VKORC1

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.{{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}} 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.{{cite book | vauthors = Garcia AA, Reitsma PH | chapter = VKORC1 and the vitamin K cycle | volume = 78 | pages = 23–33 | year = 2008 | pmid = 18374188 | doi = 10.1016/S0083-6729(07)00002-7 | series = Vitamins & Hormones | isbn = 9780123741134 | title = Vitamin K }} 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.{{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 = 537–541 | date = February 2004 | pmid = 14765194 | doi = 10.1038/nature02214 | s2cid = 4424197 | bibcode = 2004Natur.427..537R }}

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.{{cite web|title=Warfarin Sodium|url=https://www.drugs.com/monograph/warfarin-sodium.html|website=Drugs.com}} Warfarin causes inhibition on VKORC1 activities and leads to a reduced amount of vitamin K available to serve as a cofactor for clotting proteins. 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.{{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 = 40–48 | date = 2004 | pmid = 14676821 | doi = 10.1038/sj.tpj.6500220 | doi-access = free }}

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

{{Unreferenced section|date=October 2016}}

In humans, mutations in this gene are associated with deficiencies in vitamin-K-dependent clotting factors.{{cite journal | vauthors = Perrone S, Raso S, Napolitano M | title = Clinical, Laboratory, and Molecular Characteristics of Inherited Vitamin K-Dependent Coagulation Factors Deficiency | journal = Seminars in Thrombosis and Hemostasis | volume = 51 | issue = 2 | pages = 170–179 | date = March 2025 | pmid = 39496305 | doi = 10.1055/s-0044-1792031 }} 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 genetic polymorphism on the VKORC1 gene results alter substrate stereo-selectivity (contributing to warfarin resistance) and VKORC1 activity (such as warfarin metabolism).{{Citation |last1=Garcia |first1=Andrea A. |title=VKORC1 and the Vitamin K Cycle |date=2008-01-01 |journal=Vitamins & Hormones |volume=78 |pages=23–33 |url=https://linkinghub.elsevier.com/retrieve/pii/S0083672907000027 |access-date=2025-03-10 |publisher=Academic Press |doi=10.1016/s0083-6729(07)00002-7 |last2=Reitsma |first2=Pieter H.|pmid=18374188 |isbn=978-0-12-374113-4 }}

Warfarin is an anticoagulant that opposes the procoagulant effect of vitamin K by inhibiting the VKORC enzyme. A patient's VKORC1 genotype will dictate the optimal dosage of warfarin as mutations in the VKORC1 gene can be associated with decreased enzymatic activity resulting in higher warfarin concentrations.{{Citation |last=Dean |first=Laura |title=Warfarin Therapy and VKORC1 and CYP Genotype |date=2012 |work=Medical Genetics Summaries |editor-last=Pratt |editor-first=Victoria M. |url=https://pubmed.ncbi.nlm.nih.gov/28520347/ |access-date=2025-03-11 |place=Bethesda (MD) |publisher=National Center for Biotechnology Information (US) |pmid=28520347 |editor2-last=Scott |editor2-first=Stuart A. |editor3-last=Pirmohamed |editor3-first=Munir |editor4-last=Esquivel |editor4-first=Bernard}} Genetic testing can reveal the presence of the genetic mutation and FDA recommends lower starting doses of warfarin in these patients.

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.{{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 = 1246–1254 | date = April 1989 | pmid = 2730023 }} The end result is a decreased amount of clotting factors and therefore, a decreased ability to clot.{{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 = 1745–1751 | date = July 2005 | pmid = 15888487 | doi = 10.1093/hmg/ddi180 | doi-access = free }} These isoform mutations are rare except in Ethiopian and Ashkenazi Jewish populations.{{cite journal | vauthors = Sominsky S, Korostishevsky M, Kurnik D, Aklillu E, Cohen Y, Ken-Dror G, Loebstein R, Halkin H, Gak E | title = The VKORC1 Asp36Tyr variant and VKORC1 haplotype diversity in Ashkenazi and Ethiopian populations | journal = Journal of Applied Genetics | volume = 55 | issue = 2 | pages = 163–171 | date = May 2014 | pmid = 24425227 | doi = 10.1007/s13353-013-0189-2 }}

{{reflist|33em}}

{{refbegin|33em}}

• {{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 = 347–353 | year = 2006 | pmid = 16677080 | doi = 10.1089/ars.2006.8.347 }}
• {{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 | pages = 197–209 | date = September 2016 | pmid = 27617219 | pmc = 5006145 | doi = 10.1016/j.mgene.2016.07.002 }}
• {{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 | doi-access = free }}
• {{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 = 955–961 | 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 = 6837–6851 | date = August 2015 | pmid = 26287237 | pmc = 4555152 | doi = 10.3390/nu7085313 | doi-access = free }}
• {{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 = 428–436 | date = August 2015 | pmid = 26186657 | doi = 10.1097/FTD.0000000000000192 | s2cid = 20381277 | url = https://boris.unibe.ch/70720/1/00007691-201508000-00002.pdf }}
• {{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 = 537–544 | 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 = 4234–4243 | 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 | bibcode = 2012PLoSO...744064J | doi-access = free }}
• {{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 = 625–629 | date = October 2011 | pmid = 21900891 | pmc = 3187550 | doi = 10.1038/clpt.2011.185 }}

{{refend}}