenting to the emergency department (ED) with an acute asthma exacerbation recruited between July 2002 and September 2004. METHODS. The ED physician's diagnosis was based on the presence of wheezing with increased difficulty of breathing. Children were excluded if they had wheeze attributable to other factors (ie, cystic fibrosis, bronchopulmonary dysplasia, foreign body). The standard management of children presenting with an asthma exacerbation included oxygen if saturations were ≤94%, β2 agonist (salbutamol) and an anticholinergic (ipratropium bromide) via metered-dose inhaler with large-volume spacer at 20-minute intervals for the first hour, and prednisolone 1 mg/kg (maximum 40 mg). The initial severity of the asthma episode was determined by using a previously validated scoring system with a possible score of 5 to 15 (5–7 indicated mild; 8–11, moderate; 12–15, severe). An age-specific score of 1 to 3 was assigned to 5 variables (oxygen saturation, respiratory rate, work of breathing, auscultation, and ability to talk). Response to inhaled β2 agonist was measured by determining the time taken to reduce the frequency of β2 agonists from 20-minute intervals to administration at 1, 2, and 4 hourly intervals, with longer times indicating poorer response to treatment. Polymerase chain reaction was used on peripheral blood samples to amplify the 2 polymorphisms of interest (Arg16Gly and Gln27Glu). RESULTS. There were 58 (39.2%) patients who were homozygous Gln27Gln, 69 (46.6%) patients who were heterozygous Gln27Glu, and 21 (14.2%) patients who were homozygous Glu27Glu. Subjects homozygous for Gln were slowest to respond to inhaled β2 agonists and took the longest to reach 1, 2, and 4 hourly β2-agonist treatments (time to 1 hourly: 2.6 ± 2.9 hours; time to 2 hourly: 10.6 ± 9.3 hours; time to 4 hourly: 29.8 ± 23.5 hours). Heterozygotes for Gln had an intermediate response (time to 1 hourly: 2.0 ± 2.8 hours; time to 2 hourly: 10.7 ± 18.1 hours; time to 4 hourly: 28.5 ± 26.2 hours). Homozygotes for Glu had the most rapid response (time to 1 hourly: 1.4 ± 1.2 hours; time to 2 hourly: 6.8 ± 8.9 hours; time to 4 hourly: 24.3 ± 22.2 hours). No significant associations were found between Arg16Gly and response to treatment. After controlling for asthma severity score, previous use of asthma medications, age, gender, and concurrent upper respiratory infection symptoms, homozygotes for Gln were still more likely to have the slowest response to treatment. No associations were found between β2-adrenoreceptor genotype and asthma severity scores or asthma patterns. CONCLUSIONS. This study demonstrates an association between single-nucleotide polymorphisms and response to β2-agonist treatment for children during an acute asthma exacerbation as compared with stable nonacute disease. Children who are homozygous for β2-adrenoceptor Gln27Gln respond less effectively to inhaled β2-agonist therapy. REVIEWER COMMENTS. As the authors pointed out in the report, most children are treated effectively during an acute asthma exacerbation. The length of treatment with inhaled β2 agonists, however, can be variable and unpredictable. The results of this study explain, at least in part, this variability. In the future, knowledge of a patient's β2-adrenoceptor genotype can possibly guide decisions about duration and need for additional therapies during an acute asthma exacerbation.