VKORC1 GG VKORC1 AG (wild-type)WARFARIN VKORC1 AA Vitamin K Vitamin K (epoxidized) (reduced) Inactivated Proteins Activated ClottingFactors II, VII, IX, and X Factors Proteins C, S, and Z Blood. 2005;105:645-649.
Patients possessing variant genotypes: • achieve stable anticoagulation on lower warfarin doses4 • are at significantly increased risk of a serious or life-threatening bleeding event5Lancet. 1999;353(9154):717-719. JAMA. 2002;287(13):1690-1698.
• A single VKORC1 variantallele explains 30% ofvariation in dose.• CYP2C9 variants *2 and *3explain approx. 12% of thevariation. Blood. 2008;113:784-792.
•Derivation Cohort (n=4043)•Validation Cohort (n=1009)•Algorithm more accurately identifiedpts requiring:≤21 mg/week (49.4% v. 33.3%; P<0.001)≥49 mg/week (24.8% v. 7.2%; P<0.001) N Engl J Med. 2009;360:753-764.
Algorithm is available fordownload at:www.pharmgkb.org
Quality data is lacking.2011 Study:Pharmacogenetic model accuratelyidentified therapeutic dose moreoften than clinical algorithms.65.3% v. 34.7%; P<0.001 Genet Med. 2011;13(6):509-518.
1. Budnitz DS, Pollock DA, Weidenbach KN, Mendelsohn AB, Schroeder TJ, Annest JL. National surveillance of emergency department visits for outpatient adverse drug events. JAMA. 2006;296(15):1858-1866.2. Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol. 1998;45:525-538.3. D’Andrea G, D’Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood. 2005;105:645-649.4. Aithal GP, Day CP, Kesteven PJL, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. 1999;353(9154):717-719.5. Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh, Farin FM et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA. 2002;287(13):1690-1698.6. Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJR, Bumpstead S. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood. 2008;113:784-792.7. International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009;360:753-764.8. Burmester JK, Berg RL, Yale SH, Rottscheit CM, Glurich IE, Schmelzer JR et al. A randomized controlled trial of genotype-based Coumadin initiation. Genet Med. 2011;13(6):509-518.