β2-Adrenergic Receptor Polymorphisms Affect Response to Treatment in Children With Severe Asthma Exacerbations

Abstract

Carroll CL, Stoltz P, Schramm CM, Zucker AR. Chest. 2009;135(5):1186–1192PURPOSE OF THE STUDY. The purpose of this study was to explore the hypothesis that genotypic differences of the β2-adrenergic receptor (β2-AR) affect patient responses to short-term β2-AR agonist treatment for children who experience severe exacerbations of asthma.STUDY POPULATION. Children between 2 and 18 years of age with physician-diagnosed asthma admitted to the ICU at a Connecticut medical center during a 4-year period (N = 37).METHODS. A modified pulmonary index score (MPIS) was used to assess the severity of asthma exacerbation. β2-AR therapy was titrated on the basis of hourly MPISs. Children who did not respond to high-dose nebulized therapy were treated with intravenously administered terbutaline. Children also received intravenously administered methylprednisolone at 4 mg/kg per day. Genetic samples were obtained from saliva. Genotyping of the adjacent Arg16Gly and Gln27Glu was performed to determine the frequency of the 4 most common haplotypes. Clinical data were retrospectively extracted from the medical record.RESULTS. At baseline, children with the Gly/Gly genotype at amino acid position 16 of the β2-AR were more likely to have intermittent asthma exacerbations than were those with either the Arg/Arg or Arg/Gly genotype. Otherwise, there were no statistical differences in the demographic features, baseline characteristics, or medical histories between these 2 patient groups. No differences were found in admission MPISs among the study groups; however, children with the Gly/Gly genotype had significantly shorter ICU length of stay, duration of continuously nebulized albuterol therapy, and duration of supplemental oxygen therapy and were significantly less likely to require intravenous β2-AR agonist therapy, compared with those with the Arg/Arg or Arg/Gly genotype. Genetic polymorphisms at position 27 were not associated with response to β2-AR agonist therapy or with the other clinical outcomes measured.CONCLUSIONS. In this group of children with severe asthma exacerbations, those with the Gly/Gly genotype at position 16 of the β2-AR had more-rapid responses to β2-AR agonist therapy and shorter ICU lengths of stay.REVIEWERS COMMENTS. This article provides further evidence of the complexity of asthma genetics. The relationship between β2-AR genotypes and responses to β2-AR agonists is controversial, with different studies coming to opposing conclusions. Responses may depend largely on how the β2-AR agonist is dosed (short-term, single-dose treatment versus long-term, repeated dosing). This study was limited by the small study size. However, the study presents another step toward linking asthma genotypes with asthma phenotypes. This should allow the use of pharmacogenetics to treat specific patient populations in an evidence-based manner, an exciting future!