Vitamin K epOxide Reductase Complex subunit 1 (VKORC) is an enzyme that in humans is encoded by the VKORC1gene.[5] This enzymatic protein complex is responsible for reducing vitamin K 2,3-epoxide to its active form, which is important for effective clotting (coagulation).[6] In humans, mutations in this gene can be associated with deficiencies in vitamin-K-dependent clotting factors.[7]
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.[8] 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.[5][9] 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.[10]
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.[11] Warfarin causes inhibition on VKORC1 activities and leads to a reduced amount of vitamin K available to serve as a cofactor for clotting proteins.[10] 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.[12]
Gene
The human gene is located on chromosome 16. Two pseudogenes have been identified on chromosome 1 and the X chromosome.
In humans, mutations in this gene are associated with deficiencies in vitamin-K-dependent clotting factors.[13] 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).[14]
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.[15]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.[16] The end result is a decreased amount of clotting factors and therefore, a decreased ability to clot.[17] These isoform mutations are rare except in Ethiopian and Ashkenazi Jewish populations.[18]
↑ Dean L (2012), Pratt VM, Scott SA, Pirmohamed M, Esquivel B (eds.), "Warfarin Therapy and VKORC1 and CYP Genotype", Medical Genetics Summaries, Bethesda (MD): National Center for Biotechnology Information (US), PMID28520347
↑ Yamamura M, Yamamoto M (April 1989). "[Tumor metastasis and the fibrinolytic system]". Gan to Kagaku Ryoho. Cancer & Chemotherapy. 16 (4 Pt 2-1): 1246–1254. PMID2730023.
↑ Sominsky S, Korostishevsky M, Kurnik D, Aklillu E, Cohen Y, Ken-Dror G, etal. (May 2014). "The VKORC1 Asp36Tyr variant and VKORC1 haplotype diversity in Ashkenazi and Ethiopian populations". Journal of Applied Genetics. 55 (2): 163–171. doi:10.1007/s13353-013-0189-2. PMID24425227.
Further reading
Oldenburg J, Bevans CG, Müller CR, Watzka M (2006). "Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle". Antioxidants & Redox Signaling. 8 (3–4): 347–353. doi:10.1089/ars.2006.8.347. PMID16677080.
Zhang J, Tian L, Zhang Y, Shen J (November 2015). "The influence of VKORC1 gene polymorphism on warfarin maintenance dosage in pediatric patients: A systematic review and meta-analysis". Thrombosis Research. 136 (5): 955–961. doi:10.1016/j.thromres.2015.09.018. PMID26433837.
Gaikwad T, Ghosh K, Shetty S (September 2014). "VKORC1 and CYP2C9 genotype distribution in Asian countries". Thrombosis Research. 134 (3): 537–544. doi:10.1016/j.thromres.2014.05.028. PMID24908449.
Yang J, Chen Y, Li X, Wei X, Chen X, Zhang L, etal. (October 2013). "Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis". International Journal of Cardiology. 168 (4): 4234–4243. doi:10.1016/j.ijcard.2013.07.151. PMID23932037.
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