1. ¹Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2. ²Center for Clinical Epidemiology and Biostatistics, and Department of Biostatistics and Epidemiology, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
3. ³Department of Pharmacology and Centre for Pharmacogenetics, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
4. ⁴Department of Genetics, Stanford University Medical Center, Stanford, CA, USA

Correspondence: Dr SE Kimmel, University of Pennsylvania School of Medicine, 717 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021, USA. E-mail: skimmel@cceb.med.upenn.edu

Received 2 August 2006; Revised 26 November 2006; Accepted 12 December 2006; Published online 27 February 2007.

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