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, or “attacks.”
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’ genetic patterns.
“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 differences.
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 to albuterol.
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 asthma.
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; 364: 1505-1512.
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Resources
Guidelines
for the Diagnosis and Management of Asthma (http://www.nhlbi.nih.gov/guidelines/asthma/index.htm)
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)
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