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Exploring warfarin pharmacogenomics with the extreme-discordant-phenotype methodology: impact of FVII polymorphisms on stable anticoagulation with warfarin

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To explore the pharmacogenomics of warfarin using the extreme-discordant-phenotype (EDP) methodology.

Methods

The target phenotype was the stable warfarin dose prescribed to 353 patients. Pharmacogenetic polymorphisms assessed were coagulation factor VII (FVII) -401G>T and FVII -402G>A, VKORC1 3673G>A, and CYP2C9*2, *3, *5, and *11 alleles. The EDP analyses contrasted the frequencies of these polymorphisms at different cutoff points (5th through 30th percentiles of the warfarin dose distribution) at opposite ends of the warfarin dose distribution.

Results

Significant differences existed in FVII -402G>A genotype frequency at the 5th percentile with an over-representation of the wildtype GG genotype at low warfarin doses and in VKORC1 3673G>A and CYP2C9 polymorphisms at all cutoff points where the variant alleles were overrepresented at low warfarin doses.

Conclusion

The EDP methodology provides increased statistical power for detection of small contributions of genetic polymorphisms to multiplex drug-response phenotypes, such as warfarin dose requirement for adequate anticoagulation.

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Acknowledgements

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior (Capes) and Financiadora de Estudos e Projetos (Finep).

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Authors and Affiliations

  1. Divisão de Farmacologia, Coordenação de Pesquisa, Instituto Nacional de Câncer, Rua André Cavalcanti 37, Rio de Janeiro, 21230-050, Brazil

    Mateus Fuchshuber-Moraes, Jamila A. Perini & Guilherme Suarez-Kurtz

  2. Institut für Pharmakologie, Ernst Moritz-Arndt Universität Greifswald, Greifswald, Germany

    Dieter Rosskopf

Authors
  1. Mateus Fuchshuber-Moraes
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  2. Jamila A. Perini
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  3. Dieter Rosskopf
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  4. Guilherme Suarez-Kurtz
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Correspondence to Guilherme Suarez-Kurtz.

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Fuchshuber-Moraes, M., Perini, J.A., Rosskopf, D. et al. Exploring warfarin pharmacogenomics with the extreme-discordant-phenotype methodology: impact of FVII polymorphisms on stable anticoagulation with warfarin. Eur J Clin Pharmacol 65, 789–793 (2009). https://doi.org/10.1007/s00228-009-0651-6

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  • DOI: https://doi.org/10.1007/s00228-009-0651-6

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