CYK4F-2 genetic variant alters required warfarin dose

Michael D. Caldwell, Tarif Awad, Julie A. Johnson, Brian F. Gage, Mat Falkowski, Paul Gardina, Jason Hubbard, Yaron Turpaz, Taimour Y. Langaee, Charles Eby, Cristi R. King, Amy Brower, John R. Schmelzer, Ingrid Glurich, Humberto J. Vidaillet, Steven H. Yale, Kai Qi Zhang, Richard L. Berg, James K. Burmester

Research output: Contribution to journalArticlepeer-review

409 Scopus citations

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.

Original languageEnglish
Pages (from-to)4106-4112
Number of pages7
JournalBlood
Volume111
Issue number8
DOIs
StatePublished - Apr 15 2008

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