Annotated PGx Gene Information for VKORC1
Submitted by: Ryan Owen
Reviewed by: Under Review
Submitted date: January 29th, 2007
| Gene HGNC Name: | VKORC1 |
|---|---|
| Gene Common Name: | Vitamin K epoxide reductase complex, subunit 1, VKOR |
| Introductory Information: | Introductory Information The VKORC1 gene encodes the VKORC1 (Vitamin K epoxide reductase) protein, which is an enzyme in the Vitamin K cycle. [14765194 14765195]. VKORC1 is a 163 amino acid integral membrane protein associated with the endoplasmic reticulum [16677080], and VKORC1 mRNA is broadly expressed in many different tissues, although the highest expression occurs in the liver [14765194]. VKORC1 is predicted to have at least one, and most likely three transmembrane domains. Several studies have highlighted candidate residues that likely form the active site [17124179 16270630 15514077 15276181]. VKORC1 is responsible for the conversion of Vitamin K-epoxide to Vitamin K, which is the rate-limiting step in the physiological process of Vitamin K recycling [15640149 16030016]. The availability of reduced Vitamin K is of particular importance for several coagulation factor proteins that require it as a cofactor, including Factor VII, Factor IX, and Factor X [16102054]. VKORC1 is of therapeutic interest both for its putative role in warfarin resistance, and as a potential player in vitamin K-deficiency disorders [14765194]. Warfarin Warfarin is a commonly administered oral anticoagulant used in the treatment of bleeding disorders in humans [16960144], and is also used as a rodenticide [16421894 15879509]. Warfarin, as well as other coumarin type drugs with similar mechanisms of action, act as inhibitors of VKORC1, which physiologically leads to a reduced amount of Vitamin K available to serve as a cofactor for clotting proteins [14765194]. One of the goals of warfarin therapy is to maintain a stable international normalized ratio (INR), typically of 2.0-3.0 [15597574 15865594 15938684]. INR is a clinically defined measure that should give similar values independent of the laboratory that conducts the measurement. Commercial warfarin is administered as a racemic mixture of its R and S enantiomers [17124101]. The metabolic fates of the two enantiomers are different [17124101]. The more potent S-warfarin is metabolized primarily by CYP2C9, and is excreted in the bile, whereas the R-warfarin enantiomer is metabolized by other members of the cytochrome P450 family and is excreted in the urine [17124101]. Although warfarin is an effective drug, some physicians are reluctant to prescribe it due to its narrow therapeutic index, and the risk of induced bleeding [16960144 16983400 16888441 14765195]. The response to warfarin shows a high degree of inter-individual variability, with some patients responding to a "high" dose of warfarin, and others responding to a "low" dose [15358623 15930419 16888441]. Those patients who responded to a low dose of warfarin were at increased risk for induced bleeding as a consequence of a high initial dose of warfarin [16983400]. Due to its role in the Vitamin K cycle, VKORC1 was considered a candidate gene for the variability in warfarin response [9684798]. Cloning of VKORC1 Although VKORC1 activity was described as early as the 1970s [5497142], it would prove resistant to all cloning efforts until 2004 when it was cloned by two different groups [PMID 14765194 14765195]. The eventual cloning of VKORC1 set off an avalanche of studies that examined the role of genetic variation of VKORC1 in warfarin resistance (see important variants of warfarin for tables containing PMIDs]. The subsequent examination of VKORC1 variants has shown that polymorphisms in the VKORC1 gene are associated with high and low warfarin dose phenotypes in humans [17110455 17124101]. Factors in warfarin resistance The high degree of inter-individual variation in the response to warfarin has lead to many studies that have attempted to explain the factors that influence warfarin response [17161452 16960144 16888441 16722840]. Prior to the cloning and characterization of VKORC1, it was known that the CYP2C9 genotype of patients played a role in warfarin metabolism and subsequent response [11127854 14676821]. However, more recent studies have consistently shown that VKORC1 genotype appears to be the single biggest predictor of warfarin dose [17161452 17111199 17048007 17015052 16815313]. Although the genotype of VKORC1 and CYP2C9 are clearly the most important genetic factors for warfarin response, other studies have shown a minor association with genetic variation in other genes including apolipoprotein E (APOE) [16847429 17048007 17112295], and the vitamin K cycle genes GGCX [16676068 17048007 17049586 17112295 17189218] and CALU [17189218]. Other, non-genetic factors are also known to play a role in warfarin response including age, BMI, gender, weight, INR, and serum albumin concentration [17042764, 17015052, 16493479]. Some studies have attempted to define a warfarin dosing algorithm that takes into account both genetic and non-genetic factors in order to predict an optimal warfarin dose [17111199 17042764 17015052 15947090]. VKORC1 variants Several studies in independent populations have shown the importance of genetic variation in VKORC1, and a few important polymorphisms and haplotypes have been defined [15930419 16270629 16869821]. In the sections that follow, we summarize the importance of three of the most common and well-studied VKORC1 polymorphisms in detail. However, there have been several studies that examined the influence of rare VKORC1 variants, or variants that were more common in special populations that we do not review [17110455 17059426 15978113 15630486 15358623]. |
| Key PubMed IDs: | 14765194 14765195 16677080 15640149 16030016 16102054 17110455 17124101 15930419 16270629 16869821 17161452 16960144 16888441 16722840 11127854 14676821 17111199 17048007 17015052 16815313 17042764 15947090 15597574 15865594 15938684 16983400 15358623 9684798 |
| Drugs/Substrates: |
Warfarin, Coumarin, Acenocoumarol |
| Phenotypes/Diseases: |
Atrial Fibrillation, Coagulation Protein Disorders, Hemorrhage, Vascular Diseases |
| Important Variants: | G3673A, C6484T, G9041A |
| Important Haplotypes: |
VKORC1*1, VKORC1*2, VKORC1*3, VKORC1*4 |
| If this gene has a standard set of important haplotypes, what is the definitive publication or website? Please fill out a "PGRN Haplotype Worksheet" for each allele. | VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Geisen et al [PMID: 16270629] and Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. Rieder et al [PMID: 15930419] |