VKORC1: molecular target of coumarins

Abstract

Summary. The genetic diagnosis of a single family with combined vitamin K-dependent clotting factor deficiency (VKCFD2, OMIM #607473) finally led to the identification and molecular characterization of vitamin K epoxide reductase (VKORC1). VKORC1 is the key enzyme of the vitamin K cycle and the molecular target of coumarins, which represent the most commonly prescribed drugs for therapy and prevention of thromboembolic conditions. However, coumarins are known to have a narrow therapeutic window and a considerable risk of bleeding complications caused by a broad variation of intra-and inter-individual drug requirement. Now, 3 years after its identification, VKORC1 has greatly improved our understanding of the vitamin K cycle and has led to the translation of basic research into clinical practise in at least three directions: (i) Mutations within VKORC1 have been shown to cause a coumarin-resistant phenotype and a single SNP (rs9923231) within the VKORC1 promoter region has been identified as the major pharmacodynamic determinant of coumarin dose. Together with the previously described CYP2C9 variants and other dose-influencing factors, such as age, gender and weight, individualized dosing algorithms have become available.(ii) Preliminary studies indicate that concomitant application of low-dose vitamin K (80-100 lg day )1) and warfarin significantly improves INR stability and time of INR within the therapeutic range. (iii) Co-expression studies of FIX and FX with VKORC1 have shown that VKOR activity is the rate-limiting step in the synthesis of biologically active vitamin K-dependent factors. Thus, co-expression of VKORC1 leads to a more efficient production of recombinant vitamin K-dependent coagulation factors such as FIX and FVII. This could improve production of recombinant factor concentrates in the future.

Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements

“…Moreover, there is evidence indicating that the rs9923231 T allele is associated with a reduction of VKORC1 mRNA levels of up to 70%, in comparison to the wild-type allele. 13 This variation in mRNA levels may therefore be causing some of the variability observed in warfarin dosing among individuals. The significance of this polymorphism is further evidenced by studies showing that it may be accountable for all of the variability in warfarin metabolism that is due to the VKORC1 haplotype.…”

“…Vitamin K epoxide reductase subunit 1 (VKORC1), having a major role in the vitamin K pathway, is the target protein of warfarin. 13 Within the VKORC1 gene, the single nucleotide polymorphism (SNP) rs9923231 has been extensively studied among European and Asian populations. Original research by Wadelius 10 showed that VKORC1 predicts 30% of the variance observed in warfarin dose.…”

Impact of GGCX polymorphisms on warfarin doserequirements in atrial fibrillation patients

“…VKORC1 is responsible for the biosynthesis of vitamin K-dependent coagulation factors (factors II, VII, IX, and X) through transformation of epoxide (vitamin K-2,3-epoxide) to a reduced form of vitamin K and gamma-carboxylation of the vitamin K-dependent coagulation factors (37). Warfarin inhibits VKORC1-catalyzed gamma-carboxylation of coagulation factors, thus preventing the regeneration of the reduced form of vitamin K (38). Mutations in the VKORC1 gene can lead to warfarin resistance, which might enhance warfarin dose requirements (39,40).…”

Frequencies of polymorphisms in CYP2C9 and VKORC1 genes influencing warfarin metabolism in Slovak population: implication for clinical practice

“…Polymorphisms in VKORC1 gene signifi cantly change the pharmacodynamics and dosage adequacy of warfarin (16). The most frequent and most deeply studied polymorphisms are VKORC1 -1639G>A and 1173C>T. These SNPs, in the promotor and fi rst intron of VKORC1 gene infl uence the enzymatic activity of VKOR (17) which is an enzyme in vitamin K cycles and the pharmacological target of coumarins (18). VKORC1 1173C>T, rs9934438 is in almost complete linkage disequilibrium with the polymorphism of VKORC1 -1639G>A, rs9923231 where both associate with increased sensitivity to warfarin (16).…”