title: Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians.
abstract: BACKGROUND
  CYP2C9 and VKORC1 are two major genetic factors associated with inter-individual variability in warfarin dose. Additionally, genes in the warfarin metabolism pathway have also been associated with dose variance. We analyzed Single Nucleotide Polymorphisms (SNPs) in these genes to identify genetic factors that might confer warfarin sensitivity in Indonesian patients.
  
  
  METHODS
  Direct sequencing method was used to identify SNPs in CYP2C9, VKORC1, CYP4F2, EPHX1, PROC and GGCX genes in warfarin-treated patients. Multiple linear regressions were performed to model the relationship warfarin daily dose requirement with genetic and non-genetic variables measured and used to develop a novel algorithm for warfarin dosing.
  
  
  RESULTS
  From the 40 SNPs analyzed, CYP2C9 rs17847036 and VKORC1 rs9923231 showed significant association with warfarin sensitivity. In our study population, no significant correlation could be detected between CYP2C9*3, CYP2C9C-65 (rs9332127), CYP4F2 rs2108622, GGCX rs12714145, EPHX1 rs4653436 and PROC rs1799809 with warfarin sensitivity.
  
  
  CONCLUSIONS
  VKORC1 rs9923231 AA and CYP2C9 rs17847036 GG genotypes were associated with low dosage requirements of most patients (2.05 ± 0.77 mg/day and 2.09 ± 0.70 mg/day, respectively). CYP2C9 and VKORC1 genetic variants as well as non-genetic factors such as age, body weight and body height account for 15.4% of variance in warfarin dose among our study population. Additional analysis of this combination could allow for personalized warfarin treatment in ethnic Indonesians.
authors.affiliation: Mochtar Riady Institute for Nanotechnology, Tangerang, Indonesia. isuriapranata@mrinstitute.org
authors.forename: Ivet M
authors.initials: IM
authors.lastname: Suriapranata
authors.forename: Wen Ye
authors.initials: WY
authors.lastname: Tjong
authors.forename: Tingliang
authors.initials: T
authors.lastname: Wang
authors.forename: Andi
authors.initials: A
authors.lastname: Utama
authors.forename: Sunu B
authors.initials: SB
authors.lastname: Raharjo
authors.forename: Yoga
authors.initials: Y
authors.lastname: Yuniadi
authors.forename: Susan Sw
authors.initials: SS
authors.lastname: Tai
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044466:Asian People / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D015233:Models, Statistical; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D057285:Precision Medicine; D012307:Risk Factors; D013923:Thromboembolism / Q000188:drug therapy*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases