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Thromb Haemost 2008; 100(02): 229-239
DOI: 10.1160/TH07-09-0552
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients

Lisa M. Meckley
1   Department of Pharmacy
,
Ann K. Wittkowsky
1   Department of Pharmacy
,
Mark J. Rieder
2   Department of Genome Sciences
,
Allan E. Rettie
3   Department of Medicinal Chemistry, University of Wa shington, Seattle, Washington, USA
,
David L. Veenstra
1   Department of Pharmacy
› Author AffiliationsFinancial support: This work was supported in part by a Centers for Disease Control (CDC) Seed Funding for Public Health Genomics Research (DLV), NS053646 (MJR), GM68797 (AER), the University of Washington Drug Metabolism, Transport, and Pharmacogenomic Research (DMTPR) Program, and a PhRMA Foundation pre-doctoral award to LMM.
Further Information

Publication History

Received 07 September 2007

Accepted after major revision: 12 June 2008

Publication Date:
22 November 2017 (online)

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Summary

The objective of this study was to assess the relative influence of VKORC1 and CYP2C9 genetic variants on several clinical outcomes related to warfarin treatment. We conducted a retrospective cohort analysis of 172 anticoagulation clinic patients followed from warfarin initiation. We assessed the following clinical outcomes: time to stable dose; time in, above, and below therapeutic range; the probability of overanticoagulation (international normalized ratio [INR] >5); frequency of anticoagulation clinic visits; and the contribution of genetics to maintenance dose. Patients with CYP2C9 variants, compared to those without, achieved stable dose 48% later (p<0.01),spent a higher proportion of time above range in the first month of therapy (14% vs. 25%, p=0.07), and had a higher odds ratio (OR) of an INR >5 (OR: 4.15, p=0.03). In contrast, the only statistically significant effect withVKORC1 was a higher odds of an INR >5 (OR: 4.47,p=0.03) for patients homozygous for theVKORC1 low-dose haplotype (AA) compared to heterozygotes. We did not detect an influence of CYP2C9 norVKORC1 on the frequency of clinic visits. CYP2C9 alone,VKORC1 alone, and a combination of genetic and clinical factors explained 12%, 27%, and 50%,respectively, of the variation in warfarin maintenance dose. In conclusion, genetic variation in VKORC1 appears to have a different influence than CYP2C9 on anticoagulation-related outcomes such as bleeding events and time in therapeutic range. This difference may be due, in part, to pharmacokinetics factors (e.g. drug half-life), which are influenced primarily by CYP2C9; these findings should be confirmed in additional studies.

Keywords

Anticoagulation - pharmacogenetics - pharmacogenomics
 

  • References

  • 1 Higashi MK, Veenstra DL, Kondo LM. et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. J Am Med Assoc 2002; 287: 1690-1698.
    CrossrefPubMedGoogle Scholar
  • 2 Margaglione M, Colaizzo D, D’Andrea G. et al. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 2000; 84: 775-778.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Aithal GP, Day CP, Kesteven PJ. et al. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717-719.
    CrossrefPubMedGoogle Scholar
  • 4 Joffe HV, Xu R, Johnson FB. et al. Warfarin dosing and cytochrome P450 2C9 polymorphisms. Thromb Haemost 2004; 91: 1123-1128.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Voora D, Eby C, Linder MW. et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost 2005; 93: 700-705.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Sconce EA, Khan TI, Wynne HA. et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005; 106: 2329-2333.
    CrossrefPubMedGoogle Scholar
  • 7 Kamali F, Khan TI, King BP. et al. Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin Pharmacol Ther 2004; 75: 204-212.
    CrossrefPubMedGoogle Scholar
  • 8 Hillman MA, Wilke RA, Caldwell MD. et al. Relative impact of covariates in prescribing warfarin according to CYP2C9 genotype. Pharmacogenetics 2004; 14: 539-547.
    CrossrefPubMedGoogle Scholar
  • 9 Schalekamp T, Brasse BP, Roijers JF. et al. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther 2006; 80: 13-22.
    CrossrefPubMedGoogle Scholar
  • 10 Schalekamp T, van Geest-Daalderop JH, de Vries-Goldschmeding H. et al. Acenocoumarol stabilization is delayed in CYP2C93 carriers. Clin Pharmacol Ther 2004; 75: 394-402.
    CrossrefPubMedGoogle Scholar
  • 11 Tassies D, Freire C, Pijoan J. et al. Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation. Haematologica 2002; 87: 1185-1191.
    PubMedGoogle Scholar
  • 12 Visser LE, van Schaik RH, van Vliet M. et al. The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Thromb Haemost 2004; 92: 61-66.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Hummers-Pradier E, Hess S, Adham IM. et al. Determination of bleeding risk using genetic markers in patients taking phenprocoumon. Eur J Clin Pharmacol 2003; 59: 213-219.
    CrossrefPubMedGoogle Scholar
  • 14 Schalekamp T, Oosterhof M, van Meegen E. et al. Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status. Clin Pharmacol Ther 2004; 76: 409-417.
    CrossrefPubMedGoogle Scholar
  • 15 Ufer M. Effects of CYP2C9 polymorphisms on phenprocoumon anticoagulation status. Clin Pharmacol Ther 2005; 77: 335-336.
    CrossrefPubMedGoogle Scholar
  • 16 Visser LE, van Vliet M, van Schaik RH. et al. The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Pharmacogenetics 2004; 14: 27-33.
    CrossrefPubMedGoogle Scholar
  • 17 Kirchheiner J, Ufer M, Walter EC. et al. Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and S-phenprocoumon in healthy volunteers. Pharmacogenetics 2004; 14: 19-26.
    CrossrefPubMedGoogle Scholar
  • 18 Rieder MJ, Reiner AP, Gage BF. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352: 2285-2293.
    CrossrefPubMedGoogle Scholar
  • 19 Veenstra DL, You JH, Rieder MJ. et al. Association of vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population. Pharmacogenet Genomics 2005; 15: 687-691.
    CrossrefPubMedGoogle Scholar
  • 20 Obayashi K, Nakamura K, Kawana J. et al. VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients. Clin Pharmacol Ther 2006; 80: 169-178.
    CrossrefPubMedGoogle Scholar
  • 21 D’Andrea G, D’Ambrosio RL, Di Perna P. et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 2005; 105: 645-649.
    CrossrefPubMedGoogle Scholar
  • 22 Harrington DJ, Underwood S, Morse C. et al. Pharmacodynamic resistance to warfarin associated with a Va l66Met substitution in vitamin K epoxide reductase complex subunit 1. Thromb Haemost 2005; 93: 23-26.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Yuan HY, Chen JJ, Lee MT. et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 2005; 14: 1745-1751.
    CrossrefPubMedGoogle Scholar
  • 24 Wadelius M, Chen LY, Downes K. et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 2005; 05: 262-270.
    CrossrefPubMedGoogle Scholar
  • 25 Geisen C, Watzka M, Sittinger K. et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost 2005; 94: 773-779.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Takahashi H, Wilkinson GR, Nutescu EA. et al. Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics 2006; 16: 101-110.
    CrossrefPubMedGoogle Scholar
  • 27 Mushiroda T, Ohnishi Y, Saito S. et al. Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients. J Hum Genet 2006; 51: 249-253.
    CrossrefPubMedGoogle Scholar
  • 28 Osman A, Enstrom C, Arbring K. et al. Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: a retrospective analysis of case records. J Thromb Haemost 2006; 04: 1723-1729.
    CrossrefPubMedGoogle Scholar
  • 29 Herman D, Peternel P, Stegnar M. et al. The influence of sequence variations in factor VII, gammaglutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Thromb Haemost 2006; 95: 782-787.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Li T, Lange L, Li X. et al. Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation. J Med Genet 2006; 43: 740-744.
    CrossrefPubMedGoogle Scholar
  • 31 Aquilante CL, Langaee TY, Lopez LM. et al. Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin Pharmacol Ther 2006; 79: 291-302.
    CrossrefPubMedGoogle Scholar
  • 32 Reitsma PH, van der Heijden JF, Groot AP. et al. A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk. PLoS Med 2005; 02: e312.
    CrossrefPubMedGoogle Scholar
  • 33 Montes R, Ruiz de Gaona E, Martinez-Gonzalez MA. et al. The c.-1639G > A polymorphism of the VKORC1 gene is a major determinant of the response to acenocoumarol in anticoagulated patients. Br J Haematol 2006; 133: 183-187.
    CrossrefPubMedGoogle Scholar
  • 34 Schalekamp T, Brasse BP, Roijers JFM. et al. VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: Interaction between both genotypes affects dose requirement. Clin Pharmacol Ther 2007; 81: 185.
    CrossrefPubMedGoogle Scholar
  • 35 Veenstra DL, Blough DK, Higashi MK. et al. CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomes. Clin Pharmacol Ther 2005; 77: 353-364.
    CrossrefPubMedGoogle Scholar
  • 36 Harrison L, Johnston M, Massicotte MP. et al. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med 1997; 126: 133-136.
    CrossrefPubMedGoogle Scholar
  • 37 Rosendaal FR, Cannegieter SC, van der Meer FJ. et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-239.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Fihn SD, McDonell M, Martin D. et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group. Ann Intern Med 1993; 118: 511-520.
    CrossrefPubMedGoogle Scholar
  • 39 Linder MW, Looney S, Adams 3rd JE. et al. Warfarin dose adjustments based on CYP2C9 genetic polymorphisms. J Thromb Thrombolysis 2002; 14: 227-232.
    CrossrefPubMedGoogle Scholar
  • 40 Fihn SD, Gadisseur AA, Pasterkamp E. et al. Comparison of control and stability of oral anticoagulant therapy using acenocoumarol versus phenprocoumon. Thromb Haemost 2003; 90: 260-266.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Schwarz UI, Ritchie MD, Bradford Y. et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 2008; 358: 999-1008.
    CrossrefPubMedGoogle Scholar
  • 42 Schelleman H, Chen Z, Kealey C. et al. Wa rfarinresponse and vitamin K epoxide reductase complex 1 in African Americans and Caucasians. Clin Pharmacol Ther 2007; 81: 742-747.
    CrossrefPubMedGoogle Scholar
  • 43 Kealey C, Chen Z, Christie J. et al. Warfarin and cytochrome P450 2C9 genotype: possible ethnic variation in warfarin sensitivity. Pharmacogenomics 2007; 08: 217-225.
    CrossrefPubMedGoogle Scholar
  • 44 Sarawate C, Sikirica M, Willey V. et al. Monitoring anticoagulation in atrial fibrillation. J Thromb Thrombolysis 2006; 21: 191.
    CrossrefPubMedGoogle Scholar
  • 45 Pengo V, Pegoraro C, Cucchini U. et al. Worldwide Management of Oral Anticoagulant Therapy: the ISAM Study. J Thromb Thrombolysis 2006; 21: 73.
    CrossrefPubMedGoogle Scholar
  • 46 Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000; 96: 1816-1819.
    PubMedGoogle Scholar
  • 47 Limdi NA, McGwin G, Goldstein JA. et al. Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on warfarin. Clin Pharmacol Ther 2008; 83: 312-321.
    CrossrefPubMedGoogle Scholar
  • 48 Gage B, Eby C, Johnson J. et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther. 2008 in press.
    PubMedGoogle Scholar
  • 49 Hamberg AK, Dahl ML, Barban M. et al. A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy. Clin Pharmacol Ther 2007; 81: 529-538.
    CrossrefPubMedGoogle Scholar