Variant: VIP

rs9923231 in BCKDK,PRSS53,VKORC1

Alleles (on + chromosomal strand)
  1. C > A
  2. C > G
  3. C > T

Clinical Annotations

PharmGKB clinical annotations provide information about variant-drug pairs based on a summary of the individual variant annotations in the database. Therefore, each clinical annotation could represent information from a single paper or multiple papers. The rating system used to assign "Strength of Evidence" levels is described here. The individual variant annotations, including the PMID for each supporting PubMed publication, can be found on the "PGx Research" tab above.

This information is manually curated by PharmGKB. All alleles are displayed on the positive chromosomal strand.

Variant Annotations

PharmGKB variant annotations provide information about variant-drug pairs or variant-disease pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.

Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.

List of all variant annotations for this variant.

There are 205 annotations for this variant. Register or sign in to see them.

Variant Overview

PharmGKB Accession ID: PA166155091
Type: SNP
Class: 5' Flanking
Clinical Significance: Not reported
Genes: BCKDK, PRSS53, VKORC1

Primary Locus

Name:
[GRCh37]chr16:31107689
Location:
NC_000016.9 31107689 - 31107689
  • C > A
  • C > G
  • C > T
Sequence Type:
genomic
Source:
dbSnp

Alternate Locations

None specified

Variant Frequencies

Population variation data is sourced from HapMap 3.

Alternate Names

  • NC_000016.10:g.31096368C=
  • NC_000016.10:g.31096368C>T
  • NC_000016.9:g.31107689C=
  • NC_000016.9:g.31107689C>T
  • NG_011564.1:g.3588G=
  • NG_011564.1:g.3588G>A
  • NM_001311311.1:c.-1639G=
  • NM_001311311.1:c.-1639G>A
  • NM_024006.5:c.-1639G=
  • NM_024006.5:c.-1639G>A
  • NM_206824.2:c.-1639G=
  • NM_206824.2:c.-1639G>A
  • XM_005255568.1:c.-1639G=
  • XM_005255568.1:c.-1639G>A
  • XM_011545943.1:c.-1639G=
  • XM_011545943.1:c.-1639G>A
  • XM_011545944.1:c.-1252G=
  • XM_011545944.1:c.-1252G>A
  • XM_011545945.1:c.-1252G=
  • XM_011545945.1:c.-1252G>A
  • XR_243303.1:n.-990G=
  • XR_243303.1:n.-990G>A
  • XR_950848.1:n.-31G=
  • XR_950848.1:n.-31G>A
  • rs117572127
  • rs17878363
  • rs60511154

VIP Variant in VKORC1

Note: The VKORC1 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations and haplotypes may differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.


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 [Article: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 [Article: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.

PopulationNAllele Frequency of ""A""PMID
Japanese9393%[Article:17049586]
Swedish18139%[Article:17048007]
Japanese (anticoagulated)26089%[Article:16890578]
Japanese (healthy)22894%[Article:16890578]
Spanish (anticoagulated)10552%[Article:16611310]
Florida VA hospital35634%[Article:16580898]
German20042%[Article:16270629]
English29747%[Article:15947090]
Caucasian9237%[Article:15888487]
Chinese9591%[Article:15888487]
Chinese on warfarin10488%[Article:15888487]
Swedish20139%[Article:15883587]
French26342%[Article:15790782]
Japanese82891%[Article: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 [Article: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 [Article: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 [Article:18305455].

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

Citation VKORC1 pharmacogenomics summary. Pharmacogenetics and genomics. 2010. Owen Ryan P, Gong Li, Sagreiya Hersh, Klein Teri E, Altman Russ B. PubMed
Key Publications:
Drugs / Other Molecules

Appendix

gp positionchr16:31015190(hg18)

Connected Chemicals and Chemical Classes

Evidence Drug

Connected Diseases

Evidence Disease

Related Publications

Evidence Publication