7. VKORC1 GG
VKORC1 AG (wild-type)
WARFARIN VKORC1 AA
Vitamin K Vitamin K
(epoxidized) (reduced)
Inactivated Proteins Activated Clotting
Factors II, VII, IX, and X Factors
Proteins C, S, and Z
Blood. 2005;105:645-649.
8. Patients possessing variant genotypes:
• achieve stable anticoagulation on
lower warfarin doses4
• are at significantly increased risk of a
serious or life-threatening bleeding
event5
Lancet. 1999;353(9154):717-719. JAMA. 2002;287(13):1690-1698.
9. • A single VKORC1 variant
allele explains 30% of
variation in dose.
• CYP2C9 variants *2 and *3
explain approx. 12% of the
variation.
Blood. 2008;113:784-792.
10. •Derivation Cohort (n=4043)
•Validation Cohort (n=1009)
•Algorithm more accurately identified
pts 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.
13. Quality data is lacking.
2011 Study:
Pharmacogenetic model accurately
identified therapeutic dose more
often than clinical algorithms.
65.3% v. 34.7%; P<0.001
Genet Med. 2011;13(6):509-518.
14.
15.
16. 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.
