Combined genetic profiles of components and regulators of the vitamin K-dependent γ-carboxylation system affect individual sensitivity to warfarin

Abstract

SummaryWe examined the influence of combined genotypes on interindividual variability in warfarin dose-response. In 100 anticoagulated patients we quantified the effects of polymorphisms in: CYP2C9, VKORC1, calumenin (CALU), γ-glutamyl carboxylase (GGCX) and microsomal epoxide hydrolase (EPHX1) on warfarin dose requirements. The G1542C VKORC1 polymorphism was associated with decreased warfarin doses in the heteroand homozygous mutant patients (21% and 50% lower, respectively; p<0.0001). Warfarin daily dose was predominantly determined by VKORC1 and CYP2C9 genotypes (partial r2= 0.21; 0.20, respectively). Together with age and body weight, these two genotypes explained 63% of the dose variance. A single patient, homozygous for G11A CALU mutant allele, required an excep tionally high warfarin dose (20mg/day) and the prevalence of heterozygous 11A allele carriers in the upper 10th dose percentile was significantly higher (0.27 vs. 0.18, p<0.02). Combined genotype analysis revealed that CYP2C9 andVKORC1 wild type and CALU mutant patients required the highest warfarin doses (7. 8±1. 5mg/day; n=9) as compared to the CYP2C9 and VKORC1 mutant and CALU wild type genotypes (2. 8±0. 3mg/day; n=18; p<0.01). The odds ratio for doses <3mg/day was 5. 9 (1.9–18. 4) for this genotype. Compound genetic profiles comprising VKORC1, CALU and CYP2C9 improve categorization of individual warfarin dose requirements in more than 25% of patients at steady-state anticoagulation.