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
-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. (Clin Pharmacol Ther 2005;77:365-72.)
Ronen Loebstein, MD, Manuela Vecsler, BSc, Daniel Kurnik, MD,
Naomi Austerweil, BSc, Eva Gak, PhD, Hillel Halkin, MD, and Shlomo Almog, PhD
Tel Hashomer and Tel Aviv, Israel
Interindividual variation in the dose-response rela-
tionship of warfarin is the result of multiple factors
mostly affecting the pharmacokinetics of the drug. Ag-
ing, body weight,
1-3
and concurrent interacting medi-
cations, such as amiodarone,
4,5
are well-known modi-
fiers of warfarin dose response. In addition, genetic
polymorphisms in the metabolizing enzyme of
S-warfarin (cytochrome P450 [CYP] 2C9), specifically
CYP2C9*2 and CYP2C9*3, cause reduced warfarin
dose requirements, mainly as a result of decreased
S-warfarin clearance.
6-8
Because these factors, together
with pharmacodynamic factors such as genetic poly-
morphisms in coagulation factors II and VII,
8
explain
only 30% to 50% of the variability in warfarin dose
response, the remaining unexplained 50% to 70% may
theoretically stem from either environmental factors or
genetic variability in the pharmacodynamics of warfa-
rin as a result of other genes that have been studied to
a far lesser extent.
Within the vitamin K redox cycle, warfarin inhibits
the vitamin K epoxide reductase (VKOR) enzyme com-
From the Institute of Clinical Pharmacology and Toxicology and Danek
Gertner Institute of Human Genetics, Sheba Medical Center, Tel
Hashomer, and Sackler School of Medicine, Tel Aviv University,
Tel Aviv.
Received for publication July 26, 2004; accepted Jan 12, 2005.
Reprint requests: Ronen Loebstein, MD, Institute of Clinical Phar-
macology & Toxicology, Chaim Sheba Medical Center, Tel
Hashomer 52621, Israel.
E-mail: ronen.loebstein@sheba.health.gov.il
0009-9236/$30.00
Copyright © 2005 by the American Society for Clinical Pharmacology
and Therapeutics.
doi:10.1016/j.clpt.2005.01.010
365