title: Predicting warfarin dosage in European-Americans and African-Americans using DNA samples linked to an electronic health record.
abstract: OBJECTIVE
  Warfarin pharmacogenomic algorithms reduce dosing error, but perform poorly in non-European-Americans. Electronic health record (EHR) systems linked to biobanks may allow for pharmacogenomic analysis, but they have not yet been used for this purpose.
  
  
  METHODS
  We used BioVU, the Vanderbilt EHR-linked DNA repository, to identify European-Americans (n = 1022) and African-Americans (n = 145) on stable warfarin therapy and evaluated the effect of 15 pharmacogenetic variants on stable warfarin dose.
  
  
  RESULTS
  Associations between variants in VKORC1, CYP2C9 and CYP4F2 with weekly dose were observed in European-Americans as well as additional variants in CYP2C9 and CALU in African-Americans. Compared with traditional 5 mg/day dosing, implementing the US FDA recommendations or the International Warfarin Pharmacogenomics Consortium (IWPC) algorithm reduced error in weekly dose in European-Americans (13.5-12.4 and 9.5 mg/week, respectively) but less so in African-Americans (15.2-15.0 and 13.8 mg/week, respectively). By further incorporating associated variants specific for European-Americans and African-Americans in an expanded algorithm, dose-prediction error reduced to 9.1 mg/week (95% CI: 8.4-9.6) in European-Americans and 12.4 mg/week (95% CI: 10.0-13.2) in African-Americans. The expanded algorithm explained 41 and 53% of dose variation in African-Americans and European-Americans, respectively, compared with 29 and 50%, respectively, for the IWPC algorithm. Implementing these predictions via dispensable pill regimens similarly reduced dosing error.
  
  
  CONCLUSIONS
  These results validate EHR-linked DNA biorepositories as real-world resources for pharmacogenomic validation and discovery.
authors.affiliation: Department of Medicine, Vanderbilt University in Nashville, TN 37232, USA.
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Ramirez
authors.forename: Yaping
authors.initials: Y
authors.lastname: Shi
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Schildcrout
authors.forename: Jessica T
authors.initials: JT
authors.lastname: Delaney
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Oetjens
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Zuvich
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Basford
authors.forename: Erica
authors.initials: E
authors.lastname: Bowton
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.forename: Peter
authors.initials: P
authors.lastname: Speltz
authors.forename: Raquel
authors.initials: R
authors.lastname: Zink
authors.forename: James
authors.initials: J
authors.lastname: Cowan
authors.forename: Jill M
authors.initials: JM
authors.lastname: Pulley
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Masys
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D057286:Electronic Health Records; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019966:Substance-Related Disorders; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*; D044465:White People / Q000235:genetics*
chemical_list: D000925:Anticoagulants; C510527:CALU protein, human; D002135:Calcium-Binding Proteins; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases