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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.
CLINICAL TRIALS AND OBSERVATIONS A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose1 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
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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. 
