Common Genetic Variants of Microsomal Epoxide Hydrolase Affect Warfarin Dose Requirements Beyond the Effect of Cytochrome P450 2C9

Background Warfarin dose response is partially explained by the polymorphisms in the cytochrome P450 (CYP) 2C9 gene, affecting S ‐warfarin clearance, as well as by age and body weight. We examined the influence on warfarin dose requirements of candidate genes encoding microsomal epoxide hydrolase (mEH), as well as glutathione S ‐transferase A1 (GSTA1) components of vitamin K epoxide reductase and the γ‐glutamylcarboxylase (GGCX) gene. Methods We studied the effects of CYP2C9, mEH, GSTA1, and GGCX genotypes on warfarin maintenance doses, accounting for age, weight, vitamin K plasma concentrations and concurrent medications, in 100 patients undergoing therapeutic anticoagulation. Results Allele frequencies were 76.5%, 12.5%, and 11% for CYP2C9*1 , *2 , and *3 , respectively; 75% and 25% for mEH T 612 C; 75.8% and 24.2% for mEH A 691 G; 73.5% and 26.5% for GSTA1 T 631 G; and 70.5% and 29.5% for GGCX G 8762 A. Warfarin doses differed among the CYP2C9 ( 2C9*1 , 2C9*2 , and 2C9*3 ) genotype groups: 6.3 ± 1.9 mg/d, 5.3 ± 1.8 mg/d, and 3.8 ± 1.7 mg/d, respectively (F = 4.83, P < .01). There were no differences in any of the other genotype groups. Among the 62 wild‐type CYP2C9 patients, variant mEH T 612 C homozygotes required higher doses than heterozygotes and wild‐type patients (7.5 ± 2.9 mg/d, 6.5 ± 4.2 mg/d, and 6.0 ± 2.6 mg/d, respectively [F = 3.57, P = .03]). The odds ratio for requiring greater than 7 mg/d in variant mEH T 612 C patients versus wild‐type patients was 3.14 (95% confidence interval, 1.47–6.67), accounting for CYP2C9. Conclusions Variant mEH T 612 C genotypes are associated with warfarin doses of greater than 50 mg/wk beyond the effect of CYP2C9. Clinical Pharmacology & Therapeutics (2005) 77 , 365–372; doi: 10.1016/j.clpt.2005.01.010