Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans

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 epsilon 4 allele was more common among African Americans (37.8 versus 26.4% for Caucasians). In multivariable analyses, the presence of the e4 allele was associated with a statistically significantly higher warfarin dose among African Americans (median 45.0 mg in epsilon 4 carriers versus 35.0 mg in non-epsilon 4 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 (epsilon 2/epsilon 2 or epsilon 2/epsilon 3: 30.0 mg; epsilon 3/epsilon 3: 35.0 mg; epsilon 3/epsilon 4 or epsilon 4/epsilon 4: 45.0 mg; P = 0.012), although the epsilon 4/epsilon 4 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.