Taking the blinders off pg. 4
Wilkinson and his colleagues, including Richard Kim, M.D., and David Haas, M.D., also discovered that a polymorphism in a drug-metabolizing enzyme gene impairs the ability to metabolize the AIDS drug efavirenz. This polymorphism is about six times more common in African-Americans than in Caucasians, which may explain why efavirenz blood levels are generally higher in African-Americans.
Individuals with this genetic variant tend to accumulate higher levels of the drug in their blood, and as a result they may experience mental confusion, strange dreams and other central nervous system disturbances, says Haas, director of the Vanderbilt AIDS Clinical Trials Center. The side effects can be so disturbing that patients stop taking their medication.
Pharmacogenomics—the study of how genetic differences affect drug response—may lead to more “rational” drug development and prescribing. “It may be possible in the not-to-distant future to screen a person’s genome for polymorphisms that have clinical implications and then choose an appropriate regimen or an appropriate drug dose based on knowing their genetic background,” Haas says.
Haas says the polymorphism that affects the metabolism of the AIDS drug could not have been discovered without the help of a national DNA “repository” established by the Adult AIDS Clinical Trials Group, a federally funded group of 34 centers in the United States, including Vanderbilt, which evaluates new AIDS treatments.
In 2000, Haas and his colleagues began developing a process for obtaining informed consent to collect an extra blood sample for DNA studies from patients participating in AIDS clinical trials. Since then, the repository, which is housed at Vanderbilt, has collected about 8,000 samples from different individuals.
As of 2005, about 10 genetic studies had been undertaken using the DNA samples. Information from these studies is being used to help develop a vaccine against the AIDS-causing human immunodeficiency virus (HIV), and to develop treatments that can rebuild or “reconstitute” the immune systems of patients that have been damaged by HIV infection.
“It’s really just a glorious explosion of discovery,” Haas says.
DNA on deposit
Vanderbilt also has joined forces with the U.S. Food and Drug Administration, the pharmaceutical giant GlaxoSmithKline and First Genetic Trust, a Chicago-based company that has pioneered DNA banking, to advance genetic-based medicines and diagnostics.
The goal: to expand the collection of DNA samples from patients who suffer a rare adverse drug event called long QT syndrome. The syndrome can lead to potentially fatal arrhythmias, abnormal heart rhythms.
When physicians anywhere in the country report drug-induced long QT syndrome to the FDA, the agency will refer them and their patients to Vanderbilt for participation in the study.
“We’ve been interested in this rare adverse drug effect for many years, with the idea that it is genetically determined,” says Dan Roden, M.D., director of the John A. Oates Institute for Experimental Therapeutics at Vanderbilt and a principal investigator in the collaboration.
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