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

Daniel Kurnik; Husam Qasim; Sophie Sominsky; Aharon Lubetsky; Noa Markovits; Chun Li; C. Michael Stein; Hillel Halkin; Eva Gak; Ronen Loebstein

doi:10.1160/TH12-03-0151

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 108(04): 781-788
DOI: 10.1160/TH12-03-0151

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

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

Daniel Kurnik

¹Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel

³Sackler School of Medicine, Tel Aviv University, Israel

⁵Departments of Medicine and Pharmacology, Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA

,

Husam Qasim

¹Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel

,

Sophie Sominsky

³Sackler School of Medicine, Tel Aviv University, Israel

,

Aharon Lubetsky

²Institute of Thrombosis and Haemostasis, Sheba Medical Center, Tel Hashomer, Israel

³Sackler School of Medicine, Tel Aviv University, Israel

,

Noa Markovits

¹Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel

,

Chun Li

⁴Department of Biostatistics and Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, USA

,

C. Michael Stein

⁵Departments of Medicine and Pharmacology, Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA

,

Hillel Halkin

¹Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel

³Sackler School of Medicine, Tel Aviv University, Israel

,

Eva Gak

³Sackler School of Medicine, Tel Aviv University, Israel

,

Ronen Loebstein

¹Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel

³Sackler School of Medicine, Tel Aviv University, Israel

› Author Affiliations

Abstract

Summary

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.

Keywords

Warfarin - pharmacogenetics - VKORC1 - dose prediction - ethnicity

Full Text

References

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