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

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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.

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References

  1. Weiss P, Halkin H, Almog S (1986) The negative impact of biological variation in the effect and clearance of warfarin on methods for prediction of dose requirements. Thromb Haemost 56(3):371–375

    CAS  PubMed  Google Scholar 

  2. Carlquist JF, Anderson JL (2004) Pharmacogenomics in cardiovascular medicine. Drug Develop Res 62:180–190

    Article  CAS  Google Scholar 

  3. Bachmann K (2002) Genotyping and phenotyping the cytochrome p-450 enzymes. Am J Ther 9(4):309–316

    Article  PubMed  Google Scholar 

  4. Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR (1994) Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 4(1):39–42

    Article  CAS  PubMed  Google Scholar 

  5. Furuya H, Fernandez-Salguero P, Gregory W, Taber H, Steward A, Gonzalez FJ, Idle JR (1995) Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics 5(6):389–392

    Article  CAS  PubMed  Google Scholar 

  6. Stubbins MJ, Harries LW, Smith G, Tarbit MH, Wolf CR (1996) Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics 6(5):429–439

    Article  CAS  PubMed  Google Scholar 

  7. Yasar U, Eliasson E, Dahl ML, Johansson I, Ingelman-Sundberg M, Sjoqvist F (1999) Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem Biophys Res Commun 254(3):628–631

    Article  CAS  PubMed  Google Scholar 

  8. Crespi CL, Miller VP (1997) The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH: cytochrome P450 oxidoreductase. Pharmacogenetics. 7(3):203–210

    Article  CAS  PubMed  Google Scholar 

  9. Takanashi K, Tainaka H, Kobayashi K, Yasumori T, Hosakawa M, Chiba K (2000) CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates. Pharmacogenetics. 10(2):95–104

    Article  CAS  PubMed  Google Scholar 

  10. Aithal GP, Day CP, Kesteven PJ, Daly AK (1999) Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353(9154):717–719

    Article  CAS  PubMed  Google Scholar 

  11. Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, Rettie AE (2002) Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 287(13):1690–1698

    Article  CAS  PubMed  Google Scholar 

  12. Taube J, Halsall D, Baglin T (2000) Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 96(5):1816–1819

    CAS  PubMed  Google Scholar 

  13. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352(22):2285–2293

    Article  CAS  PubMed  Google Scholar 

  14. Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW (2004) Identification of the gene for vitamin K epoxide reductase. Nature 427(6974):541–544

    Google Scholar 

  15. D’Andrea G, D’Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, Grandone E, Margaglione M (2005) A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 105(2):645–649

    Article  CAS  PubMed  Google Scholar 

  16. Landefeld CS, Beyth RJ (1993) Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 95(3):315–328

    Article  CAS  PubMed  Google Scholar 

  17. Sanderson S, Emery J, Higgins J (2005) CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med 7(2):97–104

    Article  CAS  PubMed  Google Scholar 

  18. Hamby L, Weeks WB, Malikowski C (2000) Complications of warfarin therapy: causes, costs, and the role of the anticoagulation clinic. Eff Clin Pract 3(4):179–184

    CAS  PubMed  Google Scholar 

  19. Caro JJ (2004) An economic model of stroke in atrial fibrillation: the cost of suboptimal oral anticoagulation. Am J Manag Care 10(14 Suppl):S451–458

    PubMed  Google Scholar 

  20. Hull JH, Murray WJ, Brown HS, Williams BO, Chi SL, Koch GG (1978) Potential anticoagulant drug interactions in ambulatory patients. Clin Pharmacol Ther 24(6):644–649

    CAS  PubMed  Google Scholar 

  21. Wadelius M, Sorlin K, Wallerman O, Karlsson J, Yue QY, Magnusson PK, Wadelius C, Melhus H (2004) Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR) and other factors. Pharmacogenomics J 4(1):40–48

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Division of Cardiology, University of Utah School of Medicine, Cardiovascular Department, LDS Hospital, Salt Lake City, Utah, USA

    John F. Carlquist, Joseph B. Muhlestein & Jeffrey L. Anderson

  2. Department of Medical Informatics, Division of Genetic Epidemiology, University of Utah School of Medicine, Cardiovascular Department, LDS Hospital, Salt Lake City, Utah, USA

    Benjamin D. Horne

  3. Cardiovascular Department, LDS Hospital, Salt Lake City, Utah, USA

    Donald L. Lappé, Bryant M. Whiting, Matthew J. Kolek & Jessica L. Clarke

  4. Department of Family and Preventive Medicine, University of Utah School of Medicine, Institute for Heathcare Delivery Research, Intermountain Healthcare, Salt Lake City, Utah, USA

    Brent C. James

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  1. John F. Carlquist
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  2. Benjamin D. Horne
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  3. Joseph B. Muhlestein
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  9. Jeffrey L. Anderson
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Correspondence to John F. Carlquist.

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Carlquist, J.F., Horne, B.D., Muhlestein, J.B. et al. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis 22, 191–197 (2006). https://doi.org/10.1007/s11239-006-9030-7

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  • DOI: https://doi.org/10.1007/s11239-006-9030-7

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