Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing.
The beta2-adrenergic receptor (beta2AR) agonists are the most widely used agents in the treatment of asthma, but the genetic determinants of responsiveness to these agents are unknown. Two polymorphic loci within the coding region of the beta2AR have been recently described at amino acids 16 and 27. It has been reported that glycine at codon 16 (Gly-16) is associated with increased agonist-promoted downregulation of the beta2AR as compared with arginine-16 (Arg-16). The form of the receptor with glutamic acid at codon 27 (Glu-27), on the other hand, has been shown to be resistant to downregulation when compared with glutamine-27 (Gln-27), but only when coexpressed with Arg-16. To assess if different genotypes of these two polymorphisms would show differential responses to inhaled beta2AR agonists, we genotyped 269 children who were participants in a longitudinal study of asthma. Spirometry was performed before and after administration of 180 microg of albuterol, and a positive response was considered an increase of >15.3% predicted FEV1. There was marked linkage disequilibrium between the two polymorphisms, with 97.8% of all chromosomes that carried Arg-16 also carrying Gln-27. When compared to homozygotes for Gly-16, homozygotes for Arg-16 were 5.3 times (95% confidence interval 1.6-17.7) and heterozygotes for beta2AR-16 were 2.3 times (1.3-4.2) more likely to respond to albuterol, respectively. Similar trends were observed for asthmatic and nonasthmatic children, and results were independent of baseline lung function, ethnic origin, and previous use of antiasthma medication. No association was found between the beta2AR-27 polymorphism and response to albuterol. These results may explain some of the variability in response to therapeutic doses of albuterol in children.
Martinez
F D
FD
Respiratory Sciences Center, the University of Arizona College of Medicine, Tucson, Arizona 85724, USA. fernando@resp-sci.arizona.edu
Graves
P E
PE
Baldini
M
M
Solomon
S
S
Erickson
R
R
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use; D000420:Albuterol / Q000627:therapeutic use*; D000483:Alleles; D001120:Arginine / Q000235:genetics; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics*; D001993:Bronchodilator Agents / Q000627:therapeutic use; D002648:Child; D018698:Glutamic Acid / Q000235:genetics; D005973:Glutamine / Q000235:genetics; D005998:Glycine / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008137:Longitudinal Studies; D011110:Polymorphism, Genetic; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000235:genetics*; D012135:Respiratory Sounds / Q000235:genetics
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D018343:Receptors, Adrenergic, beta-2; D005973:Glutamine; D018698:Glutamic Acid; D001120:Arginine; D000420:Albuterol; D005998:Glycine