Seattle, WA - Researchers in Seattle say they have uncovered specific genetic variations that influence how people respond to warfarin dose. Their study suggests that haplotypes of the VKORC1 gene can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups.

"This paper describes a gene that accounts for as much as 25% of the variability of warfarin dosing, which is perhaps the single biggest genetic contributor to interpatient variability," senior author Dr Allan E Rettie (University of Washington, Seattle) explains. "This provides another tool—and a very important tool—to help determine warfarin dosing."

The paper appears in the June 2, 2005 issue of the New England Journal of Medicine [1].

Rettie and colleagues, including first author Dr Mark J Rieder (University of Washington), looked for different polymorphisms of the recently discovered "warfarin target gene," which encodes vitamin K epoxide reductase complex 1 (VKORC1), first identified in studies of warfarin resistance. Their study population consisted of almost 200 patients of European descent taking warfarin, among whom a range of VKORC1 polymorphisms was identified. When people with specific polymorphisms were then grouped and analyzed according to warfarin dose, Rieder et al found a significant correlation between genetic variant and required warfarin dose.

In a second component of the research, Rieder, Rettie, and their coinvestigators determined VKORC1 haplotype frequencies in African American, Asian American, and European American populations. They found that the frequency of haplotypes predictive of low-required warfarin dose was higher in people of Asian descent than in people of European ancestry. In contrast, haplotypes predictive of high-required warfarin dose were higher in African Americans than in European Americans.

This provides another tool—and a very important tool—to help determine warfarin dosing.

"This is one of the other major findings of the paper," Rieder told heartwire, pointing out that physicians have known for some time that people of different ethnic backgrounds often demonstrate different sensitivity to warfarin dose. Previous clinical and population-based studies, the paper notes, have indicated that people of Asian, European, and African ancestry tend to require daily warfarin doses of approximately 3.0 mg, 5.0 mg, and 6.5 mg, respectively. "This has been another factor that doctors take into consideration when dosing this drug: for example, they tend to bump down the dose a little bit if the person is of Asian descent," Rieder explained.

So in a sense, he continued, "this almost takes race out of the equation, because it really comes down to the form of the gene someone is carrying. You don't have to know the ethnicity of the patient, you just have to know the genotype."

"Different ethnic groups all carry the same haplotypes, just in different frequencies," Rettie added. "So this provides a scientific basis for the ethnic differences."

The findings should fuel the debate over the merits of genotyping patients before or during treatment with warfarin, since effectiveness depends on genetic variants of VKORC1 and an earlier identified complex, CYP2C9, believed to account for 6% to 10% of the variability in warfarin-dose response.

Today, says Rettie, "genetic testing is done very rarely, if at all, at least in terms of warfarin dosing." And while genetic testing is "probably not going to happen overnight," the basic science research is mapping out all the genetic factors that contribute to warfarin-dose variability. "A time will come, undoubtedly, when this whole field of pharmacogenetics and personalized medicine can capitalize on this basic science," Rettie says.

Rieder emphasizes that even when genetic testing is used in this setting—and Rieder and Rettie have applied for a patent on the use of VKORCI haplotypes and single-nucleotide polymorphisms—genetic testing will provide only one tool among many.

"I think that a lot of times we overemphasize the genetic effect," Rieder stated. "Here, this is a big effect, but still, the genetics are just another tool, another data point for the physicians to draw upon to accurately dose the patient. It's not the be-all and end-all, and they're going to combine it with the other patient factors that they observe, as they have traditionally done. But we think this can add significantly to how they already carry out their practice."