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

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.