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Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups

Lookup NU author(s): Professor Farhad Kamali

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Abstract

Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 –1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 –1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 –1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the –1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups.


Publication metadata

Author(s): Limdi NA, Wadelius M, Cavallari L, Eriksson N, Crawford DC, Lee MT, Chen CH, Motsinger-Reif A, Sagreiya H, Liu N, Wu AH, Gage BF, Jorgensen A, Pirmohamed M, Shin JG, Sarez-Kurtz G, Kimmel SE, Johnson JA, Klein TE, Wagner MJ, on behalf of the International Warfarin Pharmacogenetics Consortium

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2010

Volume: 115

Issue: 18

Pages: 3827-3834

Print publication date: 04/03/2010

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology

URL: http://dx.doi.org/10.1182/blood-2009-12-255992

DOI: 10.1182/blood-2009-12-255992

Notes: Prof. F. Kamali (Institute of Cellular Medicine, Newcastle University) is a member of the International Warfarin Pharmacogenetics Consortium


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