Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements.
BACKGROUND
The primary objective of this study was to determine whether variability in warfarin dose requirements is determined by common polymorphisms in genes whose products are involved in the pharmacodynamics and pharmacokinetics of warfarin, namely, the coagulation factors, vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 (CYP) 2C9.


METHODS
Patients (N = 350) receiving stable doses of warfarin at 3 consecutive visits were enrolled, and a deoxyribonucleic acid sample was collected. Samples were genotyped for polymorphisms in the factor II, factor VII, factor X, VKORC1, and CYP2C9 genes. A stepwise linear regression analysis was used to determine the independent effects of genetic and nongenetic factors on mean warfarin dose requirements.


RESULTS
Variables associated with lower warfarin dose requirements were VKORC1 3673 AA genotype (P < .0001), VKORC1 3673 GA genotype (P < .0001), 1 variant CYP2C9 allele (P < .0001), 2 variant CYP2C9 alleles (P = .0004), increasing age (P = .0005), concomitant CYP2C9 inhibitors (P = .0005), and goal international normalized ratio (P = .01). Variables associated with higher warfarin dose requirements were weight (P < .0001), current smoker status (P = .0009), mean international normalized ratio (P = .001), concomitant CYP2C9 inducers (P = .006), factor X insertion/deletion genotype (P = .01), factor X insertion/insertion genotype (P = .04), factor VII deletion/deletion genotype (P = .04), and calculated vitamin K intake (P = .05). The linear regression model explained 51.4% of the variability in warfarin dose requirements.


CONCLUSIONS
Polymorphisms in warfarin drug target and metabolizing enzyme genes, in addition to nongenetic factors, were important determinants of warfarin dose requirements.
Department of Pharmacy Practice, University of Florida College of Pharmacy, Gainesville, FL 32610, USA.
Christina L
CL
Aquilante
Taimour Y
TY
Langaee
Larry M
LM
Lopez
Hossein N
HN
Yarandi
Jennifer S
JS
Tromberg
Dagmara
D
Mohuczy
Katherine L
KL
Gaston
Cassandra D
CD
Waddell
Mark J
MJ
Chirico
Julie A
JA
Johnson
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001779:Blood Coagulation Factors / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D017931:DNA Primers; D005167:Factor VII / Q000235:genetics; D005170:Factor X / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011516:Prothrombin / Q000235:genetics; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D017931:DNA Primers; D014859:Warfarin; D005167:Factor VII; D011516:Prothrombin; D005170:Factor X; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases