Influence of Polymorphism oOf The CYP2C9 and VKORC1 Genes on the Safety of Warfarin Therapy

Abstract

Warfarin is a drug widely used as an oral anticoagulant. Its narrow therapeutic range and marked interindividual variability in response require rigorous control in its administration to avoid hemorrhagic accidents. Objectives: To correlate genetic variants of CYP2C9*2 and *3 and VKORC1 (C1173T) with response and adverse effects. Material and method: CYP2C9*1, *2, *3, and VKORC1 genotypes were obtained by PCRRFLP and the results were analyzed using the SPSS 12.0 statistical package. Results: there is a tendency to reduce doses in relation to the presence of polymorphic alleles. CYP2C9*3 carriers required the lowest maintenance dose, followed by CYP2C9*2 carriers and CYP2C9 *1 homozygotes, in that order, (4.4±1.0 versus 5.4±2.3 versus 7. 0±3.6 mg/d, p=0.03). CYP2C9*3 carriers also had an increased risk of overanticoagulation and required almost twice as many dose adjustments to achieve adequate anticoagulation. For VKORC1, T/T homozygotes needed the lowest dose, followed by C/T heterozygotes and C/C homozygotes, in that order (3.6±0.6 versus 5.5±0.5 and 7.9 ±0.7 mg/d, p <0.001). T/T patients had a higher risk of overanticoagulation than C/T and C/C patients. The T/T genotype of VKORC1 produces in all combinations with CYP2C9 a decrease close to 50% of the daily dose of warfarin. Conclusions: an increased sensitivity to warfarin is confirmed in patients carrying alleles *2 and *3 of CYP2C9, and T of VKORC1. A combined (approximately additive) effect of the variant alleles of both genes is demonstrated.