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Common VKORC1 and GGCX polymorphisms associated with warfarin dose

The Pharmacogenomics Journal volume 5, pages 262–270 (2005)Cite this article

Abstract

We report a novel combination of factors that explains almost 60% of variable response to warfarin. Warfarin is a widely used anticoagulant, which acts through interference with vitamin K epoxide reductase that is encoded by VKORC1. In the next step of the vitamin K cycle, gamma-glutamyl carboxylase encoded by GGCX uses reduced vitamin K to activate clotting factors. We genotyped 201 warfarin-treated patients for common polymorphisms in VKORC1 and GGCX. All the five VKORC1 single-nucleotide polymorphisms covary significantly with warfarin dose, and explain 29–30% of variance in dose. Thus, VKORC1 has a larger impact than cytochrome P450 2C9, which explains 12% of variance in dose. In addition, one GGCX SNP showed a small but significant effect on warfarin dose. Incorrect dosage, especially during the initial phase of treatment, carries a high risk of either severe bleeding or failure to prevent thromboembolism. Genotype-based dose predictions may in future enable personalised drug treatment from the start of warfarin therapy.

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Abbreviations

CYP2C9:

cytochrome P450 2C9

ddNTP:

dideoxynucleotide triphosphate

dNTP:

deoxynucleotide triphosphate

GGCX:

gamma-glutamyl carboxylase

LD:

linkage disequilibrium

PCR:

polymerase chain reaction

PT INR:

prothrombin time international normalised ratio

UTR:

untranslated region

VKOR:

vitamin K epoxide reductase

VKORC1:

vitamin K epoxide reductase complex subunit 1

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Acknowledgements

We are grateful to all nurses, doctors and patients who took part in the study. We thank Kristina Sörlin for going through medical records, Liz Sheridan for gene annotation, Suzannah Bumpstead for technical assistance, David Vetrie for introduction to databases and Ralph McGinnis for critical reading of the manuscript. This study was funded by the Wellcome Trust, and the Swedish Society of Medicine, Swedish Research Council (M521-2003-5730, NT621-2003-5592), Foundation for Strategic Research, 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. Ethical approval: Uppsala Research Ethics Committee approved the study, no. 00-119.

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Authors and Affiliations

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

    M Wadelius & H Melhus

  2. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

    L Y Chen, K Downes, J Ghori, S Hunt, D Bentley & P Deloukas

  3. UCR—Uppsala Clinical Research Center, Uppsala Science Park, Uppsala, Sweden

    N Eriksson

  4. Department of Genetics and Pathology, Medical Genetics, Rudbeck Laboratory, Uppsala, Sweden

    O Wallerman & C Wadelius

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  1. M Wadelius
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Correspondence to M Wadelius.

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Wadelius, M., Chen, L., Downes, K. et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 5, 262–270 (2005). https://doi.org/10.1038/sj.tpj.6500313

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