TY - JOUR
T1 - Common genetic variants of microsomal epoxide hydrolase affect warfarin dose requirements beyond the effect of cytochrome P450 2C9
AU - Loebstein, Ronen
AU - Vecsler, Manuela
AU - Kurnik, Daniel
AU - Austerweil, Naomi
AU - Gak, Eva
AU - Halkin, Hillel
AU - Almog, Shlomo
PY - 2005/5
Y1 - 2005/5
N2 - 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 T612C; 75.8% and 24.2% for mEH A691G; 73.5% and 26.5% for GSTA1 T631G; and 70.5% and 29.5% for GGCX G8762A. 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 T612C 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 T612C patients versus wild-type patients was 3.14 (95% confidence interval, 1.47-6.67), accounting for CYP2C9. Conclusions: Variant mEH T612C genotypes are associated with warfarin doses of greater than 50 mg/wk beyond the effect of CYP2C9.
AB - 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 T612C; 75.8% and 24.2% for mEH A691G; 73.5% and 26.5% for GSTA1 T631G; and 70.5% and 29.5% for GGCX G8762A. 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 T612C 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 T612C patients versus wild-type patients was 3.14 (95% confidence interval, 1.47-6.67), accounting for CYP2C9. Conclusions: Variant mEH T612C genotypes are associated with warfarin doses of greater than 50 mg/wk beyond the effect of CYP2C9.
UR - http://www.scopus.com/inward/record.url?scp=19144371313&partnerID=8YFLogxK
U2 - 10.1016/j.clpt.2005.01.010
DO - 10.1016/j.clpt.2005.01.010
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AN - SCOPUS:19144371313
SN - 0009-9236
VL - 77
SP - 365
EP - 372
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 5
ER -