1. ¹Institute of Clinical Pharmacology and Toxicology, Tel Aviv University, Tel Aviv
2. ²Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Tel Aviv University, Tel Aviv
3. ³Sackler School of Medicine, Tel Aviv University, Tel Aviv

Correspondence: Ronen Loebstein, MD, Institute of Clinical Pharmacology & Toxicology, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel E-mail: ronen.loebstein@sheba.health.gov.il

Received 26 July 2004; Accepted 12 January 2005.

Abstract

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 -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.