title: Warfarin dosage response related pharmacogenetics in Chinese population.
abstract: OBJECTIVE
  As the most frequently prescribed anticoagulant, warfarin has large inter-individual variability in dosage. Genetic polymorphisms could largely explain the differences in dosage requirement. rs9923231 (VKORC1), rs7294 (VKORC1), rs1057910 (CYP2C9), rs2108622 (CYP4F2), and rs699664 (GGCX) involved in the warfarin action mechanism and the circulatory vitamin K were selected to investigate their polymorphism characteristics and their effects on the pharmacodynamics and pharmacokinetics of warfarin in Chinese population.
  
  
  METHODS
  220 patients with cardiac valve replacement were recruited. International normalized ratio and plasma warfarin concentrations were determined. The five genetic polymorphisms were genotyping by pyro-sequencing. The relationships of maintenance dose, plasma warfarin concentration and INR were assessed among groups categorized by genotypes.
  
  
  RESULTS
  rs9923231 and rs7294 in VKORC1 had the analogous genotype frequencies (D': 0.969). 158 of 220 recruited individuals had the target INR (1.5-2.5). Patients with AA of rs9923231 and CC of rs7294 required a significantly lower maintenance dose and plasma concentration than those with AG and TC, respectively. The mean weekly maintenance dose was also significantly lower in CYP2C9 rs1057910 mutated heterozygote than in patients with the wild homozygote. Eliminating the influence from environment factors (age, body weight and gender), rs9923231 and rs1057910 could explain about 32.0% of the variability in warfarin maintenance dose; rs7294 could explain 26.7% of the variability in plasma concentration. For patients with allele G of rs9923231 and allele T of rs7294, higher plasma concentration was needed to achieve the similar goal INR.
  
  
  CONCLUSIONS
  A better understanding of the genetic variants in individuals can be the foundation of warfarin dosing algorithm and facilitate the reasonable and effective use of warfarin in Chinese.
authors.affiliation: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P. R. China.
authors.forename: Siyue
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P. R. China.
authors.forename: Yuangao
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P. R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P. R. China.
authors.forename: Xunbei
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P. R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Cardiac Surgery, West China Hospital, Sichuan University, Chengdu, P. R. China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiac Surgery, West China Hospital, Sichuan University, Chengdu, P. R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Dong
authors.affiliation: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000328:Adult; D000465:Algorithms; D002681:China; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D014859:Warfarin; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases