Genetic determinants of response to warfarin during initial anticoagulation

Ute I. Schwarz, Marylyn D. Ritchie, Yuki Bradford, Chun Li, Scott M. Dudek, Amy Frye-Anderson, Richard B. Kim, Dan M. Roden, C. Michael Stein

Research output: Contribution to journalArticlepeer-review

500 Scopus citations

Abstract

Background: Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9), and of a key pharmacologic target of warfarin, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to various warfarin doses, but the role of these variants during initial anticoagulation is not clear. Methods: In 297 patients starting warfarin therapy, we assessed CYP2C9 genotypes (CYP2C9 *1, *2, and *3), VKORC1 haplotypes (designated A and non-A), clinical characteristics, response to therapy (as determined by the international normalized ratio [INR]), and bleeding events. The study outcomes were the time to the first INR within the therapeutic range, the time to the first INR of more than 4, the time above the therapeutic INR range, the INR response over time, and the warfarin dose requirement. Results: As compared with patients with the non-A/non-A haplotype, patients with the A/A haplotype of VKORC1 had a decreased time to the first INR within the therapeutic range (P = 0.02) and to the first INR of more than 4 (P = 0.003). In contrast, the CYP2C9 genotype was not a significant predictor of the time to the first INR within the therapeutic range (P = 0.57) but was a significant predictor of the time to the first INR of more than 4 (P = 0.03). Both the CYP2C9 genotype and VKORC1 haplotype had a significant influence on the required warfarin dose after the first 2 weeks of therapy. Conclusions: Initial variability in the INR response to warfarin was more strongly associated with genetic variability in the pharmacologic target of warfarin, VKORC1, than with CYP2C9.

Original languageEnglish (US)
Pages (from-to)999-1008
Number of pages10
JournalNew England Journal of Medicine
Volume358
Issue number10
DOIs
StatePublished - Mar 6 2008

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Fingerprint

Dive into the research topics of 'Genetic determinants of response to warfarin during initial anticoagulation'. Together they form a unique fingerprint.

Cite this