An evaluation of nine genetic variants related to metabolism and mechanism of action of warfarin as applied to stable dose prediction

Warfarin anticoagulation is complicated by the highly variable inter-individual response. Approximately 50% of the dose variability arises from clinical factors and variants in two genes, CYP2C9 (*2 and *3 variants) and VKORC1 -1173 C > T. We tested variants in five additional genes (EPHX1, PROC, APOE, CYP4F2, CALU and a new variant in VKORC1 in an attempt to further reduce the variability in predicted stable warfarin dose. Consecutive consenting outpatients requiring anticoagulation on stable warfarin dose (target INR 2–3) were genotyped; the association of SNP genotypes with stable warfarin dose was evaluated using the test of linear contrasts in analysis of variance (ANOVA). Study participants were 71 ± 13 years, 53% female, 85 ± 23 kg, body mass index 29 ± 7 kg/m2. Genotypes were in Hardy–Weinberg equilibrium with the exception of VKORC1 -1639. Weekly stable dosages were 31.7 ± 13.9 mg/week; median: 30 mg/week, range: 11–70 mg/week. Significant associations with dose were seen for VKORC1 -1639 (P < 0.001), CYP2C9*2 (P = 0.005) and *3 (P = 0.003), the CYP4F2 SNP (P-trend = 0.00037), and VKORC1 3730 (p-trend = 0.042). In linear regression, age, sex, weight, and CYP2C9 *2 and *3 and VKORC1-1639 genotype explained 42% of variance. The addition of CYP4F2 genotype to the regression model increased the degree of variance explained to 47%. Addition of VKORC1 SNP -1639 to a model eliminated the association of VKORC1 3730 with warfarin dose (P-trend = 0.74), but -1639 remained highly significant. No impact on dose was observed for the other tested genetic variants.