Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity.
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.
Bodin
Laurent
L
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique, University René Descartes, Paris, France.
Verstuyft
Céline
C
Tregouet
David-Alexandre
DA
Robert
Annie
A
Dubert
Liliane
L
Funck-Brentano
Christian
C
Jaillon
Patrice
P
Beaune
Philippe
P
Laurent-Puig
Pierre
P
Becquemont
Laurent
L
Loriot
Marie-Anne
MA
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
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