Journal of Thrombosis and Thrombolysis

, Volume 22, Issue 3, pp 191–197

Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study

  • John F. Carlquist
  • Benjamin D. Horne
  • Joseph B. Muhlestein
  • Donald L. Lappé
  • Bryant M. Whiting
  • Matthew J. Kolek
  • Jessica L. Clarke
  • Brent C. James
  • Jeffrey L. Anderson
Article

DOI: 10.1007/s11239-006-9030-7

Cite this article as:
Carlquist, J.F., Horne, B.D., Muhlestein, J.B. et al. J Thromb Thrombolysis (2006) 22: 191. doi:10.1007/s11239-006-9030-7

Abstract

Background

Warfarin has a narrow therapeutic range and wide inter-individual dosing requirements that may be related to functional variants of genes affecting warfarin metabolism (i.e., CYP2C9) and activity (i.e., vitamin K epoxide reductase complex subunit 1-VKORC1). We hypothesized that variants in these two genes explain a substantial proportion of variability in stable warfarin dose and could be used as a basis for improved dosing algorithms.

Methods

Consecutive consenting outpatients (n = 213) with stable INR (2–3) for >1 month were enrolled. Buccal DNA was extracted using a Qiagen mini-column and CYP2C9*2 and VKORC1 genotyping performed by the Taqman 3′ nuclease assay. Sequencing for CYP2C9*3, genotyping was done using Big Dye v3.1 terminator chemistry Dose by genotype was assessed by linear regression.

Results

Weekly warfarin dose averaged 30.8 ± 13.9 mg/week; average INR was 2.42 ± 0.72. CYP2C9*2/*3 genotype distribution was: CC/AA (wild-type [WT]) = 71.4%, CT/AA = 18.3%, CC/AC = 9.4%, and CT/AC = 1%; VKORC1 genotypes were CC (WT) = 36.6%, CT = 50.7%, and TT = 12.7%. Warfarin doses (mg/week) varied by genotype: for CYP2C9, 33.3 mg/week for WT (CC/AA), 27.2 mg/week for CT/AA (P = 0.04 vs. WT), 23.0 mg/week for CC/AC (P = 0.003), and 6.0 mg/week for CT/AC (P < 0.001), representing dose reductions of 18–31% for single and 82% for double variant carriers; for VKORC1: 38.4 mg/week for WT (CC), 28.6 mg/week for CT (P < 0.001 vs. WT), 20.95 mg/week for TT (P < 0.001). In multiple linear regression, genotype was the dominant predictor of warfarin dose (P = 2.4 × 10−15); weak predictors were age, weight, and sex. Genotype-based modeling explained 33% of dose-variance, compared with 12% for clinical variables alone.

Conclusion

In this large prospective study of warfarin genetic dose-determinants, carriage of a single or double CYP2C9 variant, reduced warfarin dose 18–72%, and of a VKORC1 variant by 65%. Genotype-based modeling explained almost one-half of dose-variance. A quantitative dosing algorithm incorporating genotypes for 2C9 and VKORC1 could substantially improve initial warfarin dose-selection and reduce related complications.

Keywords

Anticoagulation Pharmacogenetics Vitamin K Warfarin 

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • John F. Carlquist
    • 1
  • Benjamin D. Horne
    • 2
  • Joseph B. Muhlestein
    • 1
  • Donald L. Lappé
    • 3
  • Bryant M. Whiting
    • 3
  • Matthew J. Kolek
    • 3
  • Jessica L. Clarke
    • 3
  • Brent C. James
    • 4
  • Jeffrey L. Anderson
    • 1
  1. 1.Department of Medicine, Division of CardiologyUniversity of Utah School of Medicine, Cardiovascular Department, LDS HospitalSalt Lake CityUSA
  2. 2.Department of Medical Informatics, Division of Genetic EpidemiologyUniversity of Utah School of Medicine, Cardiovascular Department, LDS HospitalSalt Lake CityUSA
  3. 3.Cardiovascular DepartmentLDS HospitalSalt Lake CityUSA
  4. 4.Department of Family and Preventive MedicineUniversity of Utah School of Medicine, Institute for Heathcare Delivery Research, Intermountain HealthcareSalt Lake CityUSA

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