Genetics Play Role In Response To Most Common Asthma Drug

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 http://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.