Warfarin pharmacogenomics

Abstract

Warfarin, an anticoagulant, is used to prevent and treat thromboembolic disease. One of the drawbacks of this agent, also known as Coumadin (Bristol-Myers Squibb), is that it is difficult to administer at the correct dose as a result of its narrow therapeutic index, its tendency to cause bleeding, and the individual variability in patient response. Achieving safe and effective doses of warfarin therapy is both an urgent and important concern for many clinicians.Recent research has focused on single-nucleotide polymorphisms (SNPs) of genes that encode two proteins: the cytochrome P450 2C9 enzyme and VKORC1 (vitamin K epoxide reductase complex). Studies suggest that CYP 2C9 influences warfarin metabolism, whereas VKORC1 plays a role in the pharmacodynamic response in expression of the enzymatic target of warfarin. Patients who carry CYP 2C9*2 and CYP 2C9*3 alleles tend to require lower warfarin maintenance doses because of their slowed metabolism compared with patients who carry the "wild-type" allele. Patients who carry the VKORC1 A haplotype tend to require lower wafarin maintenance doses as a result of a decreased expression of messenger RNA (mRNA), which produces the proteins necessary for the formation of VKORC1.

Figure 1

Overview of the mechanism of action and metabolism of warfarin. CYP = cytochrome P450. (From Schwarz UI, Stein CM. Clin Pharmacol Ther 2006;80:7–12. Reprinted by permission from Macmillan Publishers Ltd.3)

Figure 2

A–D, Study findings. Association between specific genetic variants and study outcomes. The graphs show the association between the time to the first International Normalized Ratio (INR) within the therapeutic range and the time to the first INR of above 4 for patients carrying genetic variants for vitamin K epoxide reductase (VKORC1) (A, B) and for cytochrome P-450 2C9 (CYP 2C9) (C, D). (From Schwarz UI, Ritchie MD, Bradford Y, et al. N Engl J Med 2008;358:999–1008. Copyright © 2008, Massachusetts Medical Society. All rights reserved.10)

Figure 3

Representation of warfarin dose requirements based on genotypic differences. (From Sconce EA, Khan TI, Wynne HA, et al. Blood 2005;106(7): 2329–2333. © American Society of Hematology.13)