Skip Navigation



Human Molecular Genetics Advance Access published online on May 6, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi175
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
14/12/1671    most recent
ddi175v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Tantisira, K. G.
Right arrow Articles by Liggett, S. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tantisira, K. G.
Right arrow Articles by Liggett, S. B.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved
Received March 9, 2005
Revised April 22, 2005
Accepted April 29, 2005

Article

Molecular properties and pharmacogenetics of a polymorphism of adenylyl cyclase 9 in asthma: interaction between {beta}-agonist and corticosteroid pathways

Kelan G. Tantisira 1, Kersten M. Small 2, Augusto A. Litonjua 1, Scott T. Weiss 3, and Stephen B. Liggett 2*

1 Channing Laboratory, Brigham and Womenapos;s Hospital and Harvard Medical School, Boston, MA 02115, USA; Pulmonary Division, Brigham and Womenapos;s Hospital and Harvard Medical School, Boston, MA 02115, USA
2 Department of Medicine and the CardioPulmonary Research Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
3 Channing Laboratory, Brigham and Womenapos;s Hospital and Harvard Medical School, Boston, MA 02115, USA

* To whom correspondence should be addressed.
Stephen B. Liggett, E-mail: stephen.liggett{at}uc.edu


  Abstract

In asthma, the response to {beta}-agonists acting at {beta}2-adrenergic receptors ({beta}2AR) displays extensive interindividual variation. One effector for airway {beta}2AR, adenylyl cyclase type 9 (AC9), was considered a candidate locus for predicting {beta}-agonist efficacy in the absence and presence of corticosteroid treatment. One nonsynonymous 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%) compared to those expressing Ile772 (~20%, P=0.02). An equivalent increase in {beta}2AR 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 FEV1 (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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 ChestHome page
K. Blake, R. Madabushi, H. Derendorf, and J. Lima
Population Pharmacodynamic Model of Bronchodilator Response to Inhaled Albuterol in Children and Adults With Asthma
Chest, November 1, 2008; 134(5): 981 - 989.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
A. Panebra, M. R. Schwarb, S. M. Swift, S. T. Weiss, E. R. Bleecker, G. A. Hawkins, and S. B. Liggett
Variable-length poly-C tract polymorphisms of the {beta}2-adrenergic receptor 3'-UTR alter expression and agonist regulation
Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L190 - L195.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
J. G. Martin and T. Jo
Genetic Differences in Airway Smooth Muscle Function
Proceedings of the ATS, January 1, 2008; 5(1): 73 - 79.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
S B Liggett
Genetic variability of the {beta}2 adrenergic receptor and asthma exacerbations.
Thorax, November 1, 2006; 61(11): 925 - 927.
[Full Text] [PDF]

Home page
 NEJMHome page
D. R. Gold and A. L. Fuhlbrigge
Inhaled corticosteroids for young children with wheezing.
N. Engl. J. Med., May 11, 2006; 354(19): 2058 - 2060.
[Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
M. Johnson
Corticosteroids: Potential {beta}2-Agonist and Anticholinergic Interactions in Chronic Obstructive Pulmonary Disease
Proceedings of the ATS, November 1, 2005; 2(4): 320 - 325.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.