title: Genetic determinants of acenocoumarol and warfarin maintenance dose requirements in Slavic population: a potential role of CYP4F2 and GGCX polymorphisms.
abstract: BACKGROUND
  VKORC1 and cytochrome CYP2C9 genetic variants contribute largely to inter-individual variations in vitamin K antagonists (VKAs) dose requirements. Cytochrome P450 4F2 isoform (CYP4F2), gamma-glutamyl carboxylase (GGCX) and apolipoprotein E (APOE) polymorphisms have been suggested to be of minor significance.
  
  
  METHODS
  We sought to assess the impact of those polymorphisms on dose requirements in Central-Eastern European cohort of 479 patients receiving acenocoumarol (n=260) or warfarin (n=219).
  
  
  RESULTS
  There were no differences between the acenocoumarol and warfarin groups with regard to the gender, age, body mass index and international normalized ratio. The VKORC1 c.-1639A allele carriers required a lower dose of acenocoumarol and warfarin than the non-carriers (28.0 [21.0-35.0] vs. 42.0 [28.0-56.0] mg/week, p<0.0001; 35.0 [28.0-52.0] vs. 52.0 [35.0-70.0] mg/week, p=0.0001, respectively). Carriers of 2 and/or 3 variant alleles for CYP2C9 also required a lower dose of warfarin as compared with 1 1 carriers (35.0 [31.5-52.5] vs. 43.8 [35.0-60.2] mg/week, p=0.02; 35.0 [23.5-35.0] vs. 43.8 [35.0-60.2] mg/week, p<0.0001, respectively). Similarly, possession of G allele of GGCX c.2084+45 polymorphism was associated with lower warfarin dose (35.0 [26.3-39.2] vs. 45.5 [35.0-65.1] mg/week, p=0.03). No effect of CYP2C9*2,-*3 and GGCX c.2084+45G>C polymorphisms on acenocoumarol dosage was observed. Interestingly, carriers of CYP4F2 c.1297A variant required a higher dose of acenocoumarol and warfarin than non-carriers (43.8 [35.0-60.2] vs. 35.0 [35.0-52.5] mg/week, p=0.01; 35.0 [28.0-52.5] vs. 28.0 [28.0-42.0] mg/week, p=0.05).
  
  
  CONCLUSIONS
  We have shown for the first time, that besides VKORC1 and CYP2C9 genetic variants, the CYP4F2 c.1297A and GGCX c.2084+45G have a moderate effect on VKAs dose requirements in Slavic population from Central-Eastern Europe.
authors.affiliation: Institute of Cardiology, Jagiellonian University School of Medicine, Cracow, Poland; John Paul II Hospital, Cracow, Poland. Electronic address: ewa.wypasek@uj.edu.pl.
authors.forename: Ewa
authors.initials: E
authors.lastname: Wypasek
authors.affiliation: John Paul II Hospital, Cracow, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Branicka
authors.affiliation: John Paul II Hospital, Cracow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Awsiuk
authors.affiliation: Institute of Cardiology, Jagiellonian University School of Medicine, Cracow, Poland; John Paul II Hospital, Cracow, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Sadowski
authors.affiliation: Institute of Cardiology, Jagiellonian University School of Medicine, Cracow, Poland; John Paul II Hospital, Cracow, Poland.
authors.forename: Anetta
authors.initials: A
authors.lastname: Undas
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001777:Blood Coagulation / Q000187:drug effects; D019735:Carbon-Carbon Ligases / Q000235:genetics* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010641:Phenotype; D011044:Poland / Q000453:epidemiology; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D014812:Vitamin K / Q000037:antagonists & inhibitors; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase; D000074:Acenocoumarol
keywords: Acenocoumarol; CYP4F2 polymorphism; Slavic population; VKORC1 polymorphism; Warfarin