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Common Genetic Variants of Microsomal Epoxide Hydrolase Affect Warfarin Dose Requirements Beyond the Effect of Cytochrome P450 2C9
Author(s) -
Loebstein Ronen,
Vecsler Manuela,
Kurnik Daniel,
Austerweil Naomi,
Gak Eva,
Halkin Hillel,
Almog Shlomo
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.01.010
Subject(s) - cyp2c9 , warfarin , microsomal epoxide hydrolase , vitamin k epoxide reductase , medicine , genotype , pharmacology , epoxide hydrolase , endocrinology , cytochrome p450 , reductase , microsome , biology , chemistry , biochemistry , enzyme , gene , metabolism , atrial fibrillation
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