title: A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance.
abstract: CYP2C9 and VKORC1 genetic variants are associated with low and intermediate warfarin dose requirements, but markers of high doses are less well characterized. We analyzed the VKORC1 coding sequence and known CYP2C9 and VKORC1 polymorphisms in 15 selected warfarin-resistant (dose, 80 to 185 mg/wk) and 8 warfarin-sensitive patients (7 to 13 mg/wk) and 99 unselected controls (8 to 105 mg/wk). We identified a coding VKORC1 Asp36Tyr polymorphism in 7 of 15 resistant compared with 0 of 8 sensitive patients (P = .026) Carriers of Asp36Tyr in the control group (8 of 99) required significantly higher warfarin doses of 80.9 +/- 10.1 mg/wk compared with 42.7 +/- 7.5 mg/wk in noncarriers (F = 9.79, P = .002). Asp36Tyr was significantly associated with doses of more than 70 mg/wk (odds ratio, 13.0; 95% confidence limit, 1.3 to 124.2), while doses of 20 to 70 mg/wk were associated with Asp36Tyr (partial r(2) = .11; P = .004), CYP2C9*2 and *3 (r(2) = .08; P = .01), and VKORC1*2 and *3 markers (r(2) = .05; P = .05). All Asp36Tyr carriers also had VKORC1*1 tag-single nucleotide polymorphisms (tag-SNPs) indicating a new haplotype. Asp36Tyr was common in Jewish ethnic groups of Ethiopian (15%) and Ashkenazi (4%) origin. We suggest that Asp36Tyr is a new marker of the high end of the warfarin dosing range.
authors.affiliation: Institute of Clinical Pharmacology and Toxicology, Sheba Medical Center, Tel Hashomer, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Loebstein
authors.forename: Ilana
authors.initials: I
authors.lastname: Dvoskin
authors.forename: Hillel
authors.initials: H
authors.lastname: Halkin
authors.forename: Manuela
authors.initials: M
authors.lastname: Vecsler
authors.forename: Aharon
authors.initials: A
authors.lastname: Lubetsky
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.forename: Yoram
authors.initials: Y
authors.lastname: Cohen
authors.forename: Gie
authors.initials: G
authors.lastname: Ken-Dror
authors.forename: Shlomo
authors.initials: S
authors.lastname: Almog
authors.forename: Eva
authors.initials: E
authors.lastname: Gak
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001224:Aspartic Acid / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D014443:Tyrosine / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology*
chemical_list: D001224:Aspartic Acid; D014443:Tyrosine; D014859:Warfarin; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases