Common VKORC1 and GGCX polymorphisms associated with warfarin dose

Abstract

We report a novel combination of factors that explains almost 60% of variable response to warfarin. Warfarin is a widely used anticoagulant, which acts through interference with vitamin K epoxide reductase that is encoded by VKORC1. In the next step of the vitamin K cycle, gamma-glutamyl carboxylase encoded by GGCX uses reduced vitamin K to activate clotting factors. We genotyped 201 warfarin-treated patients for common polymorphisms in VKORC1 and GGCX. All the five VKORC1 single-nucleotide polymorphisms covary significantly with warfarin dose, and explain 29-30% of variance in dose. Thus, VKORC1 has a larger impact than cytochrome P450 2C9, which explains 12% of variance in dose. In addition, one GGCX SNP showed a small but significant effect on warfarin dose. Incorrect dosage, especially during the initial phase of treatment, carries a high risk of either severe bleeding or failure to prevent thromboembolism. Genotype-based dose predictions may in future enable personalised drug treatment from the start of warfarin therapy.

Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients

“…1). Recently, several groups have demonstrated that polymorphisms in VKORC1 are associated with warfarin sensitivity (D'Andrea et al 2005;Wadelius et al 2005;Yuan et al 2005;Rieder et al 2005;Sconce et al 2005). In a Swedish study, weekly warfarin doses varied significantly, and were associated with four VKORC1 SNPs (5¢ flankingÀ1413A>G, intron 1À136T>C, intron 2+837T>C and exon 3 343G>A), similar to our results (Wadelius et al 2005).…”

“…Recently, several groups have demonstrated that noncoding SNPs in VKORC1 influenced warfarin sensitivity (D'Andrea et al 2005;Wadelius et al 2005;Yuan et al 2005;Rieder et al 2005;Sconce et al 2005). These data strongly suggest that differences in genetic variations in both CYP2C9 and VKORC1 could explain the diversity in warfarin sensitivity and dose requirement.…”

Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements

“…3,10 Previous studies have demonstrated that two genes, VKORC1 and CYP2C9, which are involved in the vitamin K-dependent clotting pathway, explain an additional 30-54% of variance observed in warfarin dosing. 6,9,11 Warfarin exists as a mixture of two stereoisomers, R and S. 8,12 S-warfarin is approximately three times as active as the R-enantiomer 12 and works by antagonizing the vitamin K-dependent clotting pathway. Vitamin K epoxide reductase subunit 1 (VKORC1), having a major role in the vitamin K pathway, is the target protein of warfarin.…”

High-resolution SNP and haplotype maps of the human gamma-glutamyl carboxylase gene (GGCX) and association study between polymorphisms in GGCX and the warfarin maintenance dose requirement of the Japanese population

“…Although most of the variability observed in patients' response to warfarin may be attributed to genetic varations in VKORC1 (Mushiroda et al 2006;Schwartz and Stein 2006) that functions to regenerate reduced vitamin K (Rost et al 2004;Li et al 2004), polymorphisms in GGCX have also been indicated to have some association with inter-individual variation in warfarin maintenance-dose requirement (Shikata et al 2004;Chen et al 2005;Loebstein et al 2005;Wadelius et al 2005;Herman et al 2006;Kimura et al 2007;Vecsler et al 2006).…”