title: An acenocoumarol dosing algorithm exploiting clinical and genetic factors in South Indian (Dravidian) population.
abstract: OBJECTIVE
  The objective of this study was to determine the influence of CYP2C9, VKORC1, CYP4F2, and GGCX genetic polymorphisms on mean daily dose of acenocoumarol in South Indian patients and to develop a new pharmacogenetic algorithm based on clinical and genetic factors.
  
  
  METHODS
  Patients receiving acenocoumarol maintenance therapy (n = 230) were included in the study. Single nucleotide polymorphisms (SNP) of CYP2C9, VKORC1, CYP4F2, and GGCX were genotyped by real-time polymerase chain reaction (RT-PCR) method.
  
  
  RESULTS
  The mean daily acenocoumarol maintenance dose was found to be 3.7 ± 2.3 (SD) mg/day. The CYP2C9 *1*2, CYP2C9 *1*3, and CYP2C9 *2*3 variant genotypes significantly reduced the dose by 56.7 % (2.0 mg), 67.6 % (1.6 mg), and 70.3 % (1.5 mg) than wild-type carriers 4.1 mg, p < 0.0001. The genetic variants of CYP2C9 and GGCX (rs11676382) were found to be associated with lower acenocoumarol dose, whereas CYP4F2 (rs2108622) was associated with higher doses. Age, body mass index (BMI), variation of CYP2C9, VKORC1, CYP4F2, and GGCX were the major determinants of acenocoumarol maintenance dose, accounting for 61.8 % of its variability (adjusted r (2) = 0.615, p < 0.0001). Among the VKORC1 variants, rs9923231 alone contributed up to 28.6 % of the acenocoumarol dose variation.
  
  
  CONCLUSIONS
  VKORC1 rs9923231 polymorphism had the highest impact on acenocoumarol daily dose. A new pharmacogenetic algorithm was established to determine the acenocoumarol dose in South Indian population.
authors.affiliation: Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605 006, India, krishnakumarrx@hotmail.com.
authors.forename: Dhakchinamoorthi
authors.initials: D
authors.lastname: Krishna Kumar
authors.forename: Deepak Gopal
authors.initials: DG
authors.lastname: Shewade
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Loriot
authors.forename: Philippe
authors.initials: P
authors.lastname: Beaune
authors.forename: B V
authors.initials: BV
authors.lastname: Sai Chandran
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Balachander
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Adithan
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage*; D000328:Adult; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage*; D044466:Asian People / Q000235:genetics; D019735:Carbon-Carbon Ligases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D005260:Female; D005838:Genotype; D006801:Humans; D007194:India; D008297:Male; D020641:Polymorphism, Single Nucleotide; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*
chemical_list: D000925:Anticoagulants; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase; D000074:Acenocoumarol