The goal of this project is to apply pharmacogenomics to warfarin therapy, and gain new insights into the overall inter-individual genetic variation in response to this drug, so that prospective, individualized treatment with this anticoagulant becomes a reality. Warfarin is the most commonly employed oral anticoagulant used to treat thromboembolic disease and following surgery. One of the serious difficulties faced by physicians during both initiation of anticoagulation therapy and in determining a long-term maintenance dose is minimizing the risk of excessive bleeding. Consequently, patients have their prothrombin time (or international normalized ratio - INR) continuously monitored during the initiation phase of treatment and beyond. The ability to predict - a priori - the correct maintenance dose for an individual could be expected to revolutionize patient care and drastically cut healthcare costs. We have quantitated the effect of two critical genetic determinants of warfarin dose i.e. polymorphisms in the VKORC1 and CYP2C9 genes. Together with knowledge of patient age, sex, and concomitant drug medications, about 50% of the variability in warfarin dosing can now be accounted for in European ancestry populations, about 25% of which is due to genetic variants influencing expression of the VKORC1 gene. In this project, we propose to explore the relationship between single nucleotide polymorphisms (SNPs) in other key candidate genes and their association with warfarin maintenance dose. The long-term aim of this proposal is to account for 100% of the inter-individual variability in warfarin dosing. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS053646-02
Application #
7156977
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Tagle, Danilo A
Project Start
2006-01-01
Project End
2008-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
2
Fiscal Year
2007
Total Cost
$396,884
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Crawford, Dana C; Brown-Gentry, Kristin; Rieder, Mark J (2015) Measures of exposure impact genetic association studies: an example in vitamin K levels and VKORC1. Pac Symp Biocomput :161-70
Innocenti, Federico; Cooper, Gregory M; Stanaway, Ian B et al. (2011) Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. PLoS Genet 7:e1002078
Crawford, Dana C; Brown-Gentry, Kristin; Rieder, Mark J (2010) VKORC1 common variation and bone mineral density in the Third National Health and Nutrition Examination Survey. PLoS One 5:e15088
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International Warfarin Pharmacogenetics Consortium; Klein, T E; Altman, R B et al. (2009) Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 360:753-64
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Orho-Melander, Marju; Melander, Olle; Guiducci, Candace et al. (2008) Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations. Diabetes 57:3112-21
Cooper, Gregory M; Johnson, Julie A; Langaee, Taimour Y et al. (2008) A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood 112:1022-7
Meckley, Lisa M; Wittkowsky, Ann K; Rieder, Mark J et al. (2008) An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients. Thromb Haemost 100:229-39
Au, Nicholas; Rettie, Allan E (2008) Pharmacogenomics of 4-hydroxycoumarin anticoagulants. Drug Metab Rev 40:355-75

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