The influence of VKORC1 and CYP2C9 gene sequence variants on the stability of maintenance phase warfarin treatment

Abstract

IntroductionA substantial part of the inter-individual variation in vitamin K-antagonist dose can be explained by certain sequence variants in the genes CYP2C9 (NG_008385.1:g.8633C>T or *1/*2, NG_008385.1:g.47639A>C or *1/*3) and VKORC1 (NG_011564.1:g.6399C>T). Patients possessing these variant alleles require lower doses and have increased risk of overanticoagulation. MethodsWe investigated the influence of the above sequence variants on stability of maintenance phase warfarin therapy in a prospective study of 300 consecutive patients followed for one year at an anticoagulant clinic. ResultsPatients having one VKORC1 variant allele (n=144) had a time in therapeutic range of INR (TTR) of 71.4%, significantly lower (p=0.02) than the 76.7% TTR of patients with none (n=96) or two (n=46) variant alleles. Patients carrying the CYP2C9 *3 allele (n=40) trended towards lower TTR than patients without this variant allele (69.8% vs. 74.7%, p=0.09). Six patients possessed two variant alleles of CYP2C9 (*2/*3 or *3/*3) and had significantly lower TTR (60.5% vs. 74.3%, p=0.012) and higher risk of an INR>4.5 (67% vs. 23%, p=0.03) compared with the remaining patients. ConclusionsWe observed modest effects of common gene sequence variants in CYP2C9 and VKORC1 on stability of maintenance phase warfarin therapy. Patients attending an anticoagulant clinic using computer-assisted dosage were safely monitored regardless of these sequence variants, but for the small subgroup of patients with the CYP2C9 genotype *2/*3 or *3/*3, treatment stability was reduced.