Disease relevance of VKORC1

• METHODS AND RESULTS: To test the hypothesis, we studied the association of polymorphisms of VKORC1 with stroke (1811 patients), coronary heart disease (740 patients), and aortic dissection (253 patients) compared with matched controls (n=1811, 740, and 416, respectively) [1].
• We hypothesized that VKORC1-dependent effects on the coagulation cascade and atherosclerosis would contribute to susceptibility for vascular diseases [1].
• A number of factors such as patient age, body weight, co-morbidity, frailty, warfarin daily dose and CYP2C9 and VKORC1 polymorphism could affect response to vitamin K and thus the rate and extent of INR reversal [2].
• We found that VKOR expression in arteries was prominent in vascular endothelial cells and was high in the ventricular aneurysm tissue of human heart and human fetal heart [3].

High impact information on VKORC1

• PharmGKB Submission Update: VIII. PBAT Submission of Genetic Variation in VKORC1 to the PharmGKB Network [4].
• Vitamin K epoxide reductase (VKOR) recycles reduced vitamin K, which is used subsequently as a co-factor in the gamma-carboxylation of glutamic acid residues in blood coagulation enzymes [5].
• More than 21 million prescriptions for warfarin are written yearly in the U.S. Despite its importance, warfarin's target, vitamin K epoxide reductase (VKOR), has resisted purification since its identification in 1972 [6].
• Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity [7].
• Associations between a pharmacodynamic index (reduction in factor VII activity and international normalized ratio [INR] change) and several genetic polymorphisms (VKORC1: -4931T>C, -4451C>A, -2659G>C, -1877A>G, -1639G>A, 497C>G, 1173C>T, and CYP2C9*3) were investigated using haplotype and univariate analyses [7].

Biological context of VKORC1

• VKORC1 haplotypes were associated with the pharmacologic response, and this association can be explained only by the effect of the -1639G>A polymorphism (or alternatively by 1173C>T, which is in complete association with it) [7].
• The simple genotyping of 2 single-nucleotide polymorphisms (SNPs), VKORC1 -1639G>A or 1173C>T and the CYP2C9*3 polymorphisms, could thus predict a high risk of overdose before initiation of anticoagulation with acenocoumarol, and provide a safer and more individualized anticoagulant therapy [7].
• Furthermore, our results support the concept that different structural components of VKORC1 define the binding sites for vitamin K epoxide and coumarin [8].
• Mutations in VKORC1 result in two different phenotypes: warfarin resistance (WR) and multiple coagulation factor deficiency type 2 (VKCFD2) [8].
• Five common noncoding single-nucleotide polymorphisms of VKORC1 were identified in a natural haplotype block with strong linkage disequilibrium (D'>0.9, r2>0.9), then single-nucleotide polymorphism (SNP) +2255 in the block was selected for the association study [1].

Anatomical context of VKORC1

• Our results show that four hydrophobic regions predicted as the potential transmembrane domains in VKOR can individually insert across the endoplasmic reticulum membrane in vitro [9].
• Further evidence for this topological model of VKOR was obtained with freshly prepared intact microsomes from insect cells expressing HPC4-tagged full-length VKOR [9].
• The effects of overexpression and suppressing expression of VKOR on endothelial cell proliferation, migration, adhesion, and tubular network formation were explored [3].
• Stable transfection of VKOR cDNA into tumor cell line A549 and H7402 did not promote the cell proliferation [3].
• In vitro studies showed that overexpression of VKOR slightly but significantly stimulated human umbilical vein endothelial cell proliferation (by 120%), migration (by 118%), adhesion (by 117%), as well as tubular network formation [3].

Associations of VKORC1 with chemical compounds

• Warfarin is a widely used anticoagulant, which acts through interference with vitamin K epoxide reductase that is encoded by VKORC1 [10].
• 0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined [11].
• These individuals had normal vitamin-K dependent coagulation factor activities and undetectable serum PIVKAII and vitamin K1 2,3 epoxide suggesting that their basal vitamin K epoxide reductase activity was not adversely affected by the VKORC1 Val66Met substitution [12].
• VKORC1 and CYP2C9 Genotypes and Phenprocoumon Anticoagulation Status: Interaction Between both Genotypes Affects Dose Requirement [13].
• S- and R-warfarin concentrations, INR, and CYP2C9 and VKORC1 genotypes from 150 patients were used to develop a population pharmacokinetic/pharmacodynamic model in NONMEM [14].

Regulatory relationships of VKORC1

• Mean protein S activity was influenced by the VKORC1 3730G>A and CALU 20943T>A genotypes, after adjusting for confounding factors [15].

Other interactions of VKORC1

• Common VKORC1 and GGCX polymorphisms associated with warfarin dose [10].
• METHODS: Gene variations of VKORC1, CYP2C9, and CYP2C19 in 125 patients treated with warfarin and 114 healthy subjects were analyzed [16].
• Compound genetic profiles comprising VKORC1, CALU and CYP2C9 improve categorization of individual warfarin dose requirements in more than 25% of patients at steady-state anticoagulation [17].
• We propose that the PDI subunit of the complex provides electrons for reduction of the thioredoxin-like CXXC center in VKORC1 [18].
• A PK-PD Model for Predicting the Impact of Age, CYP2C9, and VKORC1 Genotype on Individualization of Warfarin Therapy [14].

Analytical, diagnostic and therapeutic context of VKORC1

• This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements [11].
• Site-directed mutagenesis of coumarin-type anticoagulant-sensitive VKORC1: evidence that highly conserved amino acids define structural requirements for enzymatic activity and inhibition by warfarin [8].
• Sequence analysis of the proposita did not identify any mutations in the VKORC1 gene but, remarkably, revealed 3 heterozygous mutations in the carboxylase gene that caused the substitutions Asp31Asn, Trp157Arg, and Thr591Lys [19].
• Immunoprecipitation and two-dimensional SDS-PAGE of microsomal membrane proteins demonstrate the existence of a VKOR enzyme complex where PDI and VKORC1 appear to be tightly associated subunits [18].

References