title: Absence of novel CYP4F2 and VKORC1 coding region DNA variants in patients requiring high warfarin doses.
abstract: OBJECTIVE
  Warfarin is an FDA-approved oral anticoagulant for long-term prevention of thromboembolism. Substantial inter-individual variation in dosing requirements and the narrow therapeutic index of this widely-prescribed drug make safe initiation and dose stabilization challenging. Single nucleotide polymorphisms (SNPs) occurring in CYP2C9, VKORC1, and CYP4F2 genes are known to impact dose, and VKORC1 and CYP4F2 polymorphisms are associated with higher therapeutic dose requirements in our cohort. However, the most advanced regression models using personal, clinical, and genetic factors to predict individual stable dose account for only 50% to 60% of the observed variability in stable therapeutic dose in Caucasians.
  
  
  METHODS
  In this study, we used DNA sequence analysis to determine whether additional variants in CYP4F2 and VKORC1 gene coding regions contribute to variable dosing requirements among individuals for whom the actual dose was the highest relative to regression model- predicted dose.
  
  
  CONCLUSIONS
  No novel DNA variants in the coding regions of these genes were identified among subjects requiring high warfarin doses, suggesting that other factors yet to be defined contribute to variability in warfarin dose requirements in this subset of our cohort.
authors.affiliation: Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI 54449, USA. burmester.jim@mcrf.mfldclin.edu
authors.forename: James K
authors.initials: JK
authors.lastname: Burmester
authors.forename: Richard L
authors.initials: RL
authors.lastname: Berg
authors.forename: Ingrid
authors.initials: I
authors.lastname: Glurich
authors.forename: Steven H
authors.initials: SH
authors.lastname: Yale
authors.forename: John R
authors.initials: JR
authors.lastname: Schmelzer
authors.forename: Michael D
authors.initials: MD
authors.lastname: Caldwell
mesh_terms: D000925:Anticoagulants / Q000008:administration & dosage*; D015331:Cohort Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D005260:Female; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D013923:Thromboembolism / Q000235:genetics* / Q000517:prevention & control*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*; D044465:White People / Q000235:genetics
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases