Schwarz UI et al. (2008) Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 358: 999–1008

Patient responses to the anticoagulant warfarin are affected by polymorphisms in the genes that code for vitamin K epoxide reductase (VKORC1) and the enzyme cytochrome P4502C9 (CYP2C9); however, it is not known how these variants affect patients' sensitivity early during warfarin therapy. Schwarz et al. genotyped venous blood samples from a group of 297 patients receiving warfarin therapy and used physician-determined target therapeutic international normalized ratio (INR) ranges to assess early anticoagulation response according to CYP2C9 or VKORC1 genotype.

A greater number of individuals carrying predetermined VKORC1 variants had a first INR within the therapeutic range and a first INR of >4 (associated with increased risk of bleeding) within 28 days than did individuals without these variants (P = 0.02 and P = 0.04, respectively). VKORC1 haplotype also affected the percentage of time that an individual had INR values in excess of the therapeutic range (P = 0.03). CYP2C9 genotype only marginally affected time to first INR within the therapeutic range or the time spent above the INR therapeutic range, although carriers of the CYP2C9*2 or the CYP2C9*3 allele reached a first INR of >4 earlier than did those with the wild-type allele (P = 0.03). Both VKORC1 haplotype and, to a lesser degree, CYP2C9 genotype affected the average required warfarin dose during the first 2 weeks of therapy.

Variation in the VKORC1 haplotype affects the sensitivity of initial anticoagulation response to warfarin therapy; genotyping for this variation could help determine whether initial warfarin dose should be reduced to prevent overcoagulation during commencement of treatment.