title: VKORC1 and CYP2C9 allelic variants influence acenocoumarol dose requirements in Greek patients.
abstract: OBJECTIVE
  To identify the frequencies of the polymorphisms CYP2C9*2, CYP2C9*3 and VKORC1-1639 G>A in the Greek population and investigate whether these polymorphisms and patient demographics (age, sex and comedication) could explain the interindividual variability of acenocoumarol dose requirements for efficient anticoagulation.
  
  
  METHODS
  CYP2C9*2 (Arg144Cys), CYP2C9*3 (Ile359Leu) and VKORC1-1639G>A allelic variants were analyzed in 98 patients treated with acenocoumarol.
  
  
  RESULTS
  Allelic frequencies of CYP2C9*2, CYP2C9*3 and VKORC1A were found to be 0.155, 0.075 and 0.485, respectively. Carriership of at least one CYP2C9*3 allele led to the most pronounced reduction in the required mean dose (p<0.0001). In contrast, the CYP2C9*2 allele played a minor role (p=0.3). VKORC1 A/A patients needed approximately a third of the dose required by wild-type patients to achieve the target INR (p<0.0001). Age was the only demographical factor significantly affecting acenocoumarol dose (p<0.0001). In a multivariable regression model, CYP2C9, VKORC1 genotypes and age explained 55% of acenocoumarol dosing variability.
  
  
  CONCLUSIONS
  VKORC1-1639G>A, CYP2C9*2 and CYP2C9*3 polymorphisms were found to predispose to acenocoumarol sensitivity in Greeks. Other hereditary and nongenetic parameters must be incorporated in an individualized dosing algorithm to achieve a safer anticoagulant effect.
authors.affiliation: ATTIKON University General Hospital, 23-27 Makrigianni Street, 11742 Athens, Greece.
authors.forename: Christos N
authors.initials: CN
authors.lastname: Markatos
authors.forename: Elissavet
authors.initials: E
authors.lastname: Grouzi
authors.forename: Marianna
authors.initials: M
authors.lastname: Politou
authors.forename: Argyri
authors.initials: A
authors.lastname: Gialeraki
authors.forename: Efrosyni
authors.initials: E
authors.lastname: Merkouri
authors.forename: Ioannis
authors.initials: I
authors.lastname: Panagou
authors.forename: Ioanna
authors.initials: I
authors.lastname: Spiliotopoulou
authors.forename: Anthi
authors.initials: A
authors.lastname: Travlou
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D006115:Greece; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011655:Pulmonary Embolism / Q000235:genetics / Q000517:prevention & control; D012044:Regression Analysis; D012189:Retrospective Studies; D020246:Venous Thrombosis / Q000235:genetics / Q000517:prevention & control; D064417:Vitamin K Epoxide Reductases
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