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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
 

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