Abstract 4116: Apolipoprotein E Genotype Alters Warfarin Dose Requirements
Objectives: Warfarin is highly efficacious when dosed properly but there is large interindividual variability in warfarin dose requirements. In particular, African Americans tend to require higher doses. One possible source of genetic variability in warfarin response is the lipoprotein, apolipoprotein E (APOE), which has been associated with plasma vitamin K levels and might alter availability of vitamin K in the liver.
Methods: A prospective cohort study was performed with a primary aim to examine the effect of APOE genotype on warfarin response. A total of 232 patients (121 Caucasian and 111 African American) were included. Detailed information on warfarin dose and variables that can alter warfarin response were collected. Maintenance dose of warfarin was defined as the dose that leads to a stable INR over three consecutive visits following initiation of the drug. APOE genotype was categorized as: any ε4 allele and as a 3-level variable associated with decreasing plasma vitamin K levels. The effect of APOE genotype on the square-root transformed weekly maintenance dose was determined using multivariable linear regression analysis to control for numerous variables, including clinical variables and CYP2C9 genotype.
Results: APOE e4 was more common among African Americans than Caucasians (38% versus 26%). Among African Americans, weekly median warfarin dose varied by genotype: e2/e2 or e2/e3 genotype (30 mg), e3/e3 genotype (35 mg), and e4/e3 or e4/e4 (45 mg; P=0.03), consistent with the hypothesis that genotype alters vitamin K transport into the liver. A similar, but not statistically significant, trend was seen among Caucasians (32.5 vs. 35 vs. 40 mg, P=0.84; interaction by race P=0.18). APOE e4 allele carrier state was associated with a higher weekly maintenance dose of warfarin among African Americans (45 mg versus 35 mg, P=0.03) but not Caucasians (38 mg versus 35 mg; P=0.41; interaction P=0.39). Among those with the homozygous wild type CYP2C9 genotype, the e4 allele was associated with higher warfarin doses in both African Americans (univariate P=0.03) and Caucasians (univariate P=0.03).
Conclusions: APOE genotype may alter maintenance dose requirements of warfarin and could explain some of the observed differences in dose requirements by race.