Genetic tests have been used mainly to detect genes that cause life-threatening diseases. But scientists now are identifying genes that affect the metabolism and interaction of certain drugs.
The era of personalized medicine promised by the human genome project moved one step closer to reality today, with a University of Washington study that explains why some people are more sensitive than others to a common blood-thinning drug.
The researchers found that gene variations determine whether people should get high, medium or low doses of the drug warfarin, also known by the brand name Coumadin. They also found that 90 percent of Asians carry low-dose versions of the genes, while African Americans are more likely to have high-dose versions.
More than 2 million Americans take warfarin to prevent blood clots, heart attack and stroke. But it can take weeks or months for doctors to figure out the best dose for each patient, a process that requires repeated office visits and blood tests. Too much of the drug can cause dangerous bleeding and other complications.
“It’s one of those drugs where there’s really a small window of dosage, and the window is different for different people,” said Allan Rettie, chair of medicinal chemistry at the UW School of Pharmacy. Rettie is a co-author of the study published today in the New England Journal of Medicine.
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More research must be done to validate the findings, but the scientists predict doctors may someday be able to perform quick genetic tests in their offices that will tell them the best dose for each patient.
“The hope is that genetic testing will save money in the long run, by requiring fewer visits to the clinic,” said lead author Mark Rieder, of the UW’s genome sciences program.
Dr. Francis Collins, director of the National Human Genome Research Institute, said the Seattle study is an example of the type of discoveries that should accelerate in coming years, building on the work of the ambitious effort to map the human genetic sequence completed two years ago.
“This is the kind of thing we have been hoping would start to happen, converting the dreams into reality,” Collins said.
Today, genetic tests are used mainly to tell people if they carry genes for life-threatening diseases such as cystic fibrosis. But Collins said a broader form of personalized medicine is on the horizon, as scientists learn about genes that affect drug metabolism and drug interactions. In the future, those gene types will probably be as much a part of a person’s medical record as blood type is now.
Warfarin is a good drug to focus on, because it is so widely used and the consequences of incorrect dosages can be severe, Collins said.
“As a physician, I have seen this drug save people’s lives and I have also seen it be extremely dangerous,” he said. “My own mother is taking warfarin right now, and they had a terrible time getting the dose right.”
Adverse drug reactions kill more than 100,000 Americans every year and cause serious side effects in 2.1 million others. A recent British study found that 10 percent of people hospitalized because of drug reactions were taking warfarin.
The UW team, joined by researchers from Washington University in St. Louis, analyzed records and blood samples from more than 550 patients on long-term warfarin therapy.
Using high-speed DNA sequencing machines developed for the human genome project, they focused on a recently discovered gene that regulates levels of a key factor in blood clotting, which warfarin disrupts.
Without the new sequencing technology and the genetic references provided by the map of the human genome, such a study would have been nearly impossible five years ago, Rieder said.
Within two weeks of starting the project, the team had results back from 200 patients that clearly showed that the type of gene a person carried was the overwhelming factor in the dose of warfarin needed.
“We were stupefied,” Rettie said. “That’s an unprecedented observation.”
For nearly 50 years, doctors have adjusted warfarin doses based on patients’ weights, age, diet and sex. But the new work shows those factors are minor compared to genetic influences.
Doctors have also based dosages on race, relying on years of observation that people of Asian descent are more sensitive to the drug, while African Americans are more resistant.
The UW team worked with reference DNA sequences from people of several races to unravel the genetics behind those differences in drug sensitivity.
People of European descent were about evenly split between high-, medium- and low-dose versions of the gene. Asians overwhelmingly carried the low-dose version. In African Americans, the genetics were more complex, but high-dose genes appeared to be more common.
The next step will be a large clinical study to see if genetic analysis will translate into better and more efficient treatment for patients who take warfarin.
There is no commercial test for the warfarin sensitivity gene the UW team studied, and even if such a test is developed, it won’t be widely available until after years of study.
Sandi Doughton: 206-464-2491 or firstname.lastname@example.org
Director of the National Human Genome Research Institute