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1. Br J Haematol. 2012 May 10. doi: 10.1111/j.1365-2141.2012.09150.x. [Epub ahead of

Polymorphisms in VKORC1 have more impact than CYP2C9 polymorphisms on early
warfarin International Normalized Ratio control and bleeding rates.

Lund K, Gaffney D, Spooner R, Etherington AM, Tansey P, Tait RC.

Department of Haematology, Royal Infirmary, Glasgow, UK.

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.

© 2012 Blackwell Publishing Ltd.

PMID: 22571356 [PubMed - as supplied by publisher]