[Impact of pharmacogenetics on interindividual variability in the response to vitamin K antagonist therapy].
Vitamin K antagonists (VKA) are difficult to use because of a narrow therapeutic index and of a marked inter- and intra individual variability among patients in the required dosage. Beside well known demographic or environmental factors (advanced age, co-morbid conditions, acute illnesses, concomitant drugs, vitamin K intake), genetic single nucleotide polymorphisms (SNPs) have been identified as strongly affecting the maintenance dosage and its variability. First, SNPs of vitamin K epoxide reductase complex subunit-1 (VKORC1) gene have been identified, affecting the enzyme shown as one of the target of VKA. Secondly, SNPs of cytochrome P450 2C9 (CYP2C9) gene have been shown to decrease the catabolism of coumarin derivatives (acenocoumarol, warfarin). Several recent studies have shown that being carrier of at least one mutated allele of either VKORC1 or CYP2C9 (CYP2C9*2, CYP2C9*3) allele is associated with a hypersensitivity to VKA therapy, i.e. a lower maintenance dose. Moreover, it has been associated with an increased risk of over-anticoagulation, a longer time to achieve the maintenance dose and an increased risk of bleeding. Finally, the combined analysis of VKORC1 and CYP2C9 SNPs with age may account for more than 50% of the individual variability of the warfarin maintenance dosage. Predicting models of warfarin maintenance dosage taking into account these individual parameters are currently developed.
Siguret
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Service d'hématologie-hémostase, Inserm U765, faculté des sciences pharmaceutiques et biologiques, université Paris-Descartes (Paris-V), France. virginie.siguret@cfx.aphp.fr
D000925:Anticoagulants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D014644:Genetic Variation; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D014812:Vitamin K / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064417:Vitamin K Epoxide Reductases
D000925:Anticoagulants; D014812:Vitamin K; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases