Ethnicity-specific pharmacogenetics: the case of warfarin in African Americans

Abstract

Using a derivation cohort (N=349), we developed the first warfarin dosing algorithm that includes recently discovered polymorphisms in VKORC1 and CYP2C9 associated with warfarin dose requirement in African Americans (AAs). We tested our novel algorithm in an independent cohort of 129 AAs and compared the dose prediction to the International Warfarin Pharmacogenetics Consortium (IWPC) dosing algorithms. Our algorithm explains more of the phenotypic variation (R(2)=0.27) than the IWPC pharmacogenomics (R(2)=0.15) or clinical (R(2)=0.16) algorithms. Among high-dose patients, our algorithm predicted a higher proportion of patients within 20% of stable warfarin dose (45% vs 29% and 2% in the IWPC pharmacogenomics and clinical algorithms, respectively). In contrast to our novel algorithm, a significant inverse correlation between predicted dose and percent West African ancestry was observed for the IWPC pharmacogenomics algorithm among patients requiring ⩾60 mg per week (β=-2.04, P=0.02).

Figure 1. Frequency distribution of predicted warfarin dose deviation from therapeutic dose

Panel A). Most over-predicted warfarin doses by the novel AA algorithm were below 10mg/week. Panel B). The IWPC pharmacogenomics algorithm over or under-predicted warfarin doses by up to 10mg/week in more than half of the patients. Panel C). The IWPC clinical algorithm under-predicted warfarin doses for the majority of patients. Our novel AA algorithm was able to predict the exact therapeutic dose in 10.9% of patients compared to 2.3% for the IWPC pharmacogenomics algorithms (p = 0.02).

Figure 2. Accuracy of novel AA algorithm in predicting warfarin doses among dosing groups

Percentage of patients whose actual warfarin dose fell within 20% of the predicted dose according to either the novel AA algorithm, IWPC pharmacogenomics algorithm, and IWPC clinical algorithm. For patients requiring low doses, all three algorithms have similar predictive dose requirements. The novel African American algorithm out performs both IWPC algorithms for patients in the high dose group (p=0.004* and p<0.0001**). Number of patients in each dose group is shown at the bottom.