SEARCH:   Advanced

Blood, 15 August 2008, Vol. 112, No. 4, pp. 1022-1027. Prepublished online as a Blood First Edition Paper on June 5, 2008; DOI 10.1182/blood-2008-01-134247. This Article Full Text Full Text (PDF) Supplemental Table All Versions of this Article: blood-2008-01-134247v1 112/4/1022    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cooper, G. M. Articles by Rieder, M. J. Search for Related Content PubMed PubMed Citation Articles by Cooper, G. M. Articles by Rieder, M. J. Related Collections Hemostasis, Thrombosis, and Vascular Biology Free Research Articles Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose Gregory M. Cooper1, Julie A. Johnson2,3, Taimour Y. Langaee2, Hua Feng2, Ian B. Stanaway1, Ute I. Schwarz4, Marylyn D. Ritchie5, C. Michael Stein6, Dan M. Roden6, Joshua D. Smith1, David L. Veenstra7, Allan E. Rettie8, and Mark J. Rieder1 1 Department of Genome Sciences, University of Washington, Seattle; 2 Department of Pharmacy Practice and Center for Pharmacogenomics and 3 Department of Medicine (Cardiovascular Medicine), University of Florida, Gainesville; 4 Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON; Departments of 5 Molecular Physiology and Biophysics and 6 Pharmacology and Medicine, Vanderbilt University, Nashville, TN; and Departments of 7 Pharmacy and 8 Medicinal Chemistry, University of Washington, Seattle Warfarin dosing is correlated with polymorphisms in vitamin K epoxide reductase complex 1 (VKORC1) and the cytochrome P450 2C9 (CYP2C9) genes. Recently, the FDA revised warfarin labeling to raise physician awareness about these genetic effects. Randomized clinical trials are underway to test genetically based dosing algorithms. It is thus important to determine whether common single nucleotide polymorphisms (SNPs) in other gene(s) have a large effect on warfarin dosing. A retrospective genome-wide association study was designed to identify polymorphisms that could explain a large fraction of the dose variance. White patients from an index warfarin population (n = 181) and 2 independent replication patient populations (n = 374) were studied. From the approximately 550 000 polymorphisms tested, the most significant independent effect was associated with VKORC1 polymorphisms (P = 6.2 x 10–13) in the index patients. CYP2C9 (rs1057910 CYP2C9*3) and rs4917639) was associated with dose at moderate significance levels (P 10–4). Replication polymorphisms (355 SNPs) from the index study did not show any significant effects in the replication patient sets. We conclude that common SNPs with large effects on warfarin dose are unlikely to be discovered outside of the CYP2C9 and VKORC1 genes. Randomized clinical trials that account for these 2 genes should therefore produce results that are definitive and broadly applicable. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. F. Meschia Pharmacogenetics and Stroke Stroke, November 1, 2009; 40(11): 3641 - 3645. [Abstract] [Full Text] [PDF] M. Teichert, M. Eijgelsheim, F. Rivadeneira, A. G. Uitterlinden, R. H.N. van Schaik, A. Hofman, P. A.G.M. De Smet, T. van Gelder, L. E. Visser, and B. H.Ch. Stricker A genome-wide association study of acenocoumarol maintenance dosage Hum. Mol. Genet., October 1, 2009; 18(19): 3758 - 3768. [Abstract] [Full Text] [PDF] F. Marin, R. Gonzalez-Conejero, P. Capranzano, T. A. Bass, V. Roldan, and D. J. Angiolillo Pharmacogenetics in cardiovascular antithrombotic therapy. J. Am. Coll. Cardiol., September 15, 2009; 54(12): 1041 - 1057. [Abstract] [Full Text] [PDF] M. G. McDonald, M. J. Rieder, M. Nakano, C. K. Hsia, and A. E. Rettie CYP4F2 Is a Vitamin K1 Oxidase: An Explanation for Altered Warfarin Dose in Carriers of the V433M Variant Mol. Pharmacol., June 1, 2009; 75(6): 1337 - 1346. [Abstract] [Full Text] [PDF] V. Perez-Andreu, V. Roldan, A. I. Anton, N. Garcia-Barbera, J. Corral, V. Vicente, and R. Gonzalez-Conejero Pharmacogenetic relevance of CYP4F2 V433M polymorphism on acenocoumarol therapy Blood, May 14, 2009; 113(20): 4977 - 4979. [Abstract] [Full Text] [PDF] M. R. Langley, J. K. Booker, J. P. Evans, H. L. McLeod, and K. E. Weck Validation of Clinical Testing for Warfarin Sensitivity: Comparison of CYP2C9-VKORC1 Genotyping Assays and Warfarin-Dosing Algorithms J. Mol. Diagn., May 1, 2009; 11(3): 216 - 225. [Abstract] [Full Text] [PDF] D. Rosskopf and M. C. Michel Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine Pharmacol. Rev., December 1, 2008; 60(4): 513 - 535. [Abstract] [Full Text] [PDF]

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020