ASSOCIATION BETWEEN GENETIC POLYMORPHISMS OF THE BETA(2)-ADRENOCEPTORAND RESPONSE TO ALBUTEROL IN CHILDREN WITH AND WITHOUT A HISTORY OF WHEEZING

The beta(2)-adrenergic receptor (beta(2)AR) agonists are the most wide ly used agents in the treatment of asthma, but the genetic determinant s of responsiveness to these agents are unknown, Two polymorphic loci within the coding region of the beta(2)AR 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 downregulati on of the beta(2)AR as compared with arginine-16 (Arg-16), The form of the receptor with glutamic acid at codon 27 (Glu-27), on the other ha nd, has been shown to be resistant to downregulation when compared wit h glutamine-27 (Gln-27), but only when coexpressed with Arg-16, To ass ess if different genotypes of these two polymorphisms would show diffe rential responses to inhaled beta(2)AR agonists, we genotyped 269 chil dren who were participants in a longitudinal study of asthma. Spiromet ry was performed before and after administration of 180 mu g of albute rol, and a positive response was considered an increase of >15.3% pred icted FEV1. There was marked linkage disequilibrium between the two po lymorphisms, with 97.8% of all chromosomes that carried Arg-16 also ca rrying Gln-27. When compared to homozygotes for Gly-16, homozygotes fo r Arg-16 were 5.3 times (95% confidence interval 1.6-17.7) and heteroz ygotes for beta(2)AR-16 were 2.3 times (1.3-4.2) more likely to respon d to albuterol, respectively, Similar trends were observed for asthmat ic and nonasthmatic children, and results were independent of baseline lung function, ethnic origin, and previous use of antiasthma medicati on, No association was found between the beta(2)AR-27 polymorphism and response to albuterol, These results may explain some of the variabil ity in response to therapeutic doses of albuterol in children.