Summary

We examined the influence of combined genotypes on interindividualvariability in warfarin dose-response. In 100 anticoagulatedpatients we quantified the effects of polymorphismsin: CYP2C9, VKORC1 , calumenin (CALU), ? -glutamyl carboxylase( GGCX ) and microsomal epoxide hydrolase (EPHX1) on warfarindose requirements.The G1542C VKORC1 polymorphism wasassociated with decreased warfarin doses in the hetero- andhomozygous mutant patients (21% and 50% lower, respectively;p<0.0001).Warfarin daily dose was predominantly determinedby VKORC1 and CYP2C9 genotypes (partial r² = 0.21; 0.20, respectively).Together with age and body weight, these two genotypesexplained 63% of the dose variance. A single patient,homozygous for G₁₁A CALU mutant allele, required an exceptionally high warfarin dose (20mg/day) and the prevalence ofheterozygous ₁₁A allele carriers in the upper 10^th dose percentilewas significantly higher (0.27 vs. 0.18, p<0.02). Combined genotypeanalysis revealed that CYP2C9 andVKORC1 wild type andCALU mutant patients required the highest warfarin doses(7.8±1.5mg/day; n=9) as compared to the CYP2C9 and VKORC1mutant 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 comprisingVKORC1 , CALU and CYP2C9 improve categorization of individualwarfarin dose requirements in more than 25% of patients atsteady-state anticoagulation.