Pharmacogenetics of ADRs: Warfarin Toxicity

Summary

Principal 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

  1. ncbi Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics
    Allan E Rettie
    Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195, USA
    Annu Rev Pharmacol Toxicol 45:477-94. 2005
  2. ncbi An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients
    Lisa M Meckley
    University of Washington, Department of Pharmacy, Seattle, WA 98195, USA
    Thromb Haemost 100:229-39. 2008
  3. ncbi A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose
    Gregory M Cooper
    Department of Genome Sciences, University of Washington, Seattle, WA98195, USA
    Blood 112:1022-7. 2008
  4. ncbi Pharmacogenomics of 4-hydroxycoumarin anticoagulants
    Nicholas Au
    Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195, USA
    Drug Metab Rev 40:355-75. 2008
  5. ncbi Novel CYP2C9 promoter variants and assessment of their impact on gene expression
    Melissa A Kramer
    Department of Pediatrics, Medical College of Wisconsin, Milwaukee WI 53226, USA
    Mol Pharmacol 73:1751-60. 2008
  6. ncbi Gamma-glutamyl carboxylase (GGCX) tagSNPs have limited utility for predicting warfarin maintenance dose
    M J Rieder
    Department of Genome Sciences, Epidemiology, and Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
    J Thromb Haemost 5:2227-34. 2007
  7. ncbi The Prevalence of CYP2C8, 2C9, 2J2, and soluble epoxide hydrolase polymorphisms in African Americans with hypertension
    Albert 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
  8. ncbi Association of Vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population
    David L Veenstra
    School of Pharmacy, The Chinese University of Hong Kong, Hong Kong
    Pharmacogenet Genomics 15:687-91. 2005
  9. ncbi Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose
    Mark J Rieder
    Department of Genome Sciences, University of Washington, Seattle, USA
    N Engl J Med 352:2285-93. 2005
  10. ncbi CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomes
    David L Veenstra
    Department of Pharmacy, Environmental Health, Genome Sciences, and Medicinal Chemistry, University of Washington, Seattle, USA
    Clin Pharmacol Ther 77:353-64. 2005

Scientific Experts

  • ALLAN EDWARD RETTIE
  • Mark Rieder
  • Albert W Dreisbach
  • David L Veenstra
  • A Choppin
  • Lisa M Meckley
  • Gregory M Cooper
  • Nicholas Au
  • Melissa A Kramer
  • David K Blough
  • I Irwin
  • L Shao
  • D M Dennis
  • M G McDonald
  • L Lach
  • X Paliard
  • M P Palme
  • S Bowersox
  • C Becker
  • P Druzgala
  • Hua Feng
  • C Michael Stein
  • Ronald N Hines
  • Joshua D Smith
  • Taimour Y Langaee
  • Julie A Johnson
  • Dan M Roden
  • Ann K Wittkowsky
  • Ute I Schwarz
  • Marylyn D Ritchie
  • Erwin T Cabacungan
  • Ian B Stanaway
  • Joyce H S You
  • Frederico M Farin
  • Hui Wen Wilkerson
  • Gregory Cheng
  • Federico M Farin
  • Hui-Wen Wilkerson
  • Mitchell K Higashi
  • Sengkeo Srinouanprachan

Detail Information

Publications12

  1. ncbi Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics
    Allan E Rettie
    Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195, USA
    Annu Rev Pharmacol Toxicol 45:477-94. 2005
    ....
  2. ncbi An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients
    Lisa 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...
  3. ncbi A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose
    Gregory 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...
  4. ncbi Pharmacogenomics of 4-hydroxycoumarin anticoagulants
    Nicholas 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...
  5. ncbi Novel CYP2C9 promoter variants and assessment of their impact on gene expression
    Melissa 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...
  6. ncbi Gamma-glutamyl carboxylase (GGCX) tagSNPs have limited utility for predicting warfarin maintenance dose
    M 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...
  7. ncbi The Prevalence of CYP2C8, 2C9, 2J2, and soluble epoxide hydrolase polymorphisms in African Americans with hypertension
    Albert 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...
  8. ncbi Association of Vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population
    David 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...
  9. ncbi Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose
    Mark 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...
  10. ncbi CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomes
    David 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...
  11. ncbi Effect of tecarfarin, a novel vitamin K epoxide reductase inhibitor, on coagulation in beagle dogs
    A 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...