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Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients

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

Abstract

Objective

The aim of this study was to investigate the influence of clinical and genetic factors on warfarin dose requirements in the Japanese population.

Methods

We enrolled 125 patients on stable warfarin anticoagulant therapy with an international normalized ratio maintained between 1.5 and 3.0. PCR-based methods were performed to analyze genetic polymorphisms in the genes pharmacokinetically and pharmacodynamically related to warfarin reactions, including cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), gamma-glutamyl carboxylase (GGCX) and factor VII (FVII).

Results

The presence of CYP2C9*3 and VKORC1-1639G>A had a significant impact on the mean maintenance dose of warfarin (CYP2C9*1/*1 2.74 ± 1.24 mg/day vs. *1/*3 and *3/*3 1.56 ± 0.85 mg/day, P = 0.009; VKORC1-1639AA 2.42 ± 0.95 mg/day vs. GA 3.71 ± 1.43 mg/day vs. GG 7.25 ± 0.35 mg/day, P < 0.001). In the multiple linear regression model, the combination of age, body surface area, and genotypes of CYP2C9*3 and VKORC1-1639G>A explained 54.8% of the variance in warfarin dose requirements.

Conclusions

The influences of CYP2C9*3 and VKORC1-1639G>A on the maintenance dose of warfarin were well-defined in Japanese patients, while polymorphisms of GGCX and FVII did not affect it. The model established in this study might provide us most likely individual maintenance dose based on clinical and genetic backgrounds.

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Acknowledgements

We are grateful to all doctors, nurses, and subjects who participated in this study. We thank Yasuko Murao for her secretarial assistance. This study was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a grant from the Ministry of Health, Labor and Welfare of Japan.

Conflict of interest

The study received no support from the pharmaceutical industry. None of the authors has any conflict of interest regarding this article.

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Author notes

  1. Junichi Azuma

    Present address: Clinical Pharmacology and Pharmacogenomics, Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Hyogo, Japan

Authors and Affiliations

  1. Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences, Osaka University, 1–6 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Masako Ohno, Akiko Yamamoto, Tomoko Tanabe, Yuiko Masunaga, Shinpei Nonen, Yasushi Fujio & Junichi Azuma

  2. Otsuki Hospital, Kochi, Japan

    Ayumu Ono

  3. Himeshima National Health Insurance Clinic, Oita, Japan

    Genta Miura

  4. Funamoto Clinic, Hyogo, Japan

    Masanobu Funamoto

  5. Department of Cardiology and Internal Medicine, Osaka City University Medical School, Osaka, Japan

    Yasuhiko Takemoto & Yasushi Kouno

  6. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Kinya Otsu

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  1. Masako Ohno
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Corresponding author

Correspondence to Junichi Azuma.

Additional information

Masako Ohno and Akiko Yamamoto contributed equally to this work.

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Ohno, M., Yamamoto, A., Ono, A. et al. Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients. Eur J Clin Pharmacol 65, 1097–1103 (2009). https://doi.org/10.1007/s00228-009-0685-9

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  • DOI: https://doi.org/10.1007/s00228-009-0685-9

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