Warfarin is the most commonly prescribed anticoagulant in the US and is the second most common drug reported to cause complications that result in emergency room visits1. Warfarin management has traditionally been complicated by the tremendous inter-individual variability in warfarin dose requirements and the narrow therapeutic index.
Variants of the CYP2C9 and VKORC1 genes are clearly associated with reduced warfarin dose requirements and increased risk of bleeding events2-5. Identifying patients with one or more variants can allow more accurate estimation of warfarin dose than was possible based on clinical factors alone, and therefore reduce the risk of complications such as hemorrhage.
CYP2C9: In a 2005 meta-analysis of nine studies (2775 mostly Caucasian patients) that evaluated warfarin dose and bleeding risk associated with CYP2C9 variants, the authors found that patients with at least one variant required 27% less warfarin and had a 2.26 relative risk of bleeding compared to those with two wild-type alleles2. Overall, CYP2C9 variants are predicted to account for 5% to 22% of the observed variability in individual warfarin dose requirements6 (about 10% in Caucasians5).
VKORC1: The -1639G>A VKORC1 gene variant appears to be the strongest genetic predictor of warfarin dose requirement. Individuals with a single VKORC1 variant (G/A) have an approximate 20-30% reduction in warfarin maintenance dose while those with two variants (A/A) have a 50-60% reduction when compared to those with no variants (G/G)3. Overall, VKORC1 gene variants account for an estimated 30% of inter-individual warfarin dose variability7.
References:
1. U.S. Food and Drug Administration. FDA News: FDA Approves Updated Warfarin (Coumadin) Prescribing Information. Released August 16, 2007. Available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html . Accessed December 2, 2007.
2. Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med 2005 Feb;7(2):97-104.
3. Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005;352:2285-93.
4. U.S. Food and Drug Administration. Coumadin Labeling. Updated August 16, 2007. Available at: http://www.fda.gov/cder/foi/label/2007/009218s105lblv2.pdf . Accessed October 31, 2007.
5. Rettie AE, Tai G. The pharmocogenomics of warfarin: closing in on personalized medicine. Mol Interv 2006 Aug;6(4):223-7.
6. YinT, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 - rationale and perspectives. Thromb Res 2007;120(1):1-10. Epub 2006 Dec 11.
7. Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N, Wallerman O, Melhus H, Wadelius C, Bentley D, Deloukas P. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 2005;5(4):262-70.