title: Common genetic variants of microsomal epoxide hydrolase affect warfarin dose requirements beyond the effect of cytochrome P450 2C9.
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 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.
authors.affiliation: Institute of Clinical Pharmacology & Toxicology, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. ronen.loebstein@sheba.health.gov.il
authors.forename: Ronen
authors.initials: R
authors.lastname: Loebstein
authors.forename: Manuela
authors.initials: M
authors.lastname: Vecsler
authors.forename: Daniel
authors.initials: D
authors.lastname: Kurnik
authors.forename: Naomi
authors.initials: N
authors.lastname: Austerweil
authors.forename: Eva
authors.initials: E
authors.lastname: Gak
authors.forename: Hillel
authors.initials: H
authors.lastname: Halkin
authors.forename: Shlomo
authors.initials: S
authors.lastname: Almog
mesh_terms: 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
chemical_list: 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