title: A novel, single algorithm approach to predict acenocoumarol dose based on CYP2C9 and VKORC1 allele variants.
abstract: The identification of CYP2C9 and VKORC1 genes has strongly stimulated the research on pharmacogenetics of coumarins in the last decade. We assessed the combined influence of CYP2C9 *2 and *3, and VKORC1 c.-1639G>A, 497C>G, and 1173C>T variants, on acenocoumarol dosage using a novel algorithm approach, in 193 outpatients who had achieved stable anticoagulation. We constructed an "acenocoumarol-dose genotype score" (AGS, maximum score = 100) based on the number of alleles associated with higher acenocoumarol dosage carried by each subject for each polymorphism. The mean AGS was higher in the high-dose (> 28 mg/week) compared with the low-dose (< 7 mg/week) group (mean(SEM) of 84.1+/-3.4 vs. 62.2+/-4.8, P = 0.008). An AGS > 70 was associated with an increased odds ratio (OR) of requiring high acenocoumarol dosage (OR: 3.347; 95%CI: 1.112-10.075; P = 0.032). In summary, although more research is necessary in other patient cohorts, and this algorithm should be replicated in an independent sample, our data suggest that the AGS algorithm could be used to help discriminating patients requiring high acenocoumarol doses to achieve stable anti-coagulation.
authors.affiliation: Universidad Europea de Madrid, Madrid, Spain.
authors.forename: Zoraida
authors.initials: Z
authors.lastname: Verde
authors.forename: Jonatan R
authors.initials: JR
authors.lastname: Ruiz
authors.forename: Catalina
authors.initials: C
authors.lastname: Santiago
authors.forename: Beatriz
authors.initials: B
authors.lastname: Valle
authors.forename: Fernando
authors.initials: F
authors.lastname: Bandrés
authors.forename: Elpidio
authors.initials: E
authors.lastname: Calvo
authors.forename: Alejandro
authors.initials: A
authors.lastname: Lucía
authors.forename: Félix
authors.initials: F
authors.lastname: Gómez Gallego
mesh_terms: D000074:Acenocoumarol / Q000493:pharmacokinetics / Q000494:pharmacology*; D000465:Algorithms; D000483:Alleles; D000925:Anticoagulants / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D064417:Vitamin K Epoxide Reductases
chemical_list: D000925:Anticoagulants; 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; D000074:Acenocoumarol