title: CYP4F2 genetic variant alters required warfarin dose.
abstract: Warfarin is an effective, commonly prescribed anticoagulant used to treat and prevent thrombotic events. Because of historically high rates of drug-associated adverse events, warfarin remains underprescribed. Further, interindividual variability in therapeutic dose mandates frequent monitoring until target anticoagulation is achieved. Genetic polymorphisms involved in warfarin metabolism and sensitivity have been implicated in variability of dose. Here, we describe a novel variant that influences warfarin requirements. To identify additional genetic variants that contribute to warfarin requirements, screening of DNA variants in additional genes that code for drug-metabolizing enzymes and drug transport proteins was undertaken using the Affymetrix drug-metabolizing enzymes and transporters panel. A DNA variant (rs2108622; V433M) in cytochrome P450 4F2 (CYP4F2) was associated with warfarin dose in 3 independent white cohorts of patients stabilized on warfarin representing diverse geographic regions in the United States and accounted for a difference in warfarin dose of approximately 1 mg/day between CC and TT subjects. Genetic variation of CYP4F2 was associated with a clinically relevant effect on warfarin requirement.
authors.affiliation: Department of Surgery, Marshfield Clinic, Marshfield, WI, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Caldwell
authors.forename: Tarif
authors.initials: T
authors.lastname: Awad
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Brian F
authors.initials: BF
authors.lastname: Gage
authors.forename: Mat
authors.initials: M
authors.lastname: Falkowski
authors.forename: Paul
authors.initials: P
authors.lastname: Gardina
authors.forename: Jason
authors.initials: J
authors.lastname: Hubbard
authors.forename: Yaron
authors.initials: Y
authors.lastname: Turpaz
authors.forename: Taimour Y
authors.initials: TY
authors.lastname: Langaee
authors.forename: Charles
authors.initials: C
authors.lastname: Eby
authors.forename: Cristi R
authors.initials: CR
authors.lastname: King
authors.forename: Amy
authors.initials: A
authors.lastname: Brower
authors.forename: John R
authors.initials: JR
authors.lastname: Schmelzer
authors.forename: Ingrid
authors.initials: I
authors.lastname: Glurich
authors.forename: Humberto J
authors.initials: HJ
authors.lastname: Vidaillet
authors.forename: Steven H
authors.initials: SH
authors.lastname: Yale
authors.forename: Kai
authors.initials: K
authors.lastname: Qi Zhang
authors.forename: Richard L
authors.initials: RL
authors.lastname: Berg
authors.forename: James K
authors.initials: JK
authors.lastname: Burmester
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015203:Reproducibility of Results; D014859:Warfarin / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human