Der Pharmacia Lettre
Abstract
Author(s): Nima Patel-Shori, Anurag Mishra, Mispa Ajua-Alemanji, Edlira Hoxha, Katsiarina Bykov, Michael R. Jacobs, Patrick McDonnell, John P. Gaughan, Ronald Rubin, John Woodward, Evgeny Krynetskiy
Genetic polymorphisms in genes coding for warfarin-metabolizing, -transporting, and target
proteins represent risk factors, which account for the significant part of the variability in
warfarin-based anticoagulation therapy. Because warfarin dose requirement is a polygenic trait,
the existing algorithms have limited capacity to predict warfarin dose. The goal of this
retrospective study was to assess the effects of genetic polymorphisms in candidate genes on
warfarin dose requirement in ethnically diverse population. We performed genotyping and
statistical analysis of association between genotype and warfarin dose, or adverse drug event
(bleeding) in 60 patients from three ethnic groups (African Americans, Caucasians, and
Hispanics) under stable anti-coagulation with warfarin. Warfarin dose was significantly
different among ethnic groups, with highest in African Americans and lowest in Hispanics, in
parallel with inter-ethnic frequencies of allelic variants of VKORC1 and GGCX genes. The
strongest predictors of the dose in stable patients were age (p<0.0001) and VKORC1 haplotype
(p<0.0001). Our results showed that single nucleotide polymorphisms (SNPs) in GGCX,
CYP2C9, and VKORC1 genes were useful biomarkers for warfarin dose requirement in an
ethnically diverse population. Warfarin dose for the carriers of VKORC1*2 allele was
significantly lower (5.45Ã?â??Ã?±1.82 vs. 2.98Ã?â??Ã?±1.09 mg/day; P=0.0069) in Caucasians but not in two
other population groups, suggesting that the same SNPs may have different effects depending on
the genetic context.
