Genetic determinants of response to warfarin during initial anticoagulation.

Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Frye-Anderson A, Kim RB, Roden DM, Stein CM
N Engl J Med. 2008 358 (10): 999-1008

PMID: 18322281 · PMCID: PMC3894627 · DOI:10.1056/NEJMoa0708078

BACKGROUND - Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9), and of a key pharmacologic target of warfarin, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to various warfarin doses, but the role of these variants during initial anticoagulation is not clear.

METHODS - In 297 patients starting warfarin therapy, we assessed CYP2C9 genotypes (CYP2C9 *1, *2, and *3), VKORC1 haplotypes (designated A and non-A), clinical characteristics, response to therapy (as determined by the international normalized ratio [INR]), and bleeding events. The study outcomes were the time to the first INR within the therapeutic range, the time to the first INR of more than 4, the time above the therapeutic INR range, the INR response over time, and the warfarin dose requirement.

RESULTS - As compared with patients with the non-A/non-A haplotype, patients with the A/A haplotype of VKORC1 had a decreased time to the first INR within the therapeutic range (P=0.02) and to the first INR of more than 4 (P=0.003). In contrast, the CYP2C9 genotype was not a significant predictor of the time to the first INR within the therapeutic range (P=0.57) but was a significant predictor of the time to the first INR of more than 4 (P=0.03). Both the CYP2C9 genotype and VKORC1 haplotype had a significant influence on the required warfarin dose after the first 2 weeks of therapy.

CONCLUSIONS - Initial variability in the INR response to warfarin was more strongly associated with genetic variability in the pharmacologic target of warfarin, VKORC1, than with CYP2C9.

Copyright 2008 Massachusetts Medical Society.

MeSH Terms (17)

Adult Aged Anticoagulants Cohort Studies Cytochrome P-450 Enzyme System Female Genotype Haplotypes Humans International Normalized Ratio Linkage Disequilibrium Male Middle Aged Mixed Function Oxygenases Polymorphism, Genetic Vitamin K Epoxide Reductases Warfarin

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