title: Influence of genetics and non-genetic factors on acenocoumarol maintenance dose requirement in Moroccan patients.
abstract: OBJECTIVE
  Coumarin derivatives such as acenocoumarol represent the therapy of choice for the long-term treatment and prevention of thromboembolic diseases. Many genetic, clinical and demographic factors have been shown to influence the anticoagulant dosage. Our aim was to investigate the contribution of genetic and non-genetic factors to variability in response to acenocoumarol in Moroccan patients.
  
  
  METHODS
  Our study included 114 adult Moroccan patients, receiving long-term acenocoumarol therapy for various indications. Tests for VKORC1 -1639G>A promoter polymorphism (rs9923231), CYP2C9*2 rs1799853, CYP2C9*3 rs1057910, and CYP4F2 rs2108622 alleles were undertaken using Taq Man(®) Pre-Developed Assay Reagents for allelic discrimination. The statistical analysis was performed using the SAS V9 statistical package.
  
  
  CONCLUSIONS
  Genotyping showed that the allele frequencies for the SNPs studied were no different to those found in Caucasians population. A significant association was observed between the weekly maintenance dose and the VKORC1 (P = 0·0027) and CYP2C9 variant genotypes (P = 0·0082). A final multivariate regression model that included the target International Normalized Ratio, VKORC1 and CYP2C9 genotypes explained 36·2% of the overall interindividual variability in acenocoumarol dose requirement.
  
  
  CONCLUSIONS
  Our study shows large interindividual variability in acenocoumarol maintenance dose requirement in our population. VKORC1 and CYP2C9 variants significantly affected acenocoumarol dose, in-line with results in other populations. For the Moroccan population, the SNPs that have the largest effect on acecoumarol dose are CYP2C9 rs1799853, CYP2C9 rs1057910 and VKORC1 rs9923231.
authors.affiliation: Medical Genetic Laboratory and Molecular Pathology, Medical School, Casablanca, Morocco. smires_fz@yahoo.fr
authors.forename: F Z
authors.initials: FZ
authors.lastname: Smires
authors.forename: C
authors.initials: C
authors.lastname: Moreau
authors.forename: R
authors.initials: R
authors.lastname: Habbal
authors.forename: V
authors.initials: V
authors.lastname: Siguret
authors.forename: S
authors.initials: S
authors.lastname: Fadili
authors.forename: J L
authors.initials: JL
authors.lastname: Golmard
authors.forename: A
authors.initials: A
authors.lastname: Assaidi
authors.forename: P
authors.initials: P
authors.lastname: Beaune
authors.forename: M A
authors.initials: MA
authors.lastname: Loriot
authors.forename: S
authors.initials: S
authors.lastname: Nadifi
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D009018:Morocco; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D013923:Thromboembolism / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol