Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements
| Autor: | Katherine L. Gaston, Jennifer S. Tromberg, Julie A. Johnson, Hossein Yarandi, Mark J. Chirico, Dagmara Mohuczy, Cassandra D. Waddell, Larry M. Lopez, Taimour Y. Langaee, Christina L. Aquilante |
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| Rok vydání: | 2005 |
| Předmět: |
Adult
Male Genotype Vitamin K Epoxide Reductase Complex Subunit 1 Biology Pharmacology Polymerase Chain Reaction Mixed Function Oxygenases chemistry.chemical_compound Vitamin K Epoxide Reductases medicine Humans Pharmacology (medical) International Normalized Ratio CYP2C9 Aged Cytochrome P-450 CYP2C9 DNA Primers Aged 80 and over Polymorphism Genetic Factor VII Factor X Warfarin Anticoagulants Middle Aged Vitamin-K-epoxide reductase (warfarin-sensitive) Blood Coagulation Factors chemistry Female Prothrombin VKORC1 Aryl Hydrocarbon Hydroxylases medicine.drug |
| Zdroj: | Clinical pharmacology and therapeutics. 79(4) |
| ISSN: | 0009-9236 |
| Popis: | Introduction 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. Conclusion Polymorphisms in warfarin drug target and metabolizing enzyme genes, in addition to nongenetic factors, were important determinants of warfarin dose requirements. Clinical Pharmacology & Therapeutics (2006) 79, 291–302; doi: 10.1016/j.clpt.2005.11.011 |
| Databáze: | OpenAIRE |
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