Genetic variants strongly influence warfarin dose

Genetic variants in a key gene targeted by warfarin strongly influence the required dose of the anticoagulant, new research has found.A research team at the University of Washington in Seattle had previously shown how variants in the CYP 2C9 enzyme altered rates of warfarin metabolism. In the same group of patients they identified variants of a gene which encodes for vitamin K epoxide reductase complex 1 (VKORC1), which is essential for vitamin-K dependent activation of clotting factors.They found five major haplotypes of the gene, which in turn could be divided into 'low-dose' variants (group A) and 'high-dose' variants (group B). The average maintenance dose of warfarin was 2.7 mg/day for patients with A/A haplotypes, rising to 4.9 mg/day for A/B and 6.2 mg/day for B/B. This gene explained about 25% of the variance in dose - three times the effect of the CYP 2C9 gene.Distribution of A and B variants was influenced by race. Group A was predominant in people of Asian descent (89%), intermediate in Europeans (37%) and low in African-Americans (14%), a pattern consistent with mean warfarin requirements in the different populations.Warfarin was well established as long-term prophylaxis of thromboembolic events, but treatment was challenged in two respects, the researchers said. First, a safe and effective stabilisation dose had to be determined during the early months of therapy. Second, doses had to be adjusted in response to changes in weight, diet or concomitant use of other medications.Apart from its research and theoretical interest, there was debate whether genotyping might be useful before or during treatment with warfarin in routine practice. It could be argued that existing dosing protocols took account of individual variations. However, experience with the CYP 2C9 gene had revealed additional effects on outcomes that were not accounted for by individualised dosing and frequent monitoring. At the very least, the new information on the VKORC1 gene would be important in guiding future research. Reference...