HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gage, B. F. Articles by Eby, C. S. Search for Related Content PubMed Articles by Gage, B. F. Articles by Eby, C. S.

PharmGKB Submission Update

PharmGKB Submission Update: VIII. PBAT Submission of Genetic Variation in VKORC1 to the PharmGKB Network

Department of Medicine, Washington University, St. Louis, Missouri

Category: genotype

Project: Pharmacogenetics, Biomarkers, and Antithrombotic Therapy

Table 1 provides the HUGO Gene Nomenclature Committee (HGNC) symbol, PharmGKB submission URL, submission date, and release date. Table 2 provides the HGNC symbol, HGNC name, synonym, GenBank accession numbers, and locus ID.

Pharmacogenetic Significance: VKORC1 haplotype groups, defined by genotype at a novel loci in the region upstream of the transcription start site of the gene, can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and explain 21 to 25% of the variability in the therapeutic warfarin dose.

Pharmacological Significance: Warfarin is an effective anticoagulant that acts by antagonism of vitamin K to prevent -carboxylation of blood-clotting proteins (factors II, VII, IX, and X). The therapeutic index for warfarin is narrow, and polymorphisms in genes associated with warfarin pharmacokinetics (CYP2C9) and pharmacodynamics (VKORC1) influence clinical response, including risk of adverse events (including hemorrhage).

Potential Drug Interactions: Amiodarone, cimetidine, metronidazole, omeprazole, zafirlukast, nandrolone, oxandrolone, oxymetholone, stanozolol, androgens, antifungals, azole, antithyroid agents, aspirin or other salicylates, cephalosporins, cinchophen, clofibrate, danazol, dextrothyroxine, diflunisal, disulfiram, fluvoxamine, lepirudin, paroxetine, propafenone, quinidine, sertraline, sulfapyridine, sulfasalazine, thyroid hormones, ticlopidine, zileuton, carbenicillin by injection, dipyridamole, divalproex, moxalactam, pentoxifylline, plicamycin, sulfinpyrazone, thrombolytic agents, ticarcillin, valproic acid, alcohol, barbiturates, carbamazepine, corticosteroids, glutethimide, griseofulvin, phenylbutazone, phenytoin, primidone, rifampin, vitamin K, simvastatin, and fluvastatin.

Functional Characteristics: The product of the VKORC1 gene encodes the enzyme that reduces vitamin K 2,3-epoxide to the enzymatically activated form that is essential for -carboxylation of several blood-clotting proteins (factors II, VII, IX, and X). VKORC1 haplotypes help explain differences in warfarin dose requirements. The molecular mechanism of this warfarin dose response seems to be regulated at the transcriptional level.

Summary of Data Submitted:

Size of sample set assayed: 340 (680 chromosomes)

Number of gene regions assayed: 4

Total bases assayed: 4

Coding bases: 0

Noncoding bases: 4

Number of variant sites: 4

Polymerase chain reaction primers reported: 8

Footnotes

Supported by National Institutes of Health Pharmacogenetics, Biomarkers, and Antithrombotic Therapy Grant R01 HL074724 First published on January 23, 2006

Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org.

doi:10.1124/pr.58.2.2.

This Article Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gage, B. F. Articles by Eby, C. S. Search for Related Content PubMed Articles by Gage, B. F. Articles by Eby, C. S.