CYP4F2 genetic variant alters required warfarin dose.
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.
Caldwell
Michael D
MD
Department of Surgery, Marshfield Clinic, Marshfield, WI, USA.
Awad
Tarif
T
Johnson
Julie A
JA
Gage
Brian F
BF
Falkowski
Mat
M
Gardina
Paul
P
Hubbard
Jason
J
Turpaz
Yaron
Y
Langaee
Taimour Y
TY
Eby
Charles
C
King
Cristi R
CR
Brower
Amy
A
Schmelzer
John R
JR
Glurich
Ingrid
I
Vidaillet
Humberto J
HJ
Yale
Steven H
SH
Qi Zhang
Kai
K
Berg
Richard L
RL
Burmester
James K
JK
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*
D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human