Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation

Tao Li ¹, Leslie Lange ², Xiangli Li ³, Lisa Susswein ², Betsy Bryant ², Robb Malone ², Ethan Lange ², Teng-Ti Huang ², Darrel Stafford ² and James P. Evans ^2*

¹ The Salk Institute for Biological Studies, United States
² University of North Carolina at Chapel Hill, United States
³ The Scripps Research Institute, United States

^* To whom correspondence should be addressed. E-mail: jpevans{at}med.unc.edu.

Accepted 30 March 2006

Abstract

Background: Warfarin is a mainstay of therapy for conditions associated with an increased risk of thromboembolic events. Yet the use of this common agent is fraught with complications and little is known regarding inter-individual variation in warfarin response.

Objective: We tested for association between single nucleotide polymorphisms (SNPs) in VKORC1 and CYP2C9 and average weekly warfarin dose required to maintain patients at their desired anticoagulation target.

Methods: The sample consisted of 93 European-American patients from anticoagulation clinics at the University of North Carolina at Chapel Hill. Mean weekly warfarin was collected over a mean treatment period of 15 months. ANCOVA models and haplotype analysis were performed.

Results: Three of six VKORC1 SNPs were found to be very strongly associated with the average warfarin dose required to achieve target INR (p<0.0001). The range in mean weekly dose by genotype ranged from approximately 27mg to 47mg. There was no evidence for an association between either of the two CYP2C9 polymorphisms studied, CYP2C9*2 and CYP2C9*3. CYP2C9*3 was significantly (p = 0.05) associated with average warfarin dosage after adjustment for VKORC1*1173.

Conclusions: These results are of considerable clinical interest and confirm recently published results regarding the role of these two genes in modifying warfarin metabolism and maintenance dosage. The consistent findings regarding the role of VKORC1 and CYP2C9 in warfarin metabolism and maintenance dosage represents a clinically useful proof-of-principal for the use of pharmacogenomic information in medicine and may lead to improved understanding of warfarin's actions.

Keywords: Anticoagulation, CYP2C9, VKORC1, pharmacogenomics, warfarin

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