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Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans

The Pharmacogenomics Journal volume 8, pages 53–60 (2008)Cite this article

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 ɛ4 allele was more common among African Americans (37.8 versus 26.4% for Caucasians). In multivariable analyses, the presence of the ɛ4 allele was associated with a statistically significantly higher warfarin dose among African Americans (median 45.0 mg in ɛ4 carriers versus 35.0 mg in non-ɛ4 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 (ɛ2/ɛ2 or ɛ2/ɛ3: 30.0 mg; ɛ3/ɛ3: 35.0 mg; ɛ3/ɛ4 or ɛ4/ɛ4: 45.0 mg; P=0.012), although the ɛ4/ɛ4 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.

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Acknowledgements

We thank Sandy Barile for editorial assistance, Joseph A Gascho, MD, for serving as the site investigator at HMC, Frederick F Samaha, MD, for serving as the site investigator at the PVAMC, and Sarah L Booth, PhD, for her critical insights. We are also indebted to Mitchell Laskin, RPh; Mabel Chin, PharmD; and Francis Herrmann, BS, RPh, for their dedication to our field work. Funded by NIH Grant R01HL066176–04; Drs Kimmel and Whitehead are also funded by NIH P20-RR020741. The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; or preparation, review, or approval of the manuscript. Dr Kimmel has received research funding from GlaxoSmithKline and has served as a consultant to Bayer and GlaxoSmithKline, all unrelated to warfarin. The data will be deposited in PharmGKB (www.pharmgkb.org). Funded by NIH grants R01HL066176 and P20RR020741.

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Authors and Affiliations

  1. Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    S E Kimmel & J Christie

  2. and Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    S E Kimmel, J Christie, Z Chen, M Price, C M Brensinger & C W Newcomb

  3. Department of Pharmacology and Centre for Pharmacogenetics, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    C Kealey & A S Whitehead

  4. Department of Genetics, Stanford University Medical Center, Stanford, CA, USA

    C F Thorn

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  1. S E Kimmel
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Correspondence to S E Kimmel.

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Kimmel, S., Christie, J., Kealey, C. et al. Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans. Pharmacogenomics J 8, 53–60 (2008). https://doi.org/10.1038/sj.tpj.6500445

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