Human Molecular Genetics Advance Access originally published online on May 6, 2005
Human Molecular Genetics 2005 14(12):1671-1677; doi:10.1093/hmg/ddi175
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Molecular properties and pharmacogenetics of a polymorphism of adenylyl cyclase type 9 in asthma: interaction between ß-agonist and corticosteroid pathways
1Channing Laboratory and 2Pulmonary Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA and 3Department of Medicine and the Cardiopulmonary Research Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
* To whom correspondence should be addressed at: Department of Medicine and the Cardiopulmonary Research Center, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0564, Cincinnati, OH 45267-0564, USA. Tel: +1 5135580484; Fax: +1 5135580835; Email: stephen.liggett{at}uc.edu
Received March 9, 2005; Revised April 22, 2005; Accepted April 29, 2005
In asthma, the response to ß-agonists acting at ß2-adrenergic receptors (ß2AR) displays extensive interindividual variation. One effector for airway ß2AR, adenylyl cyclase type 9 (AC9), was considered a candidate locus for predicting ß-agonist efficacy in the absence and presence of corticosteroid treatment. One non-synonymous AC9 polymorphism has been identified, which results in substitution of Met for Ile at amino acid 772. Under standard culture conditions in stably transfected cells, we found decreased catalytic activity of Met772. However, cells cultured in the presence of glucocorticoid expressing Met772 had a significantly increased albuterol-stimulated adenylyl cyclase response (
80%) when compared with those expressing Ile772 (20%, P=0.02). An equivalent increase in ß2AR expression was observed in both lines due to glucocorticoid, but AC9 expression was unaffected. The hypothesis that Met772-AC9 is associated with an improved albuterol bronchodilator response in asthmatics was investigated in 436 asthmatic children who were followed for 4 years and randomized to receive placebo or the inhaled corticosteroid budesonide. Met772 carriers on budesonide showed a significant improvement in forced expiratory volume in 1 s (P=0.005). Moreover, a highly significant interaction (P=0.002) was found for budesonide treatment and the AC9 polymorphism. These in vitro and human association studies are consistent with this AC9 polymorphism altering albuterol responsiveness in the context of concomitant inhaled corticosteroid administration, which is a common asthma regimen. The Met772-AC9 polymorphism represents one of most likely several multi-gene polymorphisms along the receptor-relaxation axis, which together may provide for a composite pharmacogenetic index for asthma therapy.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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