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CYP2C9 and VKORC1 polymorphisms influence warfarin dose variability in patients on long-term anticoagulation

  • Pharmacogenetics
  • Published:
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Abstract

Objectives

The main aim of this study was to determine whether CYP2C9 and VKORC1 polymorphisms influence warfarin dose variability during initial dose-finding phase and during maintenance treatment after 360 days.

Methods

Two hundred and six consecutive patients who were beginning warfarin therapy were selected. They were assessed for general and clinical characteristics; prescribed warfarin dose; response to therapy on days 7–10, 30, 60, 180, and 360; adverse events; and CYP2C9 *2, *3, *5, *6, *8, *11, and VKORC1 1639G >A assays.

Results

During the first 30 days of anticoagulation, the relative variability of warfarin dose was significantly associated with CYP2C9*2 and CYP2C9*3 polymorphisms (p = 0.02) and with VKORC1 1639G >A genotypes (p = 0.04). Warfarin variability was also statistically different according to predicted metabolic phenotype and to VKORC1 genotypes after 360 days of treatment, and in the phase between 180 and 360 days (long-term dose variability). Both CYP2C9 and VKORC1 polymorphisms were associated with the international normalized ratio (INR) made between 7 and 10 days/initial dose ratio, adjusted for covariates (p < 0.01 and p = 0.02, respectively). Patients carrying VKORC1 and CYP2C9 variants presented lower required dose (at the end of follow-up of 360 days) compared to patients carrying wild-type genotypes (p = 0.04 and p = 0.03, respectively).

Conclusions

Genetic information on CYP2C9 and VKORC1 is important both for the initial dose-finding phase and during maintenance treatment with warfarin.

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Acknowledgments

PCJLS and RAGS are recipients of fellowships from FAPESP, Brazil, Proc.2010-17465-8 and Proc.2010-17881-1. Technical assistance from the Laboratory of Genetics and Molecular Cardiology group, Heart Institute group is gratefully acknowledged.

Conflict of interests

The authors declare that they have no potential conflicts of interest.

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Authors and Affiliations

  1. Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, Sao Paulo, SP, CEP 05403-000, Brazil

    Paulo Caleb Junior Lima Santos, Carla Luana Dinardo, Isolmar Tadeu Schettert, Renata Alonso Gadi Soares, José Eduardo Krieger & Alexandre Costa Pereira

  2. University Hospital of the University of Sao Paulo, Internal Medicine Division, Sao Paulo, Brazil

    Liz Kawabata-Yoshihara, Isabela Martins Bensenor & Paulo Andrade Lotufo

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  1. Paulo Caleb Junior Lima Santos
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  2. Carla Luana Dinardo
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  4. Renata Alonso Gadi Soares
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Correspondence to Paulo Caleb Junior Lima Santos or Alexandre Costa Pereira.

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Table 1

Primers used for amplification of the CYP2C9 and VKORC1 polymorphisms and corresponding annealing temperatures (DOC 33 kb)

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Santos, P.C.J.L., Dinardo, C.L., Schettert, I.T. et al. CYP2C9 and VKORC1 polymorphisms influence warfarin dose variability in patients on long-term anticoagulation. Eur J Clin Pharmacol 69, 789–797 (2013). https://doi.org/10.1007/s00228-012-1404-5

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