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Blood, 15 August 2008, Vol. 112, No. 4, pp. 1013-1021. Prepublished online as a Blood First Edition Paper on June 3, 2008; DOI 10.1182/blood-2008-03-144899. This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: blood-2008-03-144899v1 112/4/1013    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Wang, D. Articles by Sadée, W. PubMed PubMed Citation Articles by Wang, D. Articles by Sadée, W. Related Collections Clinical Trials and Observations Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement Danxin Wang1, Huizi Chen1,2, Kathryn M. Momary3, Larisa H. Cavallari3, Julie A. Johnson4, and Wolfgang Sadée1,5 1 Program in Pharmacogenetics, Department of Pharmacology, and 2 Medical Scientist Program, School of Biomedical Science, College of Medicine, The Ohio State University, Columbus; 3 Department of Pharmacy Practice, University of Illinois at Chicago; 4 Department of Pharmacy Practice and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville; and 5 Dorothy Davis Heart and Lung Research Institute and College of Pharmacy, The Ohio State University, Columbus Warfarin dose requirements have been associated with 2 main haplotypes in VKORC1, but the responsible polymorphisms remain unknown. To search for regulatory polymorphisms, we measured allelic mRNA expression of VKORC1 in human liver, heart, and B lymphocytes. The observed 2-fold allelic mRNA expression imbalance narrowed possible candidate SNPs to –1639G>A and 1173C<T. This genotype effect was observed selectively in the liver but not in heart or lymphocytes. In vitro expression of VKORC1 gene constructs, including coding and promoter regions, failed to reveal any genotype effect on transcription and mRNA processing. Chromatin immunoprecipitation with antibodies against acetyl-histone3 and K4-trimethyl-histone3 revealed preferential association of the promoter –1639 G allele with active chromatin, consistent with enhanced mRNA expression. The minor –1639 A allele generates a suppressor E-box binding site, apparently regulating gene expression by a mechanism undetectable with reporter gene assays. A clinical association study demonstrated that promoter SNP –1639G>A, and the tightly linked intron1 SNP 1173C>T, predict warfarin dose more accurately than intron 2 SNP 1542G>C in blacks. Increased warfarin dose requirement in blacks was accounted for by lower frequency of the –1639 A allele. Therefore, –1639G>A is a suitable biomarker for warfarin dosing across ethnic populations. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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