Oct 14, 2023
Vitamin K is a fat-soluble vitamin that is necessary for the function of many proteins involved in blood clotting. Vitamin K is a type of vitamin that is naturally found in many foods of plant and animal origin. Phylloquinone (K1) is the form found in plants, and menaquinone (K2) is the form found in animals. Menadione (K3) is its synthetically produced form. Dark green leafy vegetables are good sources of vitamin K (Namıduru, S. E., & Tarakçıoğlu, M. 2011).
Vitamin K and VKORC1 Gene Relationship
Coumarin anticoagulants act by inhibiting the vitamin K epoxide reductase (VKOR) enzyme, which regenerates vitamin K during activation of clotting factors, and the VKORC1 gene encodes the coumarin anticoagulant enzyme vitamin K epoxide reductase (Daly AK., 2013). Therefore, the VKORC1 gene is a target of coumarin-based anticoagulants such as warfarin, a widely prescribed therapy for the prevention of thromboembolic diseases. VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes have been consistently associated with the dose of warfarin required for therapeutic anticoagulation (Wang, D. et al., 2008).
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VITAMIN K |
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Genes |
rs |
Minor Allel |
Minor Allel Description |
Reference |
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VKORC1 |
rs9923231 |
T |
High for reduced enzyme activity and need for low dose warfarin relative susceptibility. |
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|
VKORC1 |
rs9934438 |
A |
High for reduced enzyme activity and need for low dose warfarin relative susceptibility. |
(Enström C. et al., 2008; D'Andrea G. et al., 2004)
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The table above contains genes and polymorphisms that play a role in vitamin K metabolism. Carriers of the rs9923231 (T) allele have been shown to require significantly reduced doses of warfarin (Rieder MJ. et al., 2005). These alleles may differ in some studies. All patients sensitive to warfarin were homozygous for AA at position -1639, which showed a relationship with warfarin sensitivity. It has been demonstrated that patients with the AA genotype have the lowest dose requirements, heterozygous AG have medium dose requirements, and homozygous GG genotype require the highest dose (Yuan, H. et al., 2005).
SNP rs9934438 (1173C>T), carriers of the TT genotype have been shown to require a significantly lower dose of warfarin than carriers of the CC genotype or patients with the CT genotype (Enström C. et al., 2008; D'Andrea G. et al., 2004).
REFERENCES
D'Andrea G, D'Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, Grandone E, Margaglione M. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood. 2005 Jan 15;105(2):645-9. doi: 10.1182/blood-2004-06-2111. Epub 2004 Sep 9. PMID: 15358623.
Daly AK. Optimal dosing of warfarin and other coumarin anticoagulants: the role of genetic polymorphisms. Arch Toxicol. 2013 Mar;87(3):407-20. doi: 10.1007/s00204-013-1013-9. Epub 2013 Feb 2. PMID: 23376975.
Enström C, Osman A, Lindahl TL. A genotyping method for VKORC1 1173C > T by Pyrosequencing technology. Scand J Clin Lab Invest. 2008;68(5):427-30. doi: 10.1080/00365510701810621. PMID: 19172700.
Namıduru, S. E., & Tarakçıoğlu, M. (2011). K vitamini ve osteoporoz. Gaziantep Medical Journal, 17(1), 1-7.
Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. 2005 Jun 2;352(22):2285-93. doi: 10.1056/NEJMoa044503. PMID: 15930419.
Wang, D., Chen, H., Momary, K. M., Cavallari, L. H., Johnson, J. A., & Sadée, W. (2008). Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement. Blood, 112(4), 1013-1021. https://doi.org/10.1182/blood-2008-03-144899
Yuan, H., Chen, J., Lee, M. T., Wung, J., Chen, Y., Charng, M., Lu, M., Hung, C., Wei, C., Chen, C., Wu, J., & Chen, Y. (2005). A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Human Molecular Genetics, 14(13), 1745-1751. https://doi.org/10.1093/hmg/ddi180