The Influence of Polymorphisms in Cyp2c9 and Vkorc1 Genes on the Efficacy and Safety of Oral Anticoagulant Treatment

Inherited variants of the enzymes involved in drug metabolism, transporters, receptors may play an important role in drug response. Genotyping prior to drug administration seems to be a promising clinical approach in order to reduce the adverse effects of the drugs and to increase their efficacy. Oral anticoagulants (OAs) are drugs largely used in the prevention and treatment of thrombo-embolic diseases. Patients under treatment with OAs present a high risk for severe haemorrhage. Irreversible inhibition of VKORC1 enzyme by OA blocks regeneration of vitamin K, which leads to unfunctional pro-coagulant factors. VKORC1*2 haplotype is linked to an excessive anticoagulation risk at average doses of OAs, while other polymorphisms of the gene are linked to the resistance to OAs. Acenocoumarol is inactivated by CYP2C9 enzyme, so people carrying at least one defective allele CYP2C9*2 but particularly CYP2C9*3 are susceptible to excessive anticoagulation at average doses of acenocoumarol. In conclusion, the combined analysis of CYP2C9 and VKORC1 allows the explanation of 30-40% of the individual variability in equilibrium dose of oral anticoagulants and, consequently, in treatment response.