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Genetic and clinical predictors of warfarin dose requirements in African Americans

L H Cavallari1, T Y Langaee, K M Momary

  • 1Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, Illinois, USA. humma@uic.edu

Clinical Pharmacology and Therapeutics
|January 15, 2010
PubMed

Insights

Specific CYP2C9 gene variants significantly impact warfarin dosing in African Americans. Including additional CYP2C9 alleles improves warfarin dose prediction models for this population.

Area of Science:

  • Pharmacogenomics
  • Clinical Pharmacology
  • Genetics

Background:

  • Warfarin dosing variability exists, particularly in African-American patients.
  • Cytochrome P450 2C9 (CYP2C9) and vitamin K oxidoreductase complex subunit 1 (VKORC1) are key warfarin metabolism genes.
  • Genetic polymorphisms in these genes influence warfarin maintenance dose requirements.

Purpose of the Study:

  • To investigate the contribution of additional VKORC1, CYP4F2, and apolipoprotein E (APOE) polymorphisms to warfarin dose variability in African Americans.
  • To determine if these polymorphisms explain dose variability beyond established CYP2C9 and VKORC1 variants.
  • To assess the impact of specific CYP2C9 alleles on warfarin maintenance doses.

Main Methods:

  • A cohort of 226 African-American patients was studied.
  • Weekly warfarin maintenance doses were analyzed.
  • Genotyping for VKORC1, CYP2C9, CYP4F2, and APOE polymorphisms was performed.

Main Results:

  • Lower warfarin doses were required for patients with CYP2C9*8 allele (34 mg) and CYP2C9*2, *3, *5, *6, or *11 alleles (33 mg) compared to CYP2C9*1/*1 (43 mg).
  • A model incorporating CYP2C9 alleles, VKORC1 -1639G>A, and clinical factors explained 36% of warfarin dose variability.
  • Excluding CYP2C9*5, *6, *8, and *11 alleles reduced explained variability to 30%.
  • No significant contribution from other VKORC1, CYP4F2, or APOE polymorphisms was found.

Conclusions:

  • Specific CYP2C9 variants significantly influence warfarin maintenance dose requirements in African Americans.
  • The inclusion of additional CYP2C9 alleles enhances the predictive accuracy of warfarin dosing algorithms for African Americans.
  • VKORC1, CYP4F2, and APOE polymorphisms do not substantially contribute to warfarin dose variability in this population beyond known factors.

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