Warfarin therapy is complicated by wide variations in anticoagulant response. The CYP2C9 polymorphism affects some 15% of prescribed drugs, including warfarin. Between 5% and 40% of persons carry at least one copy of either of two major variants with reduced enzymatic activity for S-warfarin and many other drug substrates. Inappropriate dosing with warfarin leads to excessive and occasionally life-threatening bleeding, especially during the initiation of therapy. CYP2C9 explains that approximately 6-10% of the variation in dose and genotyping prior to warfarin treatment could benefit patients by reducing the risk of bleeding, especially during the high-risk period of therapy initiation. Other drugs that are subject to this polymorphism include phenytoin, tolbutamide, nonsteroidal antiinflammatory drugs (NSAIDs), and angiotensin-converting enzyme (ACE) inhibitors.
VKORC1 is the target of coumarin anticoagulant drugs such as warfarin and is emerging as an important genetic factor influencing dose and response to these drugs. The VKORC1 gene contains three exons coding for an 18-kDa integral membrane protein. It is located on the short arm of chromosome 16 at 16p11.2. Common polymorphisms in regulatory regions correlate strongly with warfarin response. At least 10 noncoding haplotypes and 5 major haplotypes have been identified. Patients with varying degrees of warfarin resistance carry mutations in one copy of VKORC1, and can be stratified into low-, intermediate-, and high-dose warfarin groups based on their VKORC1 haplotypes. The low-dose and intermediate-dose haplotype explain approximately 25% of the variance in dose. A single allelic site, 1173T/C, in intron 1 assigns European-American subjects to either the low or intermediate groups, and the well-recognized reduction in average maintenance warfarin dose for Asians is largely a consequence of the paucity of the high-dose-associated 1173T allele in this ethnic population.
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