title: Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity.
abstract: The aim of the study is to explore the contribution of genetic factors related either to drug metabolism (cytochrome P450 2C9) or to drug target (vitamin K epoxide reductase) to variability in the response to acenocoumarol among 222 healthy volunteers after a single oral dose. Associations between a pharmacodynamic index (reduction in factor VII activity and international normalized ratio [INR] change) and several genetic polymorphisms (VKORC1: -4931T>C, -4451C>A, -2659G>C, -1877A>G, -1639G>A, 497C>G, 1173C>T, and CYP2C9*3) were investigated using haplotype and univariate analyses. VKORC1 haplotypes were associated with the pharmacologic response, and this association can be explained only by the effect of the -1639G>A polymorphism (or alternatively by 1173C>T, which is in complete association with it). Indeed, it explains about one third of the variability of the pharmacologic response (37% of factor VII decrease and 30% of INR change). Moreover, the previously observed effect of the CYP2C9*3 allele is independent of the VKORC1 gene effect. These 2 polymorphisms account for up to 50% of the interindividual variability. The simple genotyping of 2 single-nucleotide polymorphisms (SNPs), VKORC1 -1639G>A or 1173C>T and the CYP2C9*3 polymorphisms, could thus predict a high risk of overdose before initiation of anticoagulation with acenocoumarol, and provide a safer and more individualized anticoagulant therapy.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique, University René Descartes, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bodin
authors.forename: Céline
authors.initials: C
authors.lastname: Verstuyft
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Tregouet
authors.forename: Annie
authors.initials: A
authors.lastname: Robert
authors.forename: Liliane
authors.initials: L
authors.lastname: Dubert
authors.forename: Christian
authors.initials: C
authors.lastname: Funck-Brentano
authors.forename: Patrice
authors.initials: P
authors.lastname: Jaillon
authors.forename: Philippe
authors.initials: P
authors.lastname: Beaune
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.forename: Laurent
authors.initials: L
authors.lastname: Becquemont
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Loriot
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D065729:Cytochrome P-450 CYP2C9; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D017930:Genes, Reporter; D006239:Haplotypes; D006801:Humans; D016014:Linear Models; D008113:Liver Neoplasms; D008156:Luciferases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011237:Predictive Value of Tests; D064417:Vitamin K Epoxide Reductases
chemical_list: D000925:Anticoagulants; D006899:Mixed Function Oxygenases; D008156:Luciferases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol