|
|
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.
 Previous Article | Next Article 
Submitted March 13, 2008
Accepted May 13, 2008
Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement
Danxin Wang*, Huizi Chen, Kathryn M Momary, Larisa H Cavallari, Julie A Johnson, and Wolfgang Sadee
Program in Pharmacogenetics, Department of Pharmacology, The Ohio State University, Columbus, Ohio, United States
Medical Scientist Program, The Ohio State University, Columbus, Ohio, United States
Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, Illinois, United States
Department of Pharmacy Practice and Center for Pharmacogenomics, University of Florida, Gainesville, Florida, United States
Dorothy Davis Heart & Lung Research Institute, and College of Pharmacy, The Ohio State University, Columbus, Ohio, United States
* Corresponding author; email: wang.808{at}osu.edu.
Warfarin dose requirements have been associated with two main haplotypes in VKORC1, but the responsible polymorphisms remains unknown. To search for regulatory polymorphisms, we measured allelic mRNA expression of VKORC1 in human liver, heart, and B-lymphocytes. The observed twofold allelic mRNA expression imbalance narrowed possible candidate SNPs to -1639 G>A and 1173 C<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. In contrast, 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 -1639 G>A, and the tightly linked intron1 SNP 1173 C>T, predict warfarin dose more accurately than intron 2 SNP 1542 G>C in African-Americans. Increased warfarin dose requirement in African-Americans was accounted for by lower frequency of the -1639 A allele. Therefore, -1639 G>A is a suitable biomarker for warfarin dosing across ethnic populations.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
E. Grundberg, T. Kwan, B. Ge, K. C.L. Lam, V. Koka, A. Kindmark, H. Mallmin, J. Dias, D. J. Verlaan, M. Ouimet, et al.
Population genomics in a disease targeted primary cell model
Genome Res.,
November 1, 2009;
19(11):
1942 - 1952.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Tahara, S. W. Yee, T. J. Urban, S. Hesselson, R. A. Castro, M. Kawamoto, D. Stryke, S. J. Johns, T. E. Ferrin, P.-Y. Kwok, et al.
Functional Genetic Variation in the Basal Promoter of the Organic Cation/Carnitine Transporters OCTN1 (SLC22A4) and OCTN2 (SLC22A5)
J. Pharmacol. Exp. Ther.,
April 1, 2009;
329(1):
262 - 271.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
