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Genomes and GenesSpecies | Pharmacogenetics of ADRs: Warfarin ToxicitySummaryPrincipal Investigator: ALLAN EDWARD RETTIE Affiliation: University of Washington Country: USA Abstract: The Iong-term aim of this research is to determine the clinical consequences of genetic variability within the human CYP2C9 gene among subjects of diverse ethnic origins, and to understand molecular mechanisms that underlie genetically-based alterations in the functional activity of the CYP2C9 enzyme. CYP2C9 is a major human liver form of P450 that metabolizes approximately 15% of all drugs that are cleared by phase I processes. It is well established that treating patients that possess the common CYP2C9*2 and CYP2C9*3 variants with low therapeutic index drugs, e.g. warfarin, has clinically important implications. These are adverse drug reactions (ADRs) due to over-medication that can result in significant, but potentially avoidable, patient health costs. Although a large body of information exists for certain CYP2C9 polymorphisms in Caucasian subjects, the full spectrum of genetic variation at the CYP2C9 locus, and attendant functional consequences, is poorly defined. Moreover, other important ethnic groups in the US, notably Hispanics, have been quite neglected in this research area, despite evidence for population-specific polymorphisms in the CYP2C9 gene. Therefore, we will; Specific Aim 1: Identify the spectrum of distal regulatory polymorphisms that exist at the CYP2C9 locus. SNP discovery will be performed in a panel of 90 DNA samples from the Polymorphism Discovery Resource. SNP validation and allele frequency determinations will then be carried out in White and Hispanic populations. Specific Aim 2: Determine the functional significance of new promoter and coding-region polymorphisms in CYP2C9. Mechanisms underlying changes in function will be probed with reporter constructs, deletion analysis, DNA/binding protein assays, recombinantly expressed proteins and stably-transfected cell lines. Specific Aim 3: Determine the impact of new CYP2C9 polymorphisms on anticoagulation-related outcomes in previously phenotyped Caucasian patients by resequencing across 60 kbp of the CYP2C9 gene from 185 pre-existing warfarin patient DNA samples. Aims 1 and 2 will test the hypothesis that; novel, functionally important polymorphisms remain to be elucidated within the CYP2C9 locus, some of which will be population-selective. Aim 3 will test the hypothesis that; promoter-region SNPs in the CYP2C9 gene are a determinant of warfarin dose. Successful completion of these studies will impact the ability of clinicians to predict the likelihood of adverse drug reactions to warfarin, and other drugs that are CYP2C9 substrates, arising in minority populations. Funding Period: 2004-04-01 - 2009-07-31 more information: NIH RePORT Top Publications
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Publications
Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogeneticsAllan E Rettie
Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195, USA
Annu Rev Pharmacol Toxicol 45:477-94. 2005....- An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patientsLisa M Meckley
University of Washington, Department of Pharmacy, Seattle, WA 98195, USA
Thromb Haemost 100:229-39. 2008..This difference may be due, in part, to pharmacokinetics factors (e.g. drug half-life), which are influenced primarily by CYP2C9; these findings should be confirmed in additional studies... 
A genome-wide scan for common genetic variants with a large influence on warfarin maintenance doseGregory M Cooper
Department of Genome Sciences, University of Washington, Seattle, WA98195, USA
Blood 112:1022-7. 2008..Randomized clinical trials that account for these 2 genes should therefore produce results that are definitive and broadly applicable...- Pharmacogenomics of 4-hydroxycoumarin anticoagulantsNicholas Au
Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195, USA
Drug Metab Rev 40:355-75. 2008..This article will review recent events in these and other related areas... - Novel CYP2C9 promoter variants and assessment of their impact on gene expressionMelissa A Kramer
Department of Pediatrics, Medical College of Wisconsin, Milwaukee WI 53226, USA
Mol Pharmacol 73:1751-60. 2008..These data suggest that genetic variation within CYP2C9 regulatory sequences is likely to contribute to differences in CYP2C9 phenotype both within and among different populations... - Gamma-glutamyl carboxylase (GGCX) tagSNPs have limited utility for predicting warfarin maintenance doseM J Rieder
Department of Genome Sciences, Epidemiology, and Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
J Thromb Haemost 5:2227-34. 2007..Gamma-glutamyl carboxylase (GGCX), in its role as a key component of the vitamin K cycle, is a potential candidate gene associated with warfarin treatment... - The Prevalence of CYP2C8, 2C9, 2J2, and soluble epoxide hydrolase polymorphisms in African Americans with hypertensionAlbert W Dreisbach
Divisions of Nephrology and Clinical Pharmacology, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
Am J Hypertens 18:1276-81. 2005..We performed a case-control study to determine the prevalence of epoxygenase-related SNP in African American individuals and to evaluate whether these SNP are associated with increased risk of hypertension... - Association of Vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient populationDavid L Veenstra
School of Pharmacy, The Chinese University of Hong Kong, Hong Kong
Pharmacogenet Genomics 15:687-91. 2005..To evaluate the association of VKORC1 genetic variants with warfarin dose requirements in a Hong Kong Chinese patient population... - Effect of VKORC1 haplotypes on transcriptional regulation and warfarin doseMark J Rieder
Department of Genome Sciences, University of Washington, Seattle, USA
N Engl J Med 352:2285-93. 2005..The management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin... - CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomesDavid L Veenstra
Department of Pharmacy, Environmental Health, Genome Sciences, and Medicinal Chemistry, University of Washington, Seattle, USA
Clin Pharmacol Ther 77:353-64. 2005..The goal of this study was to define the haplotype structure of the cytochrome P450 (CYP) 2C9 gene in a European American population and evaluate associations between CYP2C9 haplotypes and anticoagulation-related outcomes... - Effect of tecarfarin, a novel vitamin K epoxide reductase inhibitor, on coagulation in beagle dogsA Choppin
ARYx Therapeutics, Fremont, CA 94555, USA
Br J Pharmacol 158:1536-47. 2009..The objective of this study was to test and compare the efficacy of tecarfarin with that of warfarin, when administered either intravenously or once a day orally, to produce stable anticoagulation in beagle dogs...