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Polymorphisms in VKORC 1 have more impact than CYP2C9 polymorphisms on early warfarin I nternational N ormalized R atio control and bleeding rates
Author(s) -
Lund Kirstin,
Gaffney Dairena,
Spooner Richard,
Etherington Anne Marie,
Tansey Patrick,
Tait Robert Campbell
Publication year - 2012
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2012.09150.x
Subject(s) - vkorc1 , cyp2c9 , warfarin , vitamin k epoxide reductase , genotype , single nucleotide polymorphism , medicine , gastroenterology , biology , pharmacology , genetics , gene , atrial fibrillation
Summary Poor warfarin control with resultant high International Normalized Ratios ( INR s) 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 INR s > 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 INR s.