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. 2008 Mar 6;358(10):999-1008.
doi: 10.1056/NEJMoa0708078.

Genetic determinants of response to warfarin during initial anticoagulation

Ute I Schwarz  1 , Marylyn D Ritchie, Yuki Bradford, Chun Li, Scott M Dudek, Amy Frye-Anderson, Richard B Kim, Dan M Roden, C Michael Stein
Affiliations

Genetic determinants of response to warfarin during initial anticoagulation

Ute I Schwarz et al. N Engl J Med. .

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.

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Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

Figures

Figure 1
Figure 1. Association between Specific Genetic Variants and Study Outcomes
The graphs show the association between the time to the first international normalized ratio (INR) within the therapeutic range and the time to the first INR of more than 4 for patients carrying genetic variants for vitamin K epoxide reductase (VKORC1) (Panels A and B) and for cytochrome P-450 2C9 (CYP2C9) (Panels C and D).
See this image and copyright information in PMC

Comment in

  • Pharmacogenomics--ready for prime time?
    Shurin SB, Nabel EG. Shurin SB, et al. N Engl J Med. 2008 Mar 6;358(10):1061-3. doi: 10.1056/NEJMe0800801. N Engl J Med. 2008. PMID: 18322288 No abstract available.
  • Genetics of warfarin response.
    Schillinger D. Schillinger D. N Engl J Med. 2008 Jun 19;358(25):2741-2; author reply 2743-4. doi: 10.1056/NEJMc086121. N Engl J Med. 2008. PMID: 18565872 No abstract available.
  • Genetics of warfarin response.
    Neville KA, Wicklund BM, Kearns GL. Neville KA, et al. N Engl J Med. 2008 Jun 19;358(25):2742. N Engl J Med. 2008. PMID: 18572452 No abstract available.
  • Genetics of warfarin response.
    Mannucci PM, Spreafico M, Peyvandi F. Mannucci PM, et al. N Engl J Med. 2008 Jun 19;358(25):2743; author reply 2743-4. N Engl J Med. 2008. PMID: 18572453 No abstract available.
  • Genetics of warfarin response.
    Kulkarni UP, Karnad DR, Gogtay NJ. Kulkarni UP, et al. N Engl J Med. 2008 Jun 19;358(25):2742-3; author reply 2743-4. N Engl J Med. 2008. PMID: 18572454 No abstract available.

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