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Blood, 15 April 2008, Vol. 111, No. 8, pp. 4106-4112.
Prepublished online as a Blood First Edition Paper on February 4, 2008; DOI 10.1182/blood-2007-11-122010.
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Submitted November 6, 2007
Accepted January 23, 2008
CYP4F2 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 King, Amy Brower, John R. Schmelzer, Ingrid Glurich, Humberto J. Vidaillet, Steven H. Yale, Kai Qi Zhang, Richard L. Berg, and James K. Burmester*
Department of Surgery, Marshfield Clinic, Marshfield, WI, United States
Affymetrix, Inc, Santa Clara, CA, United States
Center for Pharmacogenetics, University of Florida, Gainesville, FL, United States
Medical Center, Washington University, St. Louis, MO, United States
Biocomputing and Informatics, Third Wave Technologies, Madison, WI, United States
Health Services Research Center, Marshfield Clinic Research Foundation, Marshfield, WI, United States
Office of Scientific Writing and Publications, Marshfield Clinic Research Foundation, Marshfield, WI, United States
Department of Cardiology, Marshfield Clinic, Marshfield, WI, United States
Department of General Internal Medicine, Marshfield Clinic, Marshfield, WI, United States
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, United States
Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, WI, United States
* Corresponding author; email: burmester.jim{at}mcrf.mfldclin.edu.
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 under-prescribed. Further, inter-individual 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 three independent Caucasian cohorts of patients stabilized on warfarin representing diverse geographic regions in the USA and accounted for a difference in warfarin dose of about 1 mg/day between CC and TT subjects. Genetic variation of CYP4F2 was associated with a clinically relevant effect on warfarin requirement.
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Blood,
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[Abstract]
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