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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
The human [[gene]] ''VKORC1'' encodes for the [[enzyme]], '''Vitamin K epOxide Reductase Complex (VKORC) subunit 1'''.<ref name="entrez">{{cite web | title = Entrez Gene: VKORC1 vitamin K epoxide reductase complex, subunit 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=79001| accessdate = }}</ref> This enzymatic protein complex is responsible for reducing vitamin K 2,3-epoxide to its active form, which is important for effective clotting. In humans, mutations in this gene can be associated with deficiencies in vitamin-K-dependent clotting factors.
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Vitamin K epoxide reductase complex, subunit 1
| HGNCid = 23663
| Symbol = VKORC1
| AltSymbols =; EDTP308; FLJ00289; IMAGE3455200; MGC2694; MST134; MST576; VKCFD2; VKOR
| OMIM = 608547
| ECnumber = 
| Homologene = 11416
| MGIid = 106442
| GeneAtlas_image1 = PBB_GE_VKORC1_217949_s_at_tn.png
| Function = {{GNF_GO|id=GO:0004252 |text = serine-type endopeptidase activity}} {{GNF_GO|id=GO:0016491 |text = oxidoreductase activity}} {{GNF_GO|id=GO:0047057 |text = vitamin-K-epoxide reductase (warfarin-sensitive) activity}}
| Component = {{GNF_GO|id=GO:0005783 |text = endoplasmic reticulum}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0006508 |text = proteolysis}} {{GNF_GO|id=GO:0042373 |text = vitamin K metabolic process}} {{GNF_GO|id=GO:0050820 |text = positive regulation of coagulation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 79001
    | Hs_Ensembl = ENSG00000167397
    | Hs_RefseqProtein = NP_076869
    | Hs_RefseqmRNA = NM_024006
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 16
    | Hs_GenLoc_start = 31009956
    | Hs_GenLoc_end = 31013551
    | Hs_Uniprot = Q9BQB6
    | Mm_EntrezGene = 27973
    | Mm_Ensembl = ENSMUSG00000030804
    | Mm_RefseqmRNA = NM_178600
    | Mm_RefseqProtein = NP_848715
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 7
    | Mm_GenLoc_start = 127684211
    | Mm_GenLoc_end = 127686765
    | Mm_Uniprot = Q9CRC0
  }}
}}
'''Vitamin K epoxide reductase complex, subunit 1''', also known as '''VKORC1''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: VKORC1 vitamin K epoxide reductase complex, subunit 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=79001| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
The VKORC1 protein is a key enzyme in the [[vitamin K]] cycle. VKORC1 is a 163 amino acid integral membrane protein associated with the endoplasmic reticulum and VKORC1 mRNA is broadly expressed in many different tissues. VKORC1 is involved in the vitamin K cycle by reduction of vitamin K epoxide to vitamin K, which is the rate-limiting step in the physiological process of vitamin K recycling.<ref>{{cite journal|last1=Ryan P.|first1=Owen|last2=Li|first2=Gong|last3=Hersh|first3=Sagreiya|last4=Teri E.|first4=Klein|last5=Russ B.|first5=Altmana|title=VKORC1 Pharmacogenomics Summary|journal=Pharmacogenet Genomics|date=October 2010|pages=642–644}}</ref> The availability of reduced vitamin K is of importance for activation vitamin K 2,3-epoxide. The reduction of vitamin K epoxide is then responsible for the carboxylation of glutamic acid residues in some blood-clotting proteins, including factor VII, factor IX, and factor X.<ref name="entrez" /><ref name="pmid18374188">{{cite journal | vauthors = Garcia AA, Reitsma PH | title = VKORC1 and the vitamin K cycle | journal = Vitamins and Hormones | volume = 78 | issue =  | pages = 23–33 | year = 2008 | pmid = 18374188 | doi = 10.1016/S0083-6729(07)00002-7 }}</ref> 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.<ref name="ReferenceA">{{cite journal | vauthors = Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Müller CR, Strom TM, Oldenburg J | title = Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2 | journal = Nature | volume = 427 | issue = 6974 | pages = 537–41 | date = February 2004 | pmid = 14765194 | doi = 10.1038/nature02214 }}</ref>
{{PBB_Summary
| section_title =  
| summary_text = Vitamin K is essential for blood clotting but must be enzymatically activated. This enzymatically activated form of vitamin K is a reduced form required for the carboxylation of glutamic acid residues in some blood-clotting proteins. The product of this gene encodes the enzyme that is responsible for reducing vitamin K 2,3-epoxide to the enzymatically activated form. Fatal bleeding can be caused by vitamin K deficiency and by the vitamin K antagonist warfarin, and it is the product of this gene that is sensitive to warfarin. In humans, mutations in this gene can be associated with deficiencies in vitamin-K-dependent clotting factors and, in humans and rats, with warfarin resistance. Two pseudogenes have been identified on chromosome 1 and the X chromosome. Two alternatively spliced transcripts encoding different isoforms have been described.<ref name="entrez">{{cite web | title = Entrez Gene: VKORC1 vitamin K epoxide reductase complex, subunit 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=79001| accessdate = }}</ref>
}}


==References==
Warfarin is a commonly prescribed oral anticoagulant, or blood thinner used to treat blood clots such as deep vein thrombosis and pulmonary embolism and to prevent stroke in people who have atrial fibrillation, valvular heart disease or artificial heart valves.<ref>{{cite web|title=Warfarin Sodium|url=https://www.drugs.com/monograph/warfarin-sodium.html|website=Drugs.com}}</ref> Warfarin causes inhibition on VKORC1 activities and leads to a reduced amount of vitamin K available to serve as a cofactor for clotting proteins.<ref name="ReferenceA"/> Inappropriate dosing of warfarin has been associated with a substantial risk of both major and minor hemorrhage. As the pharmacological target of warfarin, VKORC1 is considered a candidate gene for the variability in warfarin response. Previous researches have shown that the CYP2C9 genotype of patients also played a role in warfarin metabolism and response.<ref>{{cite journal | vauthors = Wadelius M, Sörlin K, Wallerman O, Karlsson J, Yue QY, Magnusson PK, Wadelius C, Melhus H | title = Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors | journal = The Pharmacogenomics Journal | volume = 4 | issue = 1 | pages = 40–8 | date = 2004 | pmid = 14676821 | doi = 10.1038/sj.tpj.6500220 }}</ref>
{{reflist|2}}
 
==Further reading==
== Gene ==
{{refbegin | 2}}
 
{{PBB_Further_reading
The human gene is located on chromosome 16. Two [[pseudogenes]] have been identified on chromosome 1 and the X chromosome.
| citations =  
 
*{{cite journal | author=Oldenburg J, Bevans CG, Müller CR, Watzka M |title=Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle. |journal=Antioxid. Redox Signal. |volume=8 |issue= 3-4 |pages= 347-53 |year= 2006 |pmid= 16677080 |doi= 10.1089/ars.2006.8.347 }}
== Clinical relevance ==
*{{cite journal  | author=Oldenburg J, Bevans CG, Fregin A, ''et al.'' |title=Current pharmacogenetic developments in oral anticoagulation therapy: the influence of variant VKORC1 and CYP2C9 alleles. |journal=Thromb. Haemost. |volume=98 |issue= 3 |pages= 570-8 |year= 2007 |pmid= 17849045 |doi=  }}
{{Unreferenced section|date=October 2016}}
*{{cite journal  | author=Oldenburg J, von Brederlow B, Fregin A, ''et al.'' |title=Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex. |journal=Thromb. Haemost. |volume=84 |issue= 6 |pages= 937-41 |year= 2001 |pmid= 11154138 |doi=  }}
In humans, mutations in this gene are associated with deficiencies in vitamin-K-dependent clotting factors. Fatal bleeding (internal) and [[hemorrhage]] can result from a decreased ability to form clots.
*{{cite journal  | author=Fregin A, Rost S, Wolz W, ''et al.'' |title=Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors to the centromeric region of chromosome 16. |journal=Blood |volume=100 |issue= 9 |pages= 3229-32 |year= 2002 |pmid= 12384421 |doi= 10.1182/blood-2002-03-0698 }}
 
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
The product of the ''VKORC1'' gene encodes a subunit of the enzyme that is responsible for reducing vitamin K 2,3-epoxide to the activated form, a reduction reaction. A genetic polymorphism on the ''VKORC1'' gene results in a patient having less available VKORC enzyme to complete this reaction.
*{{cite journal | author=Clark HF, Gurney AL, Abaya E, ''et al.'' |title=The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. |journal=Genome Res. |volume=13 |issue= 10 |pages= 2265-70 |year= 2003 |pmid= 12975309 |doi= 10.1101/gr.1293003 }}
 
*{{cite journal  | author=Rost S, Fregin A, Ivaskevicius V, ''et al.'' |title=Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. |journal=Nature |volume=427 |issue= 6974 |pages= 537-41 |year= 2004 |pmid= 14765194 |doi= 10.1038/nature02214 }}
Specifically, in the ''VKORC1'' 1639 (or 3673) [[single-nucleotide polymorphism]], the common ("wild-type") G allele is replaced by the A allele. People with an A allele (or the "A haplotype") produce less VKORC1 than do those with the G allele (or the "non-A haplotype"). The prevalence of these variants also varies by race, with 90%-95% of Asians, 37% of Caucasians and 14% of Africans carrying the A allele.<ref>{{cite journal | vauthors = Yamamura M, Yamamoto M | title = [Tumor metastasis and the fibrinolytic system] | journal = Gan to Kagaku Ryoho. Cancer & Chemotherapy | volume = 16 | issue = 4 Pt 2-1 | pages = 1246–54  | date = April 1989 | pmid = 2730023 | doi = 10.1161/CIRCULATIONAHA.107.704023 | pmc = 2730023 }}</ref> The end result is a decreased amount of clotting factors and therefore, a decreased ability to clot.<ref>{{cite journal | vauthors = Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, Lu MJ, Hung CR, Wei CY, Chen CH, Wu JY, Chen YT | title = A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity | journal = Human Molecular Genetics | volume = 14 | issue = 13 | pages = 1745–51  | date = July 2005 | pmid = 15888487 | doi = 10.1093/hmg/ddi180 }}</ref>
*{{cite journal | author=Li T, Chang CY, Jin DY, ''et al.'' |title=Identification of the gene for vitamin K epoxide reductase. |journal=Nature |volume=427 |issue= 6974 |pages= 541-4 |year= 2004 |pmid= 14765195 |doi= 10.1038/nature02254 }}
 
*{{cite journal | author=Goodstadt L, Ponting CP |title=Vitamin K epoxide reductase: homology, active site and catalytic mechanism. |journal=Trends Biochem. Sci. |volume=29 |issue= 6 |pages= 289-92 |year= 2004 |pmid= 15276181 |doi= 10.1016/j.tibs.2004.04.004 }}
[[Warfarin]] is an anticoagulant that opposes the procoagulant effect of vitamin K by inhibiting the VKORC enzyme. If these patients are prescribed warfarin for another medical purpose, they will require lower doses than usual because the patient is already deficient in VKORC. They may experience severe bleeding and bruising. Lower warfarin doses are needed to inhibit VKORC1 and to produce an anticoagulant effect in carriers of the A allele. Genetic testing can reveal the presence of the genetic mutation and [[FDA]] recommends lower starting doses of warfarin in these patients.
*{{cite journal | author=D'Andrea G, D'Ambrosio RL, Di Perna P, ''et al.'' |title=A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. |journal=Blood |volume=105 |issue= 2 |pages= 645-9 |year= 2005 |pmid= 15358623 |doi= 10.1182/blood-2004-06-2111 }}
 
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
Two alternatively spliced transcripts encoding different isoforms have also been described. These isoforms result in warfarin resistance (requiring higher doses) in humans and rats, because the amount and effectiveness of the VKORC enzyme has not changed, but the ability of warfarin to exert its effect (antagonize the enzyme) has changed. These isoform mutations are rare except in Ethiopian and certain Jewish populations.
*{{cite journal | author=Harrington DJ, Underwood S, Morse C, ''et al.'' |title=Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1. |journal=Thromb. Haemost. |volume=93 |issue= 1 |pages= 23-6 |year= 2005 |pmid= 15630486 |doi= 10.1267/THRO05010023 }}
 
*{{cite journal | author=Tie JK, Nicchitta C, von Heijne G, Stafford DW |title=Membrane topology mapping of vitamin K epoxide reductase by in vitro translation/cotranslocation. |journal=J. Biol. Chem. |volume=280 |issue= 16 |pages= 16410-6 |year= 2005 |pmid= 15716279 |doi= 10.1074/jbc.M500765200 }}
== References ==
*{{cite journal | author=Bodin L, Verstuyft C, Tregouet DA, ''et al.'' |title=Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. |journal=Blood |volume=106 |issue= 1 |pages= 135-40 |year= 2005 |pmid= 15790782 |doi= 10.1182/blood-2005-01-0341 }}
{{reflist|33em}}
*{{cite journal | author=Wadelius M, Chen LY, Downes K, ''et al.'' |title=Common VKORC1 and GGCX polymorphisms associated with warfarin dose. |journal=Pharmacogenomics J. |volume=5 |issue= 4 |pages= 262-70 |year= 2005 |pmid= 15883587 |doi= 10.1038/sj.tpj.6500313 }}
 
*{{cite journal | author=Rieder MJ, Reiner AP, Gage BF, ''et al.'' |title=Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. |journal=N. Engl. J. Med. |volume=352 |issue= 22 |pages= 2285-93 |year= 2005 |pmid= 15930419 |doi= 10.1056/NEJMoa044503 }}
== Further reading ==
*{{cite journal | author=Sconce EA, Khan TI, Wynne HA, ''et al.'' |title=The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. |journal=Blood |volume=106 |issue= 7 |pages= 2329-33 |year= 2005 |pmid= 15947090 |doi= 10.1182/blood-2005-03-1108 }}
{{refbegin|33em}}
*{{cite journal | author=Wang Y, Zhen Y, Shi Y, ''et al.'' |title=Vitamin k epoxide reductase: a protein involved in angiogenesis. |journal=Mol. Cancer Res. |volume=3 |issue= 6 |pages= 317-23 |year= 2005 |pmid= 15972850 |doi= 10.1158/1541-7786.MCR-04-0221 }}
* {{cite journal | vauthors = Oldenburg J, Bevans CG, Müller CR, Watzka M | title = Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle | journal = Antioxidants & Redox Signaling | volume = 8 | issue = 3-4 | pages = 347–53 | year = 2006 | pmid = 16677080 | doi = 10.1089/ars.2006.8.347 }}
*{{cite journal | author=Bodin L, Horellou MH, Flaujac C, ''et al.'' |title=A vitamin K epoxide reductase complex subunit-1 (VKORC1) mutation in a patient with vitamin K antagonist resistance. |journal=J. Thromb. Haemost. |volume=3 |issue= 7 |pages= 1533-5 |year= 2005 |pmid= 15978113 |doi= 10.1111/j.1538-7836.2005.01449.x }}
* {{cite journal | vauthors = Zhang J, Chen Z, Chen C | title = Impact of CYP2C9, VKORC1 and CYP4F2 genetic polymorphisms on maintenance warfarin dosage in Han-Chinese patients: A systematic review and meta-analysis | journal = Meta Gene | volume = 9 | issue = | pages = 197–209 | date = September 2016 | pmid = 27617219 | pmc = 5006145 | doi = 10.1016/j.mgene.2016.07.002 }}
*{{cite journal  | author=Wajih N, Hutson SM, Owen J, Wallin R |title=Increased production of functional recombinant human clotting factor IX by baby hamster kidney cells engineered to overexpress VKORC1, the vitamin K 2,3-epoxide-reducing enzyme of the vitamin K cycle. |journal=J. Biol. Chem. |volume=280 |issue= 36 |pages= 31603-7 |year= 2005 |pmid= 16030016 |doi= 10.1074/jbc.M505373200 }}
* {{cite journal | vauthors = Takeuchi M, Kobayashi T, Brandão LR, Ito S | title = Effect of CYP2C9, VKORC1, and CYP4F2 polymorphisms on warfarin maintenance dose in children aged less than 18 years: a protocol for systematic review and meta-analysis | journal = Systematic Reviews | volume = 5 | issue = 1 | pages = 105 | date = June 2016 | pmid = 27334984 | pmc = 4917995 | doi = 10.1186/s13643-016-0280-y }}
}}
* {{cite journal | vauthors = Zhang J, Tian L, Zhang Y, Shen J | title = The influence of VKORC1 gene polymorphism on warfarin maintenance dosage in pediatric patients: A systematic review and meta-analysis | journal = Thrombosis Research | volume = 136 | issue = 5 | pages = 955–61 | date = November 2015 | pmid = 26433837 | doi = 10.1016/j.thromres.2015.09.018 }}
* {{cite journal | vauthors = Czogalla KJ, Watzka M, Oldenburg J | title = Structural Modeling Insights into Human VKORC1 Phenotypes | journal = Nutrients | volume = 7 | issue = 8 | pages = 6837–51 | date = August 2015 | pmid = 26287237 | pmc = 4555152 | doi = 10.3390/nu7085313 }}
* {{cite journal | vauthors = Shaw K, Amstutz U, Kim RB, Lesko LJ, Turgeon J, Michaud V, Hwang S, Ito S, Ross C, Carleton BC | title = Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy | journal = Therapeutic Drug Monitoring | volume = 37 | issue = 4 | pages = 428–36 | date = August 2015 | pmid = 26186657 | doi = 10.1097/FTD.0000000000000192 }}
* {{cite journal | vauthors = Gaikwad T, Ghosh K, Shetty S | title = VKORC1 and CYP2C9 genotype distribution in Asian countries | journal = Thrombosis Research | volume = 134 | issue = 3 | pages = 537–44 | date = September 2014 | pmid = 24908449 | doi = 10.1016/j.thromres.2014.05.028 }}
* {{cite journal | vauthors = Yang J, Chen Y, Li X, Wei X, Chen X, Zhang L, Zhang Y, Xu Q, Wang H, Li Y, Lu C, Chen W, Zeng C, Yin T | title = Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis | journal = International Journal of Cardiology | volume = 168 | issue = 4 | pages = 4234–43 | date = October 2013 | pmid = 23932037 | doi = 10.1016/j.ijcard.2013.07.151 }}
* {{cite journal | vauthors = Fung E, Patsopoulos NA, Belknap SM, O'Rourke DJ, Robb JF, Anderson JL, Shworak NW, Moore JH | title = Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin | journal = Seminars in Thrombosis and Hemostasis | volume = 38 | issue = 8 | pages = 893–904 | date = November 2012 | pmid = 23041981 | pmc = 4134937 | doi = 10.1055/s-0032-1328891 }}
* {{cite journal | vauthors = Jorgensen AL, FitzGerald RJ, Oyee J, Pirmohamed M, Williamson PR | title = Influence of CYP2C9 and VKORC1 on patient response to warfarin: a systematic review and meta-analysis | journal = PLoS One | volume = 7 | issue = 8 | pages = e44064 | year = 2012 | pmid = 22952875 | pmc = 3430615 | doi = 10.1371/journal.pone.0044064 }}
* {{cite journal | vauthors = Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman RB | title = Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing | journal = Clinical Pharmacology and Therapeutics | volume = 90 | issue = 4 | pages = 625–9 | date = October 2011 | pmid = 21900891 | pmc = 3187550 | doi = 10.1038/clpt.2011.185 }}
{{refend}}
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Latest revision as of 09:14, 10 January 2019

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
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View/Edit Human

The human gene VKORC1 encodes for the enzyme, Vitamin K epOxide Reductase Complex (VKORC) subunit 1.[1] This enzymatic protein complex is responsible for reducing vitamin K 2,3-epoxide to its active form, which is important for effective clotting. In humans, mutations in this gene can be associated with deficiencies in vitamin-K-dependent clotting factors.

Function

The VKORC1 protein is a key enzyme in the vitamin K cycle. VKORC1 is a 163 amino acid integral membrane protein associated with the endoplasmic reticulum and VKORC1 mRNA is broadly expressed in many different tissues. VKORC1 is involved in the vitamin K cycle by reduction of vitamin K epoxide to vitamin K, which is the rate-limiting step in the physiological process of vitamin K recycling.[2] The availability of reduced vitamin K is of importance for activation vitamin K 2,3-epoxide. The reduction of vitamin K epoxide is then responsible for the carboxylation of glutamic acid residues in some blood-clotting proteins, including factor VII, factor IX, and factor X.[1][3] 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.[4]

Warfarin is a commonly prescribed oral anticoagulant, or blood thinner used to treat blood clots such as deep vein thrombosis and pulmonary embolism and to prevent stroke in people who have atrial fibrillation, valvular heart disease or artificial heart valves.[5] Warfarin causes inhibition on VKORC1 activities and leads to a reduced amount of vitamin K available to serve as a cofactor for clotting proteins.[4] Inappropriate dosing of warfarin has been associated with a substantial risk of both major and minor hemorrhage. As the pharmacological target of warfarin, VKORC1 is considered a candidate gene for the variability in warfarin response. Previous researches have shown that the CYP2C9 genotype of patients also played a role in warfarin metabolism and response.[6]

Gene

The human gene is located on chromosome 16. Two pseudogenes have been identified on chromosome 1 and the X chromosome.

Clinical relevance

In humans, mutations in this gene are associated with deficiencies in vitamin-K-dependent clotting factors. Fatal bleeding (internal) and hemorrhage can result from a decreased ability to form clots.

The product of the VKORC1 gene encodes a subunit of the enzyme that is responsible for reducing vitamin K 2,3-epoxide to the activated form, a reduction reaction. A genetic polymorphism on the VKORC1 gene results in a patient having less available VKORC enzyme to complete this reaction.

Specifically, in the VKORC1 1639 (or 3673) single-nucleotide polymorphism, the common ("wild-type") G allele is replaced by the A allele. People with an A allele (or the "A haplotype") produce less VKORC1 than do those with the G allele (or the "non-A haplotype"). The prevalence of these variants also varies by race, with 90%-95% of Asians, 37% of Caucasians and 14% of Africans carrying the A allele.[7] The end result is a decreased amount of clotting factors and therefore, a decreased ability to clot.[8]

Warfarin is an anticoagulant that opposes the procoagulant effect of vitamin K by inhibiting the VKORC enzyme. If these patients are prescribed warfarin for another medical purpose, they will require lower doses than usual because the patient is already deficient in VKORC. They may experience severe bleeding and bruising. Lower warfarin doses are needed to inhibit VKORC1 and to produce an anticoagulant effect in carriers of the A allele. Genetic testing can reveal the presence of the genetic mutation and FDA recommends lower starting doses of warfarin in these patients.

Two alternatively spliced transcripts encoding different isoforms have also been described. These isoforms result in warfarin resistance (requiring higher doses) in humans and rats, because the amount and effectiveness of the VKORC enzyme has not changed, but the ability of warfarin to exert its effect (antagonize the enzyme) has changed. These isoform mutations are rare except in Ethiopian and certain Jewish populations.

References

  1. ↑ 1.0 1.1 "Entrez Gene: VKORC1 vitamin K epoxide reductase complex, subunit 1".
  2. ↑ Ryan P., Owen; Li, Gong; Hersh, Sagreiya; Teri E., Klein; Russ B., Altmana (October 2010). "VKORC1 Pharmacogenomics Summary". Pharmacogenet Genomics: 642–644.
  3. ↑ Garcia AA, Reitsma PH (2008). "VKORC1 and the vitamin K cycle". Vitamins and Hormones. 78: 23–33. doi:10.1016/S0083-6729(07)00002-7. PMID 18374188.
  4. ↑ 4.0 4.1 Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Müller CR, Strom TM, Oldenburg J (February 2004). "Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2". Nature. 427 (6974): 537–41. doi:10.1038/nature02214. PMID 14765194.
  5. ↑ "Warfarin Sodium". Drugs.com.
  6. ↑ Wadelius M, Sörlin K, Wallerman O, Karlsson J, Yue QY, Magnusson PK, Wadelius C, Melhus H (2004). "Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors". The Pharmacogenomics Journal. 4 (1): 40–8. doi:10.1038/sj.tpj.6500220. PMID 14676821.
  7. ↑ Yamamura M, Yamamoto M (April 1989). "[Tumor metastasis and the fibrinolytic system]". Gan to Kagaku Ryoho. Cancer & Chemotherapy. 16 (4 Pt 2-1): 1246–54. doi:10.1161/CIRCULATIONAHA.107.704023. PMC 2730023. PMID 2730023.
  8. ↑ Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, Lu MJ, Hung CR, Wei CY, Chen CH, Wu JY, Chen YT (July 2005). "A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity". Human Molecular Genetics. 14 (13): 1745–51. doi:10.1093/hmg/ddi180. PMID 15888487.

Further reading

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