Scientific background:

Summary: 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.

Gene: 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.

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%

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Hotspot sequencing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	Only in the region of interest, known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Carrier testing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	The test is only specific about the mutation already known in this kindred.

Literature: 

Gage BF et al. (2006) Pharmacogenetics-based coumarin therapy.
Wadelius M et al. (2007) Association of warfarin dose with genes involved in its action and metabolism.
Reitsma PH et al. (2005) A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk.
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.
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.
Rieder MJ et al. (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.
Yuan HY et al. (2005) A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity.
Pelz HJ et al. (2005) The genetic basis of resistance to anticoagulants in rodents.
Bodin L et al. (2005) Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity.
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.
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.
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.