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Wadelius, M. et al.

Wadelius, Chen, Downes, Ghori, Hunt, Eriksson, Wallerman, Melhus, Wadelius, Bentley, Deloukas,

Common VKORC1 and GGCX polymorphisms associated with warfarin dose.

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.[1]

References

Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Wadelius, M., Chen, L.Y., Downes, K., Ghori, J., Hunt, S., Eriksson, N., Wallerman, O., Melhus, H., Wadelius, C., Bentley, D., Deloukas, P. Pharmacogenomics J. (2005) [Pubmed]

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