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Genetic Variation in Warfarin-Dosing Needs
Is genotype-guided anticoagulation therapy on the horizon?
Knowing how an individual will respond to warfarin would help in tailoring the dose needed to maintain appropriate anticoagulation. Toward that end, researchers studied variability in the recently discovered gene for the warfarin target, vitamin K epoxide reductase complex 1 (VKORC1).
First, the researchers analyzed genetic data from 186 American patients of European descent who were recruited from anticoagulation clinics and were receiving long-term warfarin therapy. They identified 10 single-nucleotide polymorphisms (SNPs) of VKORC1 that showed significant associations with warfarin maintenance doses and that had an overall frequency of >5% in this cohort.
From these 10 SNPs, the researchers inferred five common VKORC1 haplotypes (a haplotype is a set of closely linked genetic markers present on one chromosome that tend to be inherited together). Four of the haplotypes had independent associations with warfarin maintenance doses, two with a low-dose requirement and two with a high-dose requirement. Ultimately, subjects were linked with one of three haplotype groupings; the mean daily warfarin maintenance dose differed significantly across these three subgroups (2.7 mg, 4.9 mg, and 6.2 mg, respectively). The authors report that VKORC1 haplotype explained 25% of the variance in warfarin dose, and they replicated these findings in a larger European American population. The researchers also examined VKORC1 haplotype frequencies in Asian American and African American populations and found significant variability by race.
Comment: This study advances our understanding of what underlies variability in warfarin-dosing requirements. The value of genotyping in tailoring warfarin dosing in clinical practice is still far from clear, but this study suggests a model for genotype-guided anticoagulation therapy. Another option currently under investigation is the use of direct thrombin inhibitors, which don't require anticoagulation monitoring, but potential hepatotoxicity with these drugs is being scrutinized (Journal Watch Cardiology Mar 25 2005).
— Harlan M. Krumholz, MD, SM
Published in Journal Watch Cardiology July 1, 2005
Citation(s):
Rieder MJ et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005 Jun 2; 352:2285-93.
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