title: Common VKORC1 and GGCX polymorphisms associated with warfarin dose.
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.
authors.affiliation: Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, Sweden. mia.wadelius@medsci.uu.se
authors.forename: M
authors.initials: M
authors.lastname: Wadelius
authors.forename: L Y
authors.initials: LY
authors.lastname: Chen
authors.forename: K
authors.initials: K
authors.lastname: Downes
authors.forename: J
authors.initials: J
authors.lastname: Ghori
authors.forename: S
authors.initials: S
authors.lastname: Hunt
authors.forename: N
authors.initials: N
authors.lastname: Eriksson
authors.forename: O
authors.initials: O
authors.lastname: Wallerman
authors.forename: H
authors.initials: H
authors.lastname: Melhus
authors.forename: C
authors.initials: C
authors.lastname: Wadelius
authors.forename: D
authors.initials: D
authors.lastname: Bentley
authors.forename: P
authors.initials: P
authors.lastname: Deloukas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage* / Q000627:therapeutic use; D019735:Carbon-Carbon Ligases / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase