| Genetics Play Role in Response to Most Common Asthma Drug
Study Helps Explain Why Albuterol Benefits Some Asthma Patients More Than Others
Genes affect how asthma patients respond to albuterol, according
to results of a new study of adults with mild asthma. Researchers
in the Asthma Clinical Research Network (ACRN) of the National Heart,
Lung, and Blood Institute (NHLBI), part of the National Institutes
of Health, found that over time, how participants responded to daily
doses of inhaled albuterol differed depending on which form of a
specific gene they had inherited. While a few weeks of regular use
of albuterol improved overall asthma control in individuals with
one form of the gene, stopping all use of albuterol eventually improved
asthma control in those with another form of the gene. Albuterol
is the most commonly used drug for relief of acute asthma symptoms,
The Beta-Adrenergic Response by Genotype (BARGE) trial is the first
study of an asthma drug in patients selected according to their
genotype, or which forms of a specific gene they have. Published
in the October 23-29 issue of the Lancet,*
the BARGE trial provides important insight as to why albuterol may
benefit some people with asthma more than others. The findings could
lead to better ways to individualize asthma therapy based on patients’
“If we can pinpoint which individuals will do better with
a certain type of therapy, we can improve their lives more quickly
and save them and the healthcare system the expense and risk of
trying drugs that are less effective for them,” comments Dr.
Barbara Alving, NHLBI acting director. “This study helps put
asthma at the forefront of pharmacogenetics.”
Pharmacogenetics is an emerging science that links variations in
genotypes to variations in drug responsiveness. Scientists have
long known that genes can play a role in how individuals respond
to disease and to medications. As drugs move through the body, they
interact with thousands of molecules, or proteins. Because genes
direct how proteins behave, variations in the structure of a gene
can affect how the protein responds to a medication. Many believe
that pharmacogenetics will revolutionize health care as it will
lead to the development of drugs that target specific molecules
more precisely than currently available medications, making them
more powerful and less likely to create unwanted side effects.
Asthma drugs are known to vary widely in their effects in different
patients. Research suggests that genetics may play a role in these
Albuterol targets the beta-2 adrenergic receptor molecules. As
an asthma quick-relief medication, it relaxes the muscles in the
airways and quickly opens up the air passages during an asthma attack,
when airways are narrowed. BARGE was developed based on observations
from earlier studies that suggested that genetic differences in
the beta-receptor might play an important role in how patients respond
The BARGE study examined the effects of two forms of the beta-2
adrenergic receptor in patients with mild asthma. The trial paired
78 participants with matching levels of airway function but with
different forms of the receptor gene. Researchers compared participants
who have two arginine versions of the gene (the arginine genotype)
to those with two glycine versions of the gene (the glycine genotype).
Albuterol was used daily (two puffs, four times a day) for 16 weeks,
and placebo use followed the same timeframe. When participants needed
additional symptom relief, they used ipratropium bromide, a different
type of quick-relief medication known as an anticholinergic.
While all participants initially responded well to albuterol, after
16 weeks of daily use, those with the arginine genotype had poorer
asthma control compared to their matched partners with the glycine
genotype. In addition, the arginine participants reported more symptoms,
lower FEV1 scores (a measurement of lung function) and more frequent
use of quick-relief medication.
Overall, participants with the arginine genotype had improved asthma
control when not using albuterol. In contrast, participants with
the glycine genotype had better asthma control with albuterol treatment,
although not with placebo.
Of the 15 million Americans who have asthma, about 1 out of 6 (more
than 2 million) have the arginine genotype. Moreover, the arginine
genotype is more prevalent in certain ethnic groups, such as African
Americans. Currently, tests to determine this genotype are only
available in a few research settings.
“Anyone needing regular, daily use of albuterol for asthma
control should be considered for a long-term controller medication.
Our findings suggest that in patients with the arginine genotype,
this will be especially important,” said Dr. Elliot Israel
of Brigham and Women’s Hospital, lead author of the study.
“More work is needed to determine how to integrate these findings
into clinical practice. In the future, patients with the arginine
genotype might even be advised to use an alternate reliever medication.”
The National Asthma Education and Prevention Program (NAEPP) recommends
quick-relief medication such as inhaled albuterol on an as-needed
basis for acute asthma symptoms. Other recommended reliever medications
include inhaled anticholinergics and short-acting theophylline.
NAEPP clinical guidelines call for a "step-wise" approach
to asthma management, in which treatment is adjusted depending on
disease severity and symptom frequency. Patients who have symptoms
or use quick-relief medication more than a couple of times a week,
for example, should add daily long-term control medication such
as inhaled corticosteroids or leukotriene modifiers.
“This study highlights one of several variables that plays
a role in how a medication will affect an individual,” says
Dr. James Kiley, director of the NHLBI Division of Lung Diseases.
“It also serves as a reminder of how important it is for asthma
specialists to regularly assess how their patients are responding
to medications so they can modify their drug regimen as needed.”
NHLBI established the ACRN in 1993 to conduct multiple, well-designed
clinical trials for rapid evaluation of new and existing therapeutic
approaches to asthma and to disseminate laboratory and clinical
findings to the healthcare community. The ACRN clinical centers
that participated in this study are Brigham and Women's Hospital
and Harvard Medical School (Boston), Harlem Lung Center and Columbia
University (New York City), National Jewish Medical and Research
Center (Denver), Thomas Jefferson Medical College (Philadelphia),
University of California at San Francisco, and University of Wisconsin
(Madison). Two of the clinical centers the University of California
at San Francisco and the University of Wisconsin also received support
from the NIH National Center for Research Resources. The data coordinating
center is at Pennsylvania State University College of Medicine.
In a separate study, new ACRN researchers are studying whether
similar effects occur with long-acting forms of medication similar
to albuterol. These medications, known as long-acting beta-agonists,
are increasingly used in concert with inhaled corticosteroids as
long-term control medications for patients with moderate or severe
Note: Albuterol and placebo was provided by Glaxo-SmithKline. Ipratropium
bromide was provided by Boehringer Ingelheim Pharmaceuticals, Inc.
To interview Dr. Kiley, contact the NHLBI Communications Office
at (301) 496-4236. To interview Dr. Israel, contact Brigham and
Women’s Hospital Department of Public Affairs at (617) 534-1600.
NHLBI is part of the National Institutes of Health (NIH), the
Federal Government's primary agency for biomedical and behavioral
research. NIH is a component of the U.S. Department of Health and
Human Services. NHLBI press releases, fact sheets, and resources
on asthma can be found online at www.nhlbi.nih.gov.
* Israel E, Chinchilli VM, Ford JG, et
al., for the National Heart, Lung, and Blood Institute's Asthma Clinical
Research Network. Genotype Stratified Prospective Cross-over Trial
of Regularly Scheduled Albuterol Treatment in Asthma. Lancet 2004;
Resources Guidelines for the Diagnosis and Management of Asthma
NHLBI Working Group Report Executive Summary: Polymorphisms of the Beta-adrenergic
Receptor Gene: Implications for the Pharmacotherapy of Asthma (http://www.nhlbi.nih.gov/meetings/workshops/pharm_execsum.htm)
National Asthma Education and Prevention Program (http://www.nhlbi.nih.gov/about/naepp/index.htm)