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Warfarin dose related to apolipoprotein E (APOE) genotype

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

Abstract

Objective

Warfarin is an anticoagulant which acts through interference with the recycling of vitamin K in the liver, leading to reduced activation of several clotting factors. Apolipoprotein E plays a central role in the uptake of the lipid-soluble vitamin K. The apolipoprotein E (APOE) alleles E2, E3 and E4 encode the three major isoforms of apolipoprotein E. The aim of this project was to evaluate whether variation in the APOE gene influences warfarin dose.

Methods

We genotyped APOE in 183 warfarin-treated patients. Information about warfarin dose, prothrombin time, age, gender, body weight, treatment indication and duration, other diseases and concurrent medication was taken from the patients’ medical records. Cytochrome P450 2C9 genotyping had been performed previously, and patients were stratified according to CYP2C9 genotype.

Results

Patients homozygous for APOE*E4 tended to receive higher warfarin doses than others. Among CYP2C9 extensive metabolisers, APOE*E4 homozygous patients received significantly higher warfarin doses than patients with one or no E4 alleles; 56.9 compared with 34.3 and 34.6 mg/week, (Bonferroni corrected P=0.008 and 0.007, respectively). APOE genotype explains 6% of warfarin dose variance among CYP2C9 extensive metabolisers (analysis of variance, P=0.009).

Conclusion

Previous studies have shown that individuals carrying the APOE*E4 allele have a faster uptake of lipoproteins into the liver and lower levels of circulating vitamin K than others. It is therefore plausible that patients carrying E4 alleles have an enhanced uptake of vitamin K into the liver and require higher doses of warfarin to compensate for this.

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Acknowledgements

We thank Professor Martin Kohlmeier, University of North Carolina for the idea to study APOE. We are indebted to Qun-Ying Yue and Håkan Melhus for initiating patient collection, and to all nurses, doctors and patients who took part. This study was funded by the Swedish Society of Medicine, the Swedish Foundation for Strategic Research, the Swedish Heart and Lung Foundation, Tore Nilson foundation, Federation of County Councils and Clinical Research Support (ALF) at Uppsala University. The sponsors had no role in study design, data collection, data analysis, data interpretation or writing of the report. The experiments comply with the current laws of Sweden. Uppsala Research Ethics Committee approved the study, No. 00-119. Competing interests: none declared.

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Authors and Affiliations

  1. Department of Medical Sciences, Clinical Pharmacology, University Hospital, 75185, Uppsala, Sweden

    Hugo Kohnke, Kristina Sörlin & Mia Wadelius

  2. Ariadne Exploration AB, Uppsala, Sweden

    Göran Granath

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  1. Hugo Kohnke
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Correspondence to Mia Wadelius.

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Kohnke, H., Sörlin, K., Granath, G. et al. Warfarin dose related to apolipoprotein E (APOE) genotype. Eur J Clin Pharmacol 61, 381–388 (2005). https://doi.org/10.1007/s00228-005-0936-3

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  • DOI: https://doi.org/10.1007/s00228-005-0936-3

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