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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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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DOI: https://doi.org/10.1038/sj.tpj.6500313
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