title: 1173C>T polymorphism in VKORC1 modulates the required warfarin dose.
abstract: The response to warfarin is highly variable among individuals and such variability is likely to have some genetic basis. We evaluted the effect of VKORC1 polymorphisms on warfarin response among Japanese, taking advantage of its unique population structure in which CYP2C9 *2 and *3 alleles are relatively rare. Thirty-one patients (12-34 years old; median, 22) on warfarin were recruited from a pediatric cardiology clinic. Genotyping of the C>T polymorphism at position 1173 in intron 1 of VKORC1 revealed that 26 patients (84%) were T/T homozygotes at nucleotide 1173, whereas 5 (16%) were C/T heterozygotes. Complete linkage disequilibrium was observed between the 1173C > T polymorphism and another polymorphism, the 3730G > A, in the 3' untranslated region. The C/T heterozyogtes at the 1173C > T polymorphism tended to require more warfarin than the T/T homozygotes, when adjusted for international normalized ratio (p = 0.003). Both the 1173C > T polymorphism and the 3730G > A polymorphism are likely to be inert from a functional standpoint. Rather, based on the complete linkage disequilibrium between 1173C > T and 3730G > A polymorphisms, we suspect that the actual change that defines the relative resistance to warfarin may be present in the proximity of these two polymorphisms.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Tokyo, Shinjuku-ku, 160-8582, Japan. kkosaki@sc.itc.keio.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Kosaki
authors.forename: C
authors.initials: C
authors.lastname: Yamaghishi
authors.forename: R
authors.initials: R
authors.lastname: Sato
authors.forename: H
authors.initials: H
authors.lastname: Semejima
authors.forename: H
authors.initials: H
authors.lastname: Fuijita
authors.forename: K
authors.initials: K
authors.lastname: Tamura
authors.forename: K
authors.initials: K
authors.lastname: Maeyama
authors.forename: H
authors.initials: H
authors.lastname: Yamagishi
authors.forename: A
authors.initials: A
authors.lastname: Sugaya
authors.forename: H
authors.initials: H
authors.lastname: Dodo
authors.forename: Y
authors.initials: Y
authors.lastname: Tanigawara
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage*; D044466:Asian People / Q000235:genetics*; D002648:Child; D005260:Female; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases