Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and γ-glutamyl carboxylase) gene variants with warfarin sensitivity

Abstract

We analyzed mutations of 7 vitamin K-dependent protein and cytochrome P450 2C9 genes in 45 patients and investigated whether any contribute to the large interpatient variability in the warfarin dose-effect relationship. Total clearance and daily dose, INR and INR/Cp, were used as pharmacokinetic and pharmacodynamic indexes, respectively. Patients were grouped by genotype based on a single polymorphism and combinations of polymorphisms. Among the 30 sequence variants identified, CYP2C9*3, 165Thr 3 Met of the factor II gene, ؊402G 3 A, (37-bp repeat) n , and ؊746T 3 C of the factor VII gene, and (CAA repeat) n of the ␥-glutamyl carboxylase gene were selected as candidate polymorphisms. As the analysis of single polymorphisms implied, the highest INR/Cp mean values and the lowest warfarin maintenance doses were observed in patients homozygous for the 165Met, ؊402G, (37-bp repeat) 6 and ؊746T alleles. Multiple regression analysis revealed that warfarin sensitivity was independently associated with ؊402G 3 A, (CAA repeat) n , CYP2C9*3, and 165Thr 3 Met, which accounted for 50% of variance. These results suggest that part of the considerable interpatient variation is attributable to genetic variation, and the combined genotyping of CYP2C9 and certain vitamin K-dependent protein genes is useful for predicting anticoagulant responses.

Common VKORC1 and GGCX polymorphisms associated with warfarin dose

“…43 They showed that warfarin dose increased with the number of microsatellite (CAA)n repeats in intron 6. Interestingly, the GGCX SNP in intron 6 shows the same trend, but in our material a SNP in intron 2 was the best predictor of warfarin dose.…”

Pyrosequencing Analysis of Thrombosis-Associated Risk Markers

“…Today, large interindividual variability in the anticoagulant dose effect of warfarin necessitates careful monitoring and adjustment based on measurement of the prothrombin complex, particularly at the initiation of therapy. It has been shown that combinations of genetic variants in the CYP2C9, factor VII, and prothrombin genes contribute to 50% of the interindividual variance in the warfarin sensitivity (12 ). From a clinical pharmacologic perspective, combined genotype analysis before initiation of therapy could reduce bleeding complications by identifying potential low-dose responders.…”

Population variation in VKORC1 haplotype structure

“…The high-dose and low-dose haplotypes can be identified in patients by screening a small number of polymorphisms (haplotype tag SNPs) [1]. Previously, factors such as CYP2C9 genotype have also been described as predictors for warfarin dose [4,5]. VKORC1 haplotype accounts for 21-25% of the variation in warfarin dose, and adding CYP2C9*2 and *3 genotypes improved the prediction model to 31% [4].…”