The human
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
''VKORC1'' encodes for the
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
, Vitamin K epOxide Reductase Complex (VKORC) subunit 1.
This enzymatic protein complex is responsible for reducing vitamin K 2,3-epoxide to its active form, which is important for effective
clotting
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
(
coagulation
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
). 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
Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...
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. 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.
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.
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. 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
Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...
genotype of patients also played a role in warfarin metabolism and response.
Gene
The human gene is located on chromosome 16. Two
pseudogenes
Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Most arise as superfluous copies of functional genes, either directly by DNA duplication or indirectly by reverse transcription of an mRNA transcript. Pseudogenes are ...
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
Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
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
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently lar ...
, 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. The end result is a decreased amount of clotting factors and therefore, a decreased ability to clot.
Warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent strok ...
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
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
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
Further reading
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