Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Vitamin K epoxide reductase complex, subunit 1

The translation product of the VKORC1 gene is involved in vitamin K activation. While some mutations cause a combined deficiency of vitamin-K dependent coagulation factors, polymorphisms in this gene's coding region and its promotor have been associated with decreased response or increased sensitivity to vitamin K antagonists.

Epidemiology

The G allele at position -1639 is more common in Caucasian while the A allel is more frequent in Chinese, which fully explains differences in warfarin susceptibility among these two populations. Some other more downstream polymorphisms, that also have been associated with varying therapeutic doses of vitamin K antagonists, appear to be in linkage disequilibrium.

AA AG GG
Caucasian 14,2% 46,7% 39,1%
Chinese 79,8% 18,3% 1,8%[Error: Macro 'ref' doesn't exist]

Gene Structure

The gene spans 4,1kb on chromosome 16 (16p11.2). The two splice variants consist of up to 3 exons. The promotor contains an E-Box at position -1644. A single nucleotide polymorphism, -1639G>A is located in the E-Box' consensus sequence (CANNTG). In various experiments, it could be demonstrated that the -1639G allele is associated with a more prominent expression of the gene, which ensues increased vitamin K activation and restraint effect of vitamin K antagonists.

Genetests:

Clinic Method Carrier testing
Turnaround 5
Specimen type genomic DNA
Clinic Method Genomic sequencing of the entire coding region
Turnaround 5
Specimen type genomic DNA
Clinic Method Target mutation analysis
Turnaround 5
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25
Specimen type genomic DNA

Related Diseases:

Combined deficiency of vitamin K-dependent clotting factors type 2
VKORC1
Coumarin resistance
CYP2A6
CYP2C9
CYP4F2
VKORC1

References:

1.

D'Andrea G et al. (2005) A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin.

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2.

Wajih N et al. (2005) Engineering of a recombinant vitamin K-dependent gamma-carboxylation system with enhanced gamma-carboxyglutamic acid forming capacity: evidence for a functional CXXC redox center in the system.

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3.

Bodin L et al. (2005) Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity.

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4.

Pelz HJ et al. (2005) The genetic basis of resistance to anticoagulants in rodents.

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5.

Yuan HY et al. (2005) A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity.

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6.

Rieder MJ et al. (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.

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7.

Sconce EA et al. (2005) The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen.

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8.

Wajih N et al. (2005) 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.

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9.

Reitsma PH et al. (2005) A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk.

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10.

Wadelius M et al. (2007) Association of warfarin dose with genes involved in its action and metabolism.

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11.

Gage BF et al. (2006) Pharmacogenetics-based coumarin therapy.

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Update: Sept. 26, 2018