Effect of the VKORC1 D36Y variant on warfarin dose requirement and pharmacogenetic dose prediction

Abstract

Pharmacogenetic dosing algorithms help predict warfarin maintenance doses, but their predictive performance differs in different populations, possibly due to unsuspected population-specific genetic variants. The objectives of this study were to quantify the effect of the VKORC1 D36Y variant (a marker of warfarin resistance previously described in 4% of Ashkenazi Jews) on warfarin maintenance doses and to examine how this variant affects the performance of the International Warfarin Pharmacogenetic Consortium (IWPC) dose prediction model. In 210 Israeli patients on chronic warfarin therapy recruited at a tertiary care centre, we applied the IWPC model and then added D36Y genotype as covariate to the model (IWPC+D36Y) and compared predicted with actual doses. Median weekly warfarin dose was 35 mg (interquartile range [IQR], 24.5 to 52.5 mg). Among 16 heterozygous D36Y carriers (minor allele frequency = 3.8%), warfarin weekly dose was increased by a median of 43.7 mg (IQR, 40.5 to 47.2 mg) compared to non-carriers after adjustment for all IWPC parameters, a greater than two-fold dose increase. The IWPC model performed suboptimally (coefficient of determination R²=27.0%; mean absolute error (MAE), 14.4 ± 16.2 mg/week). Accounting for D36Y genotype using the IWPC+D36Y model resulted in a significantly better model performance (R²=47.2%, MAE=12.6 ± 12.4 mg/week). In conclusion, even at low frequencies, variants with a strong impact on warfarin dose may greatly decrease the performance of a commonly used dose prediction model. Unexpected discrepancies of the performance of universal prediction models in subpopulations should prompt searching for unsuspected confounders, including rare genetic variants.

Figure 1. Weekly warfarin doses in carriers and non-carriers of D36Y

Warfarin dose requirements were significantly higher in carriers of D36Y (median [IQR] = 71.2 mg [60.6 to 102.5 mg]; n=16) compared to non-carriers (35 mg [22.5 to 47.5 mg]; n=194; P<0.001). Horizontal mid-lines represent the median, and bars the interquartile range.

Figure 2. Predicted vs. actual weekly warfarin doses for the IWPC model (left panel) and for the IWPC+D36Y model (right panel)

Carriers of D36Y are represented by closed red circles.

Figure 3. Model performance, assessed by coefficient of determination R² (upper panel) and the mean absolute error (MAE, lower panel), for increasing numbers of D36Y carriers

For the IWPC model (red circles), R² decreased and MAE increased with increasing prevalence of carriers of the D36Y variant in the population. In contrast, for a model that included the D36Y covariate in addition to the IWPC algorithm (blue triangles), R² increased substantially and MAE only slightly with an increasing prevalence of D36Y carriers. Error bars represent standard error of the mean.