Annotated PGx Gene Information for VKORC1
Submitted by: Ryan Owen, Li Gong (PharmGKB)
Reviewed by: Under Review
Submitted date: January 29th, 2007
Updated date: October 30th, 2008
| 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 a key enzyme in the Vitamin K cycle [14765194 14765195]. VKORC1 is a 163 amino acid integral membrane protein associated with the endoplasmic reticulum, and VKORC1 mRNA is broadly expressed in many different tissues [16677080]. 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 role in contributing to high interpatient variability in coumarin anticoagulant dose requirements and as a potential player in vitamin K-deficiency disorders [14765194]. Warfarin Warfarin is a commonly prescribed oral anticoagulant used to prevent thromboembolic diseases in patients with deep vein thrombosis, atrial fibrillation, recurrent stroke or heart valve prosthesis [16960144]. 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 effective, warfarin dosing is challengIng due to its narrow therapeutic index and high degree of inter-individual variability in optimal dosing (between 0.6 and 15.5 mg/day)[11926893 12931134 15358623 15930419 16888441]. Inappropriate dosing of warfarin has been associated with a substantial risk of both major and minor hemorrhage [16960144 16983400 1688844114765195]. As the pharmacological target of warfarin, VKORC1 is 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]. The CYP2C9 genotype of the patients explained ~10% of the observed variability in the therapeutic warfarin dose [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]. Overall, VKORC1 polymorphisms account for ~25% of the variance in stabilized warfarin dose [16815312 18535201]. 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 including age, BMI, gender, weight, and INR are also known to play a role in warfarin response and collectively contribute to ~20% of variance in dose [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]. In 2007, pharmacogenomic information for warfarin was approved by FDA to be included in the product label stating that VKORC1 and CYP2C9 genotypes may be useful in determining the optimal initial dose of warfarin [17906972]. A number of large scale randomized clinical trials are now in progress to develop a globally applicable dosing strategy for warfarin. 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: | 11926893 12931134 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 18535201 18370846 17906972 |
| 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 |