Important Variant Information for VKORC1

Citation: VKORC1 Pharmacogenomics Summary. Owen RP, Gong L, Sagreiya H, Klein TE, Altman RB. Pharmacogenet Genomics. 2009 Nov 24. Epub ahead of print. PMID:19940803

PharmGKB VIP Submitted by: Ryan Owen, Li Gong (PharmGKB)
PharmGKB VIP Reviewed by: Reviewed
PharmGKB VIP Submission date: January 29th, 2007
PharmGKB VIP Updated: October 30th, 2008

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VKORC1 Overview
Important Haplotype Information for VKORC1
All Annotated Genes

There are Three Important Variants for VKORC1.

VKORC1: G3673A (rs9923231)
VKORC1: C6484T (rs9934438)
VKORC1: G9041A (rs7294)

1. VKORC1: G3673A (-1639 G>A) on AY587020 (rs9923231)

Gene HGNC Name:

VKORC1

Indicate if this variant should be linked to a haplotype worksheet:

VKORC1*2

Variant Summary:

G3673A, or -1639 G>A as it is commonly called in the literature, is a polymorphism in the promoter region of VKORC1 that is believed to be the causative SNP for the low dose phenotype. This polymorphism alters a VKORC1 transcription factor binding site and luciferase assays show that the activity of the G allele was increased by 44% over the activity of the A allele [15888487]. Additionally, analysis of VKORC1 mRNA isolated from human liver samples showed that carriers of the A allele at position 3673 had reduced amounts of VKORC1 mRNA [15930419]. The changes in gene expression presumably lead to fewer functional copies of the mature VKORC1 protein, which is the rate limiting enzyme in the vitamin K cycle.

The G3673A or -1639 G>A variant has been genotyped in a number of different populations (see Table). This polymorphism
has pronounced differences in its frequency by ethnic group as it is actually the majority allele (around 90%) in Asian populations and appears to explain the lower warfarin dose requirement for individuals of Asian descent. This variant is also quite common in Caucasians, with an allele frequency typically around 40% in predominantly Caucasian populations.

Population	N	Allele Frequency of "A"	PMID
Japanese	93	93%	17049586
Swedish	181	39%	17048007
Japanese (anticoagulated)	260	89%	16890578
Japanese (healthy)	228	94%	16890578
Spanish (anticoagulated)	105	52%	16611310
Florida VA hospital	356	34%	16580898
German	200	42%	16270629
English	297	47%	15947090
Caucasian	92	37%	15888487
Chinese	95	91%	15888487
Chinese on warfarin	104	88%	15888487
Swedish	201	39%	15883587
French	263	42%	15790782
Japanese	828	91%	16432637

The universal finding with this variant is that carriers of the A allele respond to a lower initial dose of warfarin than do carriers of the G allele (see above refs). It should be noted that this effect is also additive [15930419], and that heterozygotes respond to an intermediate warfarin dose, and homozygous carriers of the A allele respond to the lowest dose of warfarin, and are at the highest risk for warfarin-related adverse events [15930419]. Recent clinical studies showed that individuals with the A allele require a 28% decrease in the therapeutic warfarin dose per allele and this SNP is the most important predictor of initiation dose for warfarin [18305455].

It is estimated that VKORC1 genotype accounts for 15-30% of the variability in warfarin response [17161452 17048007 16890578 16141794 15930419], which makes VKORC1 genotype the single biggest predictor for warfarin dosing [16270629]. The G3673A or -1639 G>A SNP is believed to be the causative SNP for the reduced warfarin dosing requirements [15888487], although many scientists genotype for other SNPs in VKORC1 that are in perfect or near perfect linkage disequilibrium with G3673A such as C6484T (see below).

Key PubMed IDs:

15888487 15930419 17049586 17048007 16890578
16611310 16580898 16270629 15947090 15883587 15790782
16432637 17161452 16141794 18305455

Genomic Variant & GenBank ID:

G3673A (-1639 G>A) on AY587020

mRNA Variant & GenBank ID:

N/A

Protein Variant & GenBank ID:

N/A

dbSNP rs#:

rs9923231 sometimes also appears in the literature as rs17878363

GoldenPath Position:

chr16:31015190;(hg18)

Drugs/Substrates:

Warfarin, coumarin, acenocoumarol

Phenotypes/Diseases:

Atrial Fibrillation, Coagulation Protein Disorders, Hemorrhage, Vascular Diseases

Please list any phenotype datasets that are of particular relevance to this variant:

WUSTL warfarin dosing data, group A

2. VKORC1: C6484T (1173C>T) on AY587020 (rs9934438)

Gene HGNC Name:

VKORC1

Indicate if this variant should be linked to a haplotype worksheet:

VKORC1*2

Variant Summary:

C6484T, or 1173C>T, is a SNP in the first intron of VKORC1, and is in near perfect linkage disequilibrium with G3673A. C6484T was the first SNP associated with the low dose warfarin phenotype [15358623], and although it is believed to be functionally inert, C6484T is still very commonly used as a marker SNP for G3673A and haplotypes containing this variant. Below is a table that shows the frequency of C6484T in several different populations. Comparison of this table with that of the frequencies in G3673A will reveal that the two polymorphisms are very closely linked. Some of the studies genotyped both SNPs with similar if not identical frequency results.

Population	N	Allele Frequency of "T"	PMID
Japanese	93	93%	17049586
Swedish	169	38%	17048007
Japanese	31	91%	17031720
Japanese (anticoagulated)	250	89%	16890578
Japanese (healthy)	228	94%	16890578
Swedish (anticoagulated)	92	36%	16879214
Swedish (healthy)	180	39%	16879214
Dutch	231	41%	16815313
Han Chinese	390	92%	16700826
Slovenian	165	44%	16676068
Caucasians (anticoagulated)	93	45%	16611750
African Americans	64	9%	16424822
Caucasians	115	42%	16424822
Japanese	64	89%	16424822
Germans	200	42%	16270629
Dutch (bleeders)	109	45%	16201835
Dutch (non-bleeders)	216	36%	16201835
Swedish	201	39%	15883587
French	263	42%	15790782
Italian	147	40%	15358623
Utah (anticoagulated)	213	38%	17111199
Japanese	828	91%	16432637

Key PubMed IDs:

15358623 17049586 17048007 17031720 16890578 16879214 16815313 16700826 16676068 16611750 16424822 16270629 16201835 15883587 15790782 17111199 16432637

Genomic Variant & GenBank ID:

C6484T (1173 C>T) on AY587020

mRNA Variant & GenBank ID:

N/A

Protein Variant & GenBank ID:

N/A

dbSNP rs#:

rs9934438

GoldenPath Position:

chr16:31012379;(hg18)

Drugs/Substrates:

Warfarin, coumarin, acenocoumarol

Phenotypes/Diseases:

Atrial Fibrillation, Coagulation Protein Disorders, Hemorrhage, Vascular Diseases

Please list any phenotype datasets that are of particular relevance to this variant:

WUSTL warfarin dosing data, group A

3. VKORC1: G9041A (3730 G>A) on AY587020 (rs7294)

Gene HGNC Name:

VKORC1

Indicate if this variant should be linked to a haplotype worksheet:

VKORC1*3

Variant Summary:

G9041A, or 3730 G>A, is a SNP in the 3'UTR of VKORC1, and it may be associated with a higher warfarin dose [15358623 16676068]. It is generally not found in the same haplotypes as G3673A or C6484T. Below is a table of the frequency of the A allele at postion 9041 in different populations, and also the number of patients in the study and the PMID number for the study.

Population	N	Allele Frequency of "A"	PMID
Japanese	93	8%	17049586
Swedish	38	38%	17048007
Japanese	9	9%	17031720
Swedish (anticoagulated)	39	39%	16879214
Swedish (healthy)	37	37%	16879214
Slovenian	36	36%	16676068
Caucasian (anticoagulated)	36	36	16611750
Florida VA hospital	39	39%	16580898
African Americans	52	52%	16424822
Caucasians	37	37%	16424822
Japanese	17	17%	16424822
Germans	38	38%	16270629
Swedish	39	39%	15883587
Italian	35	35%	15358623
Japanese	9	9%	16432637

Key PubMed IDs:

15358623 16676068 17049586 17048007 17031720 16879214 16611750 16580898 16424822 16270629 15883587 15358623 16432637

Genomic Variant & GenBank ID:

G9041A (3730 G>A) on AY587020

mRNA Variant & GenBank ID:

N/A

Protein Variant & GenBank ID:

N/A

dbSNP rs#:

rs7294

GoldenPath Position:

chr16:31009822;(hg18)

Drugs/Substrates:

Warfarin, coumarin, acenocoumarol

Phenotypes/Diseases:

Atrial Fibrillation, Coagulation Protein Disorders, Hemorrhage, Vascular Diseases

Please list any phenotype datasets that are of particular relevance to this variant:

WUSTL warfarin dosing data, group A

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