1. ¹Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, Sweden
2. ²The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
3. ³UCR—Uppsala Clinical Research Center, Uppsala Science Park, Uppsala, Sweden
4. ⁴Department of Genetics and Pathology, Medical Genetics, Rudbeck Laboratory, Uppsala, Sweden

Correspondence: Dr M Wadelius, Department of Medical Sciences, Clinical Pharmacology, University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 49 45; Fax: +46 18 51 92 37; E-mail: mia.wadelius@medsci.uu.se

Received 16 November 2004; Revised 4 March 2005; Accepted 14 March 2005; Published online 10 May 2005.

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.