title: Poor warfarin dose prediction with pharmacogenetic algorithms that exclude genotypes important for African Americans.
abstract: OBJECTIVE
  Recent clinical trial data cast doubt on the utility of genotype-guided warfarin dosing, specifically showing worse dosing with a pharmacogenetic versus clinical dosing algorithm in African Americans. However, many genotypes important in African Americans were not accounted for. We aimed to determine whether omission of the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G > A genotype affects performance of dosing algorithms in African Americans.
  
  
  METHODS
  In a cohort of 274 warfarin-treated African Americans, we examined the association between the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G > A genotype and warfarin dose prediction error with pharmacogenetic algorithms used in clinical trials.
  
  
  RESULTS
  The http://www.warfarindosing.org algorithm overestimated doses by a median (interquartile range) of 1.2 (0.02-2.6) mg/day in rs12777823 heterozygotes (P<0.001 for predicted vs. observed dose), 2.0 (0.6-2.8) mg/day in rs12777823 variant homozygotes (P = 0.004), and 2.2 (0.5-2.9) mg/day in carriers of a CYP2C9 variant (P < 0.001). The International Warfarin Pharmacogenetics Consortium (IWPC) algorithm underdosed warfarin by 0.8 (-2.3 to 0.4) mg/day for patients with the rs12777823 GG genotype (P < 0.001) and overdosed warfarin by 0.7 (-0.4 to 1.9) mg/day in carriers of a variant CYP2C9 allele (P = 0.04). Modifying the http://www.warfarindosing.org algorithm to adjust for variants important in African Americans led to better dose prediction than either the original http://www.warfarindosing.org (P < 0.01) or IWPC (P < 0.01) algorithm.
  
  
  CONCLUSIONS
  These data suggest that, when providing genotype-guided warfarin dosing, failure to account for variants important in African Americans leads to significant dosing error in this population.
authors.affiliation: Departments of aPharmacy Practice bPharmacy Systems, Outcomes and Policy cCenter for Pharmacoepidemiology and Pharmacoeconomic Research dDepartment of Medicine, Section of Hematology and Oncology, University of Illinois at Chicago, Chicago, Illinois eDepartment of Pharmacotherapy and Translational Research, University of Florida at Gainesville, Gainesville, Florida, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Drozda
authors.forename: Shan
authors.initials: S
authors.lastname: Wong
authors.forename: Shitalben R
authors.initials: SR
authors.lastname: Patel
authors.forename: Adam P
authors.initials: AP
authors.lastname: Bress
authors.forename: Edith A
authors.initials: EA
authors.lastname: Nutescu
authors.forename: Rick A
authors.initials: RA
authors.lastname: Kittles
authors.forename: Larisa H
authors.initials: LH
authors.lastname: Cavallari
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9