title: Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans.
abstract: Warfarin sodium is a vitamin K antagonist that is plagued by large variability in patient response, including higher dose requirements among African Americans. Polymorphisms in the gene encoding apolipoprotein E (APOE) may partly explain this variability by altering transport of vitamin K to the liver. In a prospective cohort study of 232 individuals (52.2% Caucasian and 47.8% African American) initiating warfarin therapy, the weekly maintenance dose was significantly higher for African Americans than for Caucasians (mean 42.9 versus mean 36.9 mg, P=0.018), and the epsilon4 allele was more common among African Americans (37.8 versus 26.4% for Caucasians). In multivariable analyses, the presence of the epsilon4 allele was associated with a statistically significantly higher warfarin dose among African Americans (median 45.0 mg in epsilon4 carriers versus 35.0 mg in non-epsilon4 carriers, P=0.014) but not Caucasians (38.1 versus 35.0 mg, P=0.60). In addition, warfarin maintenance dose increased among African Americans according to genotype previously associated with differential hepatic chylomicron clearance (epsilon2/epsilon2 or epsilon2/epsilon3: 30.0 mg; epsilon3/epsilon3: 35.0 mg; epsilon3/epsilon4 or epsilon4/epsilon4: 45.0 mg; P=0.012), although the epsilon4/epsilon4 genotype was rare and not clearly associated with higher doses. The association of APOE with warfarin dosing was independent of CYP2C9 and VKORC1 polymorphisms. APOE polymorphisms thus may be important determinants of warfarin maintenance dose and could explain at least some of the observed racial differences in dose requirements.
authors.affiliation: Department of Medicine, School of Medicine, University of Pennsylvania, 423 Guardian Drive, Philadelphia, PA 19104, USA. skimmel@cceb.med.upenn.edu
authors.forename: S E
authors.initials: SE
authors.lastname: Kimmel
authors.forename: J
authors.initials: J
authors.lastname: Christie
authors.forename: C
authors.initials: C
authors.lastname: Kealey
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Price
authors.forename: C F
authors.initials: CF
authors.lastname: Thorn
authors.forename: C M
authors.initials: CM
authors.lastname: Brensinger
authors.forename: C W
authors.initials: CW
authors.lastname: Newcomb
authors.forename: A S
authors.initials: AS
authors.lastname: Whitehead
mesh_terms: D001741:Black or African American; D000368:Aged; D000704:Analysis of Variance; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000235:genetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D004247:DNA / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D011446:Prospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000627:therapeutic use; D044465:White People
chemical_list: D000925:Anticoagulants; D001057:Apolipoproteins E; D014859:Warfarin; D004247:DNA; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases