Warfarin Pharmacogenetics

VKORC1 gene

VKORC1 is the vitamin K epoxide reductase complex subunit-1, a key enzyme in vitamin K metabolism and a target of warfarin. The VKORC1: -1639 G>A polymorphism in the promoter region of the VKORC1 gene is associated with reduced gene expression of this enzyme. Carriers of the A allele are more sensitive to warfarin and require lower doses of the drug to achieve therapeutic effect.

CYP2C9 gene

The CYP2C9 gene encodes cytochrome P450 enzyme, which is involved in metabolizing the S-isomer of warfarin. The most significant polymorphisms of this gene are CYP2C9: 430 C>T and CYP2C9: 1075 A>C. CYP2C9: 430 C and CYP2C9: 1075 A are designated as CYP2C9*1. CYP2C9: 430 T variant is denoted as CYP2C9*2, while CYP2C9: 1075 C is labeled as CYP2C9*3; such genotypes are associated with reduced enzyme activity and slower warfarin metabolism.

CYP2C9: 430 C>T polymorphism reduces the rate of formation of warfarin metabolites by about 30%, and CYP2C9: 1075 A>C - up to 80-90%. This leads to increased blood concentrations of warfarin and a higher risk of bleeding. Patients with these genotypes should receive lower doses of warfarin.

CYP4F2 gene

This gene encodes an enzyme involved in vitamin K cycle, where it regulates the formation and activation of blood clotting factors.

The CYP4F2 gene product is involved in vitamin K metabolism, which, in turn, is a cofactor for clotting factor synthesis. CYP4F2: 1347 C>T polymorphism is associated with CYP4F2 enzyme activity: carriers of the T allele have a reduced functional activity of the enzyme, which may affect the level of vitamin K and, consequently, warfarin metabolism. Patients with this polymorphism often require warfarin dose adjustment.

Special algorithms have been developed to calculate the dose of Warfarin on a case-by-case basis, the most well-known of which is WarfarinDosing.org.