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Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation
  1. T Li1,
  2. L A Lange2,
  3. X Li3,
  4. L Susswein2,
  5. B Bryant4,
  6. R Malone4,
  7. E M Lange2,
  8. T-Y Huang5,
  9. D W Stafford5,
  10. J P Evans2
  1. 1Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA
  2. 2Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  3. 3Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA
  4. 4Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  5. 5Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  1. Correspondence to:
 Dr James P Evans
 UNC Chapel Hill, 103 Mason Farm Road, Room 4200, CB#7264, Chapel Hill, NC 27599-7264, USA; jpevans{at}med.unc.edu

Abstract

Background: Warfarin is a mainstay of therapy for conditions associated with an increased risk of thromboembolic events. However, 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. Data on mean weekly warfarin dose were collected over a mean treatment period of 20.6 months. ANCOVA models were used and haplotype analysis was performed.

Results: Three of six VKORC1 SNPs were found to be very strongly associated with the average warfarin dose required to achieve the target international normalised ratio (INR; p<0.0001). The mean weekly dose by genotype ranged from approximately 27 to 47 mg. 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 represent a clinically useful proof of principal for the use of pharmacogenomic information in medicine and may lead to improved understanding of warfarin’s actions.

  • ANCOVA, analysis of covariance
  • INR, international normalised ratio
  • LD, linkage disequilibrium
  • SNP, single nucleotide polymorphism
  • VTE, venous thromboembolic events
  • anticoagulation
  • CYP2C9
  • pharmacogenomics
  • VKORC1
  • warfarin

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Footnotes

  • Published Online First 12 April 2006

  • Competing interests: none declared

  • This work was carried out at the University of North Carolina at Chapel Hill

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