Polymorphisms in factor II and factor VII genes modulate oral anticoagulation with warfarin

Abstract

BACKGROUND AND OBJECTIVES: There is very considerable inter-individual variability in warfarin dosages necessary to achieve target therapeutic anticoagulation. The variability is largely genetically determined but can only partly be explained by genetic variability in the cytochrome CYP2C9 locus. Polymorphisms within the genes coding for vitamin K-dependent proteins have been suggested to predict sensitivity to warfarin therapy. DESIGN AND METHODS: In a cohort of 147 patients followed-up at one specialized clinic from the start of anticoagulation with warfarin, we investigated whether factor II (Thr165Met; G20210A) and factor VII polymorphisms (G-402A; G-401T) affected the doses of warfarin necessary to acquire the target intensity of anticoagulation. RESULTS: Regardless of the presence of confounding variables, the mean adjusted dose of warfarin required was higher among patients with the factor II Thr/Thr 165 genotype (4.2 mg) than among patients carrying the Met165 allele (2.9 mg; p=0.041) and higher in carriers of the factor VII GG-401 genotype (4.1 mg) than in those with the T-401 allele (3.1 mg; p=0.029). No significant effect was found for factor II A20210G and factor VII G-402A polymorphisms. All together, the genetic variants investigated accounted for about a quarter (r2: 0.261) of the inter-individual variability calculated in the present setting. INTERPRETATION AND CONCLUSIONS: Genetic variants of factor II and factor VII modulate the mean daily dose of warfarin required to achieve a target intensity of anticoagulation.