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 gamma-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.
Loebstein
Ronen
R
Institute of Clinical Pharmacology & Toxicology, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. ronen.loebstein@sheba.health.gov.il
Vecsler
Manuela
M
Kurnik
Daniel
D
Austerweil
Naomi
N
Gak
Eva
E
Halkin
Hillel
H
Almog
Shlomo
S
D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004851:Epoxide Hydrolases / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D014644:Genetic Variation; D005982:Glutathione Transferase; D006720:Homozygote; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016017:Odds Ratio; D010601:Pharmacology, Clinical / Q000379:methods; D014812:Vitamin K / Q000097:blood; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D005722:gamma-Glutamylcyclotransferase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D014812:Vitamin K; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D064417:Vitamin K Epoxide Reductases; C484555:GSTA1 protein, human; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases; D005722:gamma-Glutamylcyclotransferase