Genetic determinants of response to warfarin during initial anticoagulation.
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.
Schwarz
Ute I
UI
Department of Medicine, Vanderbilt University School of Medicine, Nashville, USA.
Ritchie
Marylyn D
MD
Bradford
Yuki
Y
Li
Chun
C
Dudek
Scott M
SM
Frye-Anderson
Amy
A
Kim
Richard B
RB
Roden
Dan M
DM
Stein
C Michael
CM
D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use*; D015331:Cohort Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D019934:International Normalized Ratio; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011110:Polymorphism, Genetic; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000627:therapeutic use*
D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases