Researchers have discovered subtle differences in the DNA of people with asthma, which help to predict which patients will benefit most from a certain drug before they take it, a new study has reported.
In tests of the DNA of 121 patients with asthma, researchers led by Stephen Liggett, professor of medicine at the University of Cincinnati College of Medicine, and colleagues found 4 different patterns of DNA in a gene that helps to relax muscles in a person's lungs. Lung function was measured before and after treatment with albuterol [salbutamol], with the individual responses correlated to the sequence of variations found in discrete regions of a person's DNA.
Albuterol, a drug that is aimed at spurring the muscle-relaxing gene into greater action to treat asthmatic wheezing, worked well in those with 1 pattern, not at all in those with another, and moderately in the other 2 cases (Proc Natl Acad Sci USA 2000;97:10,483-10, 48810618444).
It is the first example, researchers said, of personalized drug treatment, made possible by the sequencing of the human genome. In the future, the researchers said, they will be able to match individual patients to different medications, using their DNA as guidance to improve the drugs' effectiveness and to eliminate harmful side effects. “Pharmacogenomics” is considered the most likely spin-off of decoding the human genome to have practical application in the near term.
Albuterol works by blocking the β2-adrenergic receptor. This causes muscles to relax and allows bronchial tubes to dilate, aiding the flow of air to the lungs. Identifying the genes that affect the way a person responds to the drug will help physicians tailor prescriptions for each patient, said Liggett.
Figure 1.
DNA can be used as guidance to improve the effectiveness of drugs
© Paul Thiessen/Chemical Graphics
“This is a step toward personalized medicine,” said Liggett. “The era of 1 drug fitting all is probably coming to an end soon.”
The regions in DNA that the researchers were examining are single nucleotide polymorphisms. Some single nucleotide polymorphisms act like typographic errors, causing abnormalities in the DNA, while others do not seem to matter. In this case, researchers had previously found that the β2-adrenergic receptor gene contains 13 of these sites where single nucleotide polymorphisms are present in the genetic code.
The scientists analyzed all the possible differences people could have and found that 4 common differences predicted how people would respond to albuterol.
Medicines now are generally tested on large numbers of people, with researchers looking at the average response of those taking the drug versus those taking place-bo. “You'll see responses that are very, very good and some that are bad,” Liggett said. “The FDA says to look at the average response.”
As a result, he said, some drugs that may be useful for a small subset of patients may never become available because they show little or no benefit, or they even harm, on the aggregate. By using examinations of DNA, researchers will be able to find sub-groups of patients who benefit from certain drugs even if, on average, most patients show no response.
Liggett said that similar genetic studies are now underway for all of the classes of drugs used to treat asthma. Eventually, he said, genetic tests of a patient with asthma will identify those drugs most likely to be useful. From this, a personalized list of probable benefits could be drawn up for each patient and used by physicians to tailor prescriptions. “This would reduce the trial-and-error period that all physicians go through when they have patients with complex conditions,” said Liggett.