Poor warfarin dose prediction with pharmacogenetic algorthms that exclude genotypes important for African Americans

Katarzyna Drozda, Shan Wong, Shitalben R. Patel, Adam P. Bress, Edith A. Nutescu, Rick A. Kittles, Larisa H. Cavallari

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

OBJECTIVES: Recent clinical trial data cast doubt on the utility of genotype-guided warfarin dosing, specifically showing worse dosing with a pharmacogenetic versus clinical dosing algorithm in African Americans. However, many genotypes important in African Americans were not accounted for. We aimed to determine whether omission of the CYP2C9∗5, CYP2C9∗6, CYP2C9∗8, CYP2C9∗11 alleles and rs12777823 G>A genotype affects performance of dosing algorithms in African Americans. Methods: In a cohort of 274 warfarin-treated African Americans, we examined the association between the CYP2C9∗5, CYP2C9∗6, CYP2C9∗8, CYP2C9∗11 alleles and rs12777823 G>A genotype and warfarin dose prediction error with pharmacogenetic algorithms used in clinical trials. Results: The http://www.warfarindosing.org algorithm overestimated doses by a median (interquartile range) of 1.2 (0.02-2.6)mg/day in rs12777823 heterozygotes (P<0.001 for predicted vs. observed dose), 2.0 (0.6-2.8)mg/day in rs12777823 variant homozygotes (P=0.004), and 2.2 (0.5-2.9)mg/day in carriers of a CYP2C9 variant (P<0.001). The International Warfarin Pharmacogenetics Consortium (IWPC) algorithm underdosed warfarin by 0.8 (-2.3 to 0.4)mg/day for patients with the rs12777823 GG genotype (P<0.001) and overdosed warfarin by 0.7 (-0.4 to 1.9)mg/day in carriers of a variant CYP2C9 allele (P=0.04). Modifying the http://www.warfarindosing.org algorithm to adjust for variants important in African Americans led to better dose prediction than either the original http://www.warfarindosing.org (P<0.01) or IWPC (P<0.01) algorithm. Conclusion: These data suggest that, when providing genotype-guided warfarin dosing, failure to account for variants important in African Americans leads to significant dosing error in this population.

Original languageEnglish (US)
Pages (from-to)73-81
Number of pages9
JournalPharmacogenetics and Genomics
Volume25
Issue number2
DOIs
StatePublished - Feb 13 2015

Keywords

  • CYP2C9
  • genotype
  • pharmacogenomics
  • rs12777823
  • warfarin

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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