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

Lisa M. Meckley; Ann K. Wittkowsky; Mark J. Rieder; Allan E. Rettie; David L. Veenstra

doi:10.1160/TH07-09-0552

Thrombosis and Haemostasis, Table of Contents

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

Authors

Lisa M. Meckley

¹Department of Pharmacy
Ann K. Wittkowsky

¹Department of Pharmacy
Mark J. Rieder

²Department of Genome Sciences
Allan E. Rettie

³Department of Medicinal Chemistry, University of Wa shington, Seattle, Washington, USA
David L. Veenstra

¹Department of Pharmacy

Abstract

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

Full Text

References

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.
2 Margaglione M, Colaizzo D, D’Andrea G. et al. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 2000; 84: 775-778.
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.
4 Joffe HV, Xu R, Johnson FB. et al. Warfarin dosing and cytochrome P450 2C9 polymorphisms. Thromb Haemost 2004; 91: 1123-1128.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
15 Ufer M. Effects of CYP2C9 polymorphisms on phenprocoumon anticoagulation status. Clin Pharmacol Ther 2005; 77: 335-336.
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.
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.
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.
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.
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.
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.
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.
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.
24 Wadelius M, Chen LY, Downes K. et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 2005; 05: 262-270.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
44 Sarawate C, Sikirica M, Willey V. et al. Monitoring anticoagulation in atrial fibrillation. J Thromb Thrombolysis 2006; 21: 191.
45 Pengo V, Pegoraro C, Cucchini U. et al. Worldwide Management of Oral Anticoagulant Therapy: the ISAM Study. J Thromb Thrombolysis 2006; 21: 73.
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.
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.
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.
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.