NHLBI Working Group
Polymorphisms of the Beta-adrenergic Receptor Gene: Implications for the
Pharmacotherapy of Asthma
Executive Summary
Genetic influences and their interaction with environmental factors are
thought to be important determinants of asthma incidence, severity, and
response to treatment. The importance of determining whether genetic determinants
shape the response to regular use of inhaled beta-agonists has been increased
by changes in the characteristics of beta-agonists, with a substantially
longer duration of bronchodilator action and improved efficacy in control
of asthma symptoms. Despite the availability of the inhaled beta-agonists
for more than 30 years, limited information is available on the role of
genetic polymorphisms and their associated responses to treatment. Recent
findings of a genotyped stratified prospective trial conducted by the
NIH Asthma Clinical Research Network (ACRN) prompted the organization
of a meeting to examine the role of polymorphisms of the beta-adrenergic
receptor gene in relation to asthma treatment as well as to consider new
opportunities in the field of asthma pharmacogenetics. Accordingly, the
National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group
entitled "Polymorphisms of the Beta-adrenergic Receptor Gene: Implications
for the Pharmacotherapy of Asthma" on June 17-18, 2003.
The working group proposed various scenarios that should be considered
for developing future studies, ranging from studies that include 1,000
to 6,000 subjects sample sizes. However, challenges are not limited to
the sample size but to phenotypic variations, pharmacological interactions,
or gene-environment interactions, just to mention a few. Given the potential
costs of such large studies, collaboration with the pharmaceutical industry
or with other governmental agencies may be desirable in performing such
studies. Despite major recent advances in the understanding of the structure
and function of the beta2 adrenergic receptor (beta2AR), several questions
with relevant clinical implications remain to be answered, requiring a
stepwise approach. Some questions relate to the genotyped stratified prospective
trial "BARGE" observations to the use of long-acting beta-agonists; the
possible selective racial/ethnic predisposition to a beta2AR polymorphism
or a related mechanism that increases risk for severe exacerbations; the
influence of inhaled steroids on the reduction in pulmonary function that
occurs within the Arg/Arg genotype with regular -agonists; the role of
gene by dose relationship on therapeutic responses; the mechanism of the
prolonged decline in pulmonary function in the Arg/Arg group that occurs
even when regular beta-agonists are discontinued; the relationship between
beta2AR polymorphisms and nocturnal asthma; and the possible functional
importance of genetic variation in the 3' UTR and its influence on the
bronchodilator phenotype. The workshop participants recognized that individual
gene or individual variant within a gene is likely to confer only a small
proportion of explained phenotypic variance, and that multiple variants
in multiple genes in a pathway will be necessary to explain a significant
percentage of variation in treatment response. Therefore, a combination
of multiple single nucleotide polymorphisms or haplotypes across many
genes will be needed to develop diagnostic tests that will be predictive
for beta-agonist treatment response.
Working Group Members
Chair: Homer Boushey, MD, Department of Medicine, University of California
San Francisco
Members:
- Scott Weiss, MD, Channing Laboratory, Brigham and Women's Hospital
- Stephen Liggett, MD, Department of Medicine, University of Cincinnati
- Carole Ober, PhD, Department of Human Genetics, University of Chicago
- Fernando Martinez, MD, Arizona Respiratory Center, University of
Arizona College of Medicine
- Elliot Israel, MD, Department of Medicine, Brigham and Women's Hospital
- Michael Wechsler, MD, Department of Medicine, Brigham and Women's
Hospital
- Julie A. Johnson, Pharm.D., Department of Pharmacy Practice, University
of Florida
- Robert Lemanske, MD, Department of Pediatrics, University of Wisconsin
- Stanley J. Szefler, MD, Department of Pharmacology, National Jewish
Medical & Research Center
- William J. Calhoun, MD, Department of Medicine, University of Pittsburgh
- Vernon M. Chinchilli, PhD, Department of Health Evaluation Sciences,
Pennsylvania State University
May 2004
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