Warfarin therapy: influence of pharmacogenetic and environmental factors on the anticoagulant response to warfarin.
Warfarin is difficult to use because of a marked inter- and intraindividual variability among patients in the required dosage. Recent advances in understanding the vitamin K cycle have been made. Besides well-known demographic or environmental factors (advanced age, vitamin K intake, concomitant drugs, comorbid conditions, and acute illnesses), genetic single nucleotide polymorphisms (SNPs) have been identified as strongly affecting the maintenance dosage and its variability. SNPs of vitamin K epoxide reductase complex subunit-1 (VKORC1) gene have been identified, affecting the enzyme shown as one of the target of vitamin K antagonist. SNPs of cytochrome P450 2C9 (CYP2C9) gene have been shown to decrease the catabolism of warfarin. The combined analysis of VKORC1, CYP2C9 SNPs, and age may account for more than 50% of the individual variability in the warfarin maintenance dosage. Predicting models of warfarin maintenance dosage taking into account these individual parameters are currently developed.
Siguret
Virginie
V
Laboratoire d'Hématologie, Assistance-Publique Hôpitaux de Paris, Hôpital Charles Foix, 94205 Ivry-sur-Seine, France.
Pautas
Eric
E
Gouin-Thibault
Isabelle
I
D000925:Anticoagulants / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001777:Blood Coagulation; D065729:Cytochrome P-450 CYP2C9; D004777:Environment; D006801:Humans; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D014812:Vitamin K / Q000037:antagonists & inhibitors / Q000502:physiology; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin; 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