title: Polymorphisms in VKORC1 have more impact than CYP2C9 polymorphisms on early warfarin International Normalized Ratio control and bleeding rates.
abstract: Poor warfarin control with resultant high International Normalized Ratios (INRs) and bleeding events is most common during the first months of treatment. The effects of genetic polymorphisms at the vitamin K epoxide reductase [VKORC1] and cytochrome P450 2C9 [CYP2C9] loci have been increasingly acknowledged as contributory factors of enhanced warfarin sensitivity. In our prospective, blinded study, 557 patients (49·1% male, mean age 65·4 years, range 18-91 years) commencing warfarin (target INR 2·5) were genotyped and monitored through the first 3 months of anticoagulation. Homozygosity for the -1639 G>A single nucleotide functional promoter polymorphism of the VKORC1 gene (genotype AA; 14·5% of cases) was associated with a significantly shortened time to therapeutic INR ≥ 2 (P < 0·01), reduced stable warfarin dose (P < 0·01), and an increased number of INRs > 5 (P < 0·001) and occurrence of bleeding events (P < 0·01) during the first month, as compared to the GG genotype. CYP2C9 genetic variations *2 and *3 were not associated with significant effect on these factors. Neither VKORC1 nor CYP2C9 polymorphisms influenced these parameters beyond the first month of treatment. These findings imply possible benefits of assessing VKORC1 polymorphisms prior to anticoagulation, particularly as a low dose induction regime in VKORC1 AA individuals appears to reduce the incidence of high INRs.
authors.affiliation: Department of Haematology, Royal Infirmary, Glasgow, UK.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Lund
authors.affiliation: Department of Clinical Biochemistry, Royal Infirmary, Glasgow, UK.
authors.forename: Dairena
authors.initials: D
authors.lastname: Gaffney
authors.affiliation: Department of Clinical Biochemistry, Royal Infirmary, Glasgow, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Spooner
authors.affiliation: Glasgow & Clyde Anticoagulant Service, Glasgow, UK.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Etherington
authors.affiliation: Department of Haematology, Victoria Infirmary, Glasgow, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tansey
authors.affiliation: Department of Haematology, Royal Infirmary, Glasgow, UK.
authors.forename: Robert Campbell
authors.initials: RC
authors.lastname: Tait
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced / Q000235:genetics; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D016037:Single-Blind Method; D013997:Time Factors; D016896:Treatment Outcome; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases