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The genetics of breathing free
SNPs and the effectiveness of asthma medication
Sarah E. DeWeerdt

When people with asthma take a quick puff of medicine from their inhaler during an asthma attack, some experience relief while others continue to gasp for breath. Now, researchers at the University of Cincinnati College of Medicine and Genaissance Pharmaceuticals, Inc. say there's a genetic explanation for this difference.

In a study published in a recent issue of the Proceedings of the National Academy of Sciences, the researchers report that the effectiveness of the most common quick-relief asthma medication depends on the combination of variations in the gene for the beta-2 adrenergic receptor (b2AR). Their results could eventually lead to more individualized, and more effective, treatments for asthma.

a person could have two SNPs with opposing effects that would cancel each other out

The researchers identified 13 different variations known as single-nucleotide polymorphisms, or SNPs, in the b2AR gene. Several previous studies had investigated individual SNPs in the gene with somewhat conflicting results. But the researchers in the current study came up with a new approach. They reasoned that a person could have two SNPs with opposing effects that would cancel each other out. For example, one SNP might cause cells to make fewer copies of the b2AR, but another SNP might make each copy of the receptor more active.

"We wanted to see if the combination of SNPs as they occur on the chromosome would give us more predictive power," says Dennis W. McGraw, MD, a member of the research team from the University of Cincinnati College of Medicine. "That was the case," he adds. Theoretically, the 13 SNPs could come in 8,192 possible combinations, or haplotypes, on the chromosome. But the researchers found that only 12 different haplotypes actually occurred in the group they studied. The most common haplotypes were 1, 2, 4, and 6.

Next, McGraw and his colleagues recruited 121 patients who came to a clinic seeking treatment for their asthma, and analyzed which b2AR haplotypes each had. All people have two copies of the b2AR gene, and these can be either two copies of the same haplotype or one copy each of two different haplotypes. Most of the patients in the study had one of five haplotype combinations: 2/2, 2/4, 2/6, 4/4, or 4/6.

The researchers then measured each patient's lung function before and after a dose of albuterol, the most commonly prescribed drug for relief of asthma attacks. Albuterol and related drugs known as b2-agonists work by attaching to b2AR proteins on airway cells in the lung. This causes the muscles around the airways to relax, dilating the airways and helping people with asthma breathe.

‘We hope to tailor the medications up front, so that therapy becomes much more individualized’

In the study, the effect of albuterol—how good it was at dilating the airways—varied from person to person, depending on which haplotypes the person had. People with a 2/2 combination had about a 50 percent greater response to the drug than people with a 4/4 combination. By contrast, the effect of albuterol was not correlated with any individual SNP. A series of follow-up studies in the laboratory bolstered these results. The researchers inserted different versions of the b2AR gene into kidney cells and found that the gene was about 50 percent more active in cells with haplotype 2 than in cells with haplotype 4.

About 17 million Americans, including 4.8 million children, suffer from asthma. Today, newly diagnosed asthma patients must often go through a frustrating period of trial and error to find out which drug works best for them. Eventually, a better understanding of genetic variation could help doctors avoid this.

"We hope to tailor the medications up front, so that therapy becomes much more individualized," says McGraw. "If we find that you're likely to be less responsive to albuterol, we can try a different type of drug." Perhaps, he speculates, researchers could one day even design slightly modified drugs to work better in people with genetic variations less responsive to current drugs.

But McGraw cautions that this study is just a first step. "The ultimate impact is going to be determined later in larger studies" with more carefully defined patient groups, he says. McGraw and his colleagues also plan to conduct similar studies with other types of asthma drugs. Even though the clinical applications are a long way off, the study was also an important one for Genaissance, which hopes to use haplotype information in drug design and clinical trials to produce genetically tailored medicine. The company calls the study "a crucial proof of concept" for this approach.

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Drysdale, C.M. et al. Complex promoter and coding region b2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 97, 10483-10488 (September 12, 2000).

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