title: The impact of the CYP2C9 and VKORC1 polymorphisms on acenocoumarol dose requirements in a Romanian population.
abstract: OBJECTIVE
  To investigate the genotype-phenotype correlation in Romanian patients treated with acenocoumarol.
  
  
  METHODS
  We studied 301 consecutive patients who required treatment with acenocoumarol, admitted within the Municipal Hospital of Cluj-Napoca and the Heart Institute "Niculae Stănciou" in Cluj-Napoca over a 3-year period. For each patient we recorded clinical parameters which could interfere with the achievement of stable therapeutic international normalized ratio (INR). We performed genetic analysis which consisted of genotyping the CYP2C9 gene and the VKORC1 gene. Patients were divided in three groups according to the acenocoumarol dose needed to reach a stable INR: the low dose group (≤7mg/week), the medium dose group (>7mg and <28mg/week) and the high acenocoumarol dose group (>28mg/week).
  
  
  RESULTS
  We found that patients' age was significantly different between groups (p<0.001). No differences existed between groups regarding the pathologies which required anticoagulation therapy or the concomitant treatment. The following parameters increased the odds of receiving a low dose of acenocoumarol: patient's age over 65years (OR, 3.2; p=0.01; 95%CI: 1.24-8.25), the presence of the CYP2C9*3 allele (OR, 3.4; p=0.006; 95%CI: 1.41-8.34), and the GA or AA genotype of c.-1639G>A polymorphism of VKORC1 (OR, 6.5; p=0.01; 95%CI: 1.38-30.5; respectively OR, 11.6; p=0.003; 95%CI: 2.26-59.58). A high acenocoumarol dose was less likely to be administered to an elderly patient (OR, 0.24; p=0.001; 95%CI: 0.1-0.56) or to a patient with the GA or AA genotype (OR, 0.2; p<0.001; 95CI%: 0.09-0.45; respectively OR, 0.05; p=0.006; 95%CI: 0.007-0.43).
  
  
  CONCLUSIONS
  The stable therapeutic dose of acenocoumarol is dependent of patient's age, the presence of the CYP2C9*3 allele and the c.-1639G>A polymorphism of VKORC1.
authors.affiliation: Department of Clinical Pharmacology, Iuliu Haţieganu University of Medicine and Pharmacy, 6th Pasteur Street, 400349, Cluj-Napoca, Cluj, Romania. abuzoianu@umfcluj.ro
authors.forename: Anca Dana
authors.initials: AD
authors.lastname: Buzoianu
authors.forename: Florentina Claudia
authors.initials: FC
authors.lastname: Militaru
authors.forename: Stefan Cristian
authors.initials: SC
authors.lastname: Vesa
authors.forename: Adrian Pavel
authors.initials: AP
authors.lastname: Trifa
authors.forename: Sorin
authors.initials: S
authors.lastname: Crişan
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012383:Romania; D064417:Vitamin K Epoxide Reductases; D044465:White People
chemical_list: D000925:Anticoagulants; 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; D000074:Acenocoumarol