|Genetic Variation Alters Response to Common Anti–Clotting Drug
Millions of people take the anticoagulant drug warfarin to prevent
harmful clotting after a heart attack, stroke, or major surgery.
But the proper dose of warfarin can vary greatly and can be hard
to predict. Some of this variability may boil down to a recently
identified gene involved in blood clotting, according to a new
study published in the June 2 issue of The New England Journal
By looking at the genetic makeup of people on warfarin, researchers
at the University of Washington in Seattle and Washington University
in St. Louis learned that variations in a gene involved in blood
clotting may explain why certain people require a lower or higher
dose of warfarin to get its full benefits. This line of work ultimately
could help doctors determine each patient’s warfarin dose
more quickly and precisely.
The study, part of the NIH Pharmacogenetics Research Network,
was supported by three components of the National Institutes of
Health (NIH): the National Institute of General Medical Sciences
(NIGMS); the National Heart, Lung, and Blood Institute (NHLBI);
and the National Institute of Environmental Health Sciences (NIEHS).
“This research points to the value of pharmacogenetics,
the study of how genetic variations can alter people’s responses
to medicines,” said NIH Director Elias A. Zerhouni, M.D. “It
shows one important way in which we are beginning to apply knowledge
about the human genome for treating disease and improving human
Warfarin (trade names include Coumadin) is the most commonly
prescribed oral anti-clotting drug. Allan E. Rettie, Ph.D., University
of Washington professor of medicinal chemistry and senior author
of the paper, estimated that 2 million people in the United States
take warfarin on any given day.
Despite its wide use, physicians find the drug challenging to
“There is a narrow window between too much and too little
effect,” explained Rettie. “A small change in dose
can have quite a large effect on blood processes.” For example,
too high of a dose can result in excessive bleeding while too little
of a dose could allow dangerous blood clots to form.
Doctors primarily use information about a patient’s sex,
age, weight, and medical history to set the initial warfarin dose.
However, it can take several months of clinic visits and needle
pricks to determine an individual’s ideal dose. Scientists
know that variations in a gene encoding the CYP2C9 enzyme that
metabolizes warfarin account for about 10 percent of the difference
in people’s responses to the drug, but tests for these genetic
variations are not routinely performed.
Rettie and his colleague Mark J. Rieder, Ph.D., an assistant professor
in the University of Washington’s department of genome sciences
and first author of the paper, wanted to better understand the
genetic basis for variability in warfarin response. “If you
want to predict dose, you need to know more about the genes that
control variability,” explained Rieder.
The team focused on another gene: vitamin K epoxide reductase
(VKORC1), which makes a protein that helps control clotting and
is the key target of warfarin. The researchers analyzed the VKORC1
gene’s DNA sequence in 186 patients on a stabilized dose
of warfarin. They searched for common DNA variations responsible
for changing the gene’s activity and the amount of protein
“We did find genetic variations that appear to turn up the
gene or turn it down,” said Rieder.
By matching the genetic variations to actual warfarin doses, the
scientists discovered that people with a particular variation of
the VKORC1 gene generally took similar doses of warfarin.
The genetic variations divided patients into three main groups:
low, high, and intermediate dose. The intermediate group included
people with a combination of the low- and high-dose gene versions.
These results, the researchers said, suggest that information about
the VKORC1 gene could predict a person’s response to the
“We found that 25 percent of the [overall] variance in warfarin
dose is due to this one gene,” said Rettie. “This is
possibly the single biggest contributor to variability in people’s
responses to the drug and could be a central factor in setting
the initial dose.”
The team also learned that certain population groups tended to
have a higher prevalence of a particular VKORC1 variation. While
Asian Americans generally had the low-dose variation, African Americans
had the high-dose version. European Americans fell in the middle.
Although Rettie and Rieder said there’s a high probability
that genetic screening for the VKORC1 gene could result in better
warfarin dosing, they agreed that more studies need to be done
“What we’ve done is the basic science,” said
Rettie. “This complete genetic analysis of VKORC1 provides
the mechanistic framework and impetus for prospective studies in
a clinical setting. Such studies could determine if knowledge of
genetic variability truly improves patient treatment with this
frontline anticoagulant drug.”
NIGMS, NHLBI, and NIEHS are among the 27 institutes and centers
at NIH, an agency of the Department of Health and Human Services.
Additional information about the three institutes is available
at their respective Web sites: http://www.nigms.nih.gov, http://www.nhlbi.nih.gov/index.htm,