title: Pharmacogenetic relevance of CYP4F2 V433M polymorphism on acenocoumarol therapy.
abstract: VKORC1 and CYP2C9 polymorphisms are used to predict the safe dose of oral anticoagulant therapy. A new variant of CYP4F2 (V433M) has recently been related to the required warfarin dose. We evaluated its influence in earliest response to acenocoumarol in 100 selected men who started anticoagulation (3 mg for 3 consecutive days). V433M genotype exerted a gene dosage-dependent effect on the decrease of factors II, VII, IX, and X in the earliest response to acenocoumarol, with homozygous 433V subjects being the most sensitive. Similarly, after the initiation of therapy, international normalized ratio also experienced a gene dosage-dependent effect (P = .015), and 433V subjects needed 4 mg/week less than 433M carriers to achieve a steady anticoagulation (P = .043). Multivariate linear regression analysis revealed a significant contribution of V433M polymorphism to variability of both early international normalized ratio value (R(2) = 0.14) and dose requirements (R(2) = 0.19). Our data underline the relevant role of CYP4F2 V433M polymorphism in the pharmacogenetics of coumarin anticoagulants.
authors.affiliation: University of Murcia, Centro Regional de Hemodonación, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pérez-Andreu
authors.forename: Vanessa
authors.initials: V
authors.lastname: Roldán
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Antón
authors.forename: Nuria
authors.initials: N
authors.lastname: García-Barberá
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
authors.forename: Rocio
authors.initials: R
authors.lastname: González-Conejero
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage / Q000627:therapeutic use*; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000627:therapeutic use; D001780:Blood Coagulation Tests; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D054796:Drug Dosage Calculations; D004351:Drug Resistance / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D013997:Time Factors; D014633:Valine / Q000235:genetics; D064417:Vitamin K Epoxide Reductases
chemical_list: D000925:Anticoagulants; D003577:Cytochrome P-450 Enzyme System; D008715:Methionine; D006899:Mixed Function Oxygenases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D014633:Valine; D000074:Acenocoumarol