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Blood, 1 July 2005, Vol. 106, No. 1, pp. 135-140.
Prepublished online as a Blood First Edition Paper on March 24, 2005; DOI 10.1182/blood-2005-01-0341.
 Previous Article | Next Article 
Submitted January 26, 2005
Accepted March 2, 2005
Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity
Laurent Bodin, Celine Verstuyft, David-Alexandre Tregouet, Annie Robert, Liliane Dubert, Christian Funck-Brentano, Patrice Jaillon, Philippe Beaune*, Pierre Laurent-Puig, Laurent Becquemont, and Marie-Anne Loriot
INSERM, UMRS 490, University Rene Descartes, Paris, France
Assistance Publique Hopitaux de Paris; Pharmacology Department, Bicetre University Hospital, University Paris-Sud, Le Kremlin Bicetre, France; Assistance Publique Hopitaux de Paris; Pharmacology Department, Saint Antoine University Hospital-University Pierre et Marie Curie Paris 6, Paris, France
INSERM, U525, Faculte de Medecine, Hopital Pitie-Salpetriere, Paris, France
Department of Immunology and Hematology, Saint-Antoine Hospital, Paris, France
Assistance Publique Hopitaux de Paris; Pharmacology Department, Saint Antoine University Hospital-University Pierre et Marie Curie Paris 6, Paris, France
Clinical Investigation Center, Saint-Antoine Hospital, Paris, France
Assistance Publique Hopitaux de Paris; Pharmacology Department, Bicetre University Hospital, University Paris-Sud, Le Kremlin Bicetre, France; Clinical Investigation Center, Saint-Antoine Hospital, Paris, France
INSERM, UMRS 490, University Rene Descartes, Paris, France; Assistance Publique Hopitaux de Paris; Biochemistry Department, European Georges Pompidou Hospital, Paris, France
* Corresponding author; email: Philippe.Beaune{at}univ-paris5.fr.
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 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 pharmacological 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 pharmacological 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 two polymorphisms account for up to 50% of the inter-individual variability. The simple genotyping of two 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.
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