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

We examined the influence of combined genotypes on interindividual variability in warfarin dose-response. In 100 anti-coagulated patients we quantified the effects of polymorphisms in: CYP2C9, VKORCI, calumenin (CALU), γ-glutamyl carboxylase (GGCX) and microsomal epoxide hydrolase (EPHXI) on warfarin dose requirements. The G₁₅₄₂C VKORCI polymorphism was associated with decreased warfarin doses in the hetero- and homozygous mutant patients (21% and 50% lower, respectively; p<0.0001). Warfarin daily dose was predominantly determined by VKORCI and CYP2C9 genotypes (partial r²= 0.2 1; 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 exceptionally 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 and VKORCI wild type and CALU mutant patients required the highest warfarin doses (7.8±1.5mg/day; n=9) as compared to the CYP2C9 and VKORCI 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 VKORCI, CALU and CYP2C9 improve categorization of individual warfarin dose requirements in more than 25% of patients at steady-state anticoagulation.