title: Extending and evaluating a warfarin dosing algorithm that includes CYP4F2 and pooled rare variants of CYP2C9.
abstract: OBJECTIVE
  Warfarin dosing remains challenging because of its narrow therapeutic window and large variability in dose response. We sought to analyze new factors involved in its dosing and to evaluate eight dosing algorithms, including two developed by the International Warfarin Pharmacogenetics Consortium (IWPC).
  
  
  METHODS
  we enrolled 108 patients on chronic warfarin therapy and obtained complete clinical and pharmacy records; we genotyped single nucleotide polymorphisms relevant to the VKORC1, CYP2C9, and CYP4F2 genes using integrated fluidic circuits made by Fluidigm.
  
  
  RESULTS
  When applying the IWPC pharmacogenetic algorithm to our cohort of patients, the percentage of patients within 1 mg/d of the therapeutic warfarin dose increases from 54% to 63% using clinical factors only, or from 38% using a fixed-dose approach. CYP4F2 adds 4% to the fraction of the variability in dose (R) explained by the IWPC pharmacogenetic algorithm (P<0.05). Importantly, we show that pooling rare variants substantially increases the R for CYP2C9 (rare variants: P=0.0065, R=6%; common variants: P=0.0034, R=7%; rare and common variants: P=0.00018; R=12%), indicating that relatively rare variants not genotyped in genome-wide association studies may be important. In addition, the IWPC pharmacogenetic algorithm and the Gage (2008) algorithm perform best (IWPC: R=50%; Gage: R=49%), and all pharmacogenetic algorithms outperform the IWPC clinical equation (R=22%). VKORC1 and CYP2C9 genotypes did not affect long-term variability in dose. Finally, the Fluidigm platform, a novel warfarin genotyping method, showed 99.65% concordance between different operators and instruments.
  
  
  CONCLUSIONS
  CYP4F2 and pooled rare variants of CYP2C9 significantly improve the ability to estimate warfarin dose.
authors.affiliation: Stanford University, Stanford, California 94305-5444, USA.
authors.forename: Hersh
authors.initials: H
authors.lastname: Sagreiya
authors.forename: Hersh
authors.initials: H
authors.lastname: Sagrieya
authors.forename: Caroline
authors.initials: C
authors.lastname: Berube
authors.forename: Alice
authors.initials: A
authors.lastname: Wen
authors.forename: Ramesh
authors.initials: R
authors.lastname: Ramakrishnan
authors.forename: Alain
authors.initials: A
authors.lastname: Mir
authors.forename: Amy
authors.initials: A
authors.lastname: Hamilton
authors.forename: Russ B
authors.initials: RB
authors.lastname: Altman
mesh_terms: D000368:Aged; D000465:Algorithms; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human