title: Novel associations of VKORC1 variants with higher acenocoumarol requirements.
abstract: BACKGROUND
  Algorithms combining both clinical and genetic data have been developed to improve oral anticoagulant therapy. Three polymorphisms in two genes, VKORC1 and CYP2C9, are the main coumarin dose determinants and no additional polymorphisms of any relevant pharmacogenetic importance have been identified.
  
  
  OBJECTIVE
  To identify new genetic variations in VKORC1 with relevance for oral anticoagulant therapy.
  
  
  RESULTS
  3949 consecutive patients taking acenocoumarol were genotyped for the VKORC1 rs9923231 and CY2C9* polymorphisms. Of these, 145 patients with a dose outside the expected range for the genetic profile determined by these polymorphisms were selected. Clinical factors explained the phenotype in 88 patients. In the remaining 57 patients, all with higher doses than expected, we sequenced the VKORC1 gene and genetic changes were identified in 14 patients. Four patients carried VKORC1 variants previously related to high coumarin doses (L128R, N = 1 and D36Y, N = 3).Three polymorphisms were also detected: rs17878544 (N = 5), rs55894764 (N = 4) and rs7200749 (N = 2) which was in linkage disequilibrium with rs17878544. Finally, 2 patients had lost the rs9923231/rs9934438 linkage. The prevalence of these variations was higher in these patients than in the whole sample. Multivariate linear regression analysis revealed that only D36Y and rs55894764 variants significantly affect the dose, although the improvement in the prediction model is small (from 39% to 40%).
  
  
  CONCLUSIONS
  Our strategy identified novel associations of VKORC1 variants with higher acenocoumarol doses albeit with a low effect size. Further studies are necessary to test their influence on the VKORC1 function and the cost/benefit of their inclusion in pharmacogenetic algorithms.
authors.affiliation: Centro Regional de Hemodonación and Morales Meseguer Hospital, University of Murcia, Murcia, Spain.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Anton
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Cerezo-Manchado
authors.forename: Jose
authors.initials: J
authors.lastname: Padilla
authors.forename: Virginia
authors.initials: V
authors.lastname: Perez-Andreu
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
authors.forename: Vanessa
authors.initials: V
authors.lastname: Roldan
authors.forename: Rocio
authors.initials: R
authors.lastname: Gonzalez-Conejero
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage*; D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage*; D001483:Base Sequence; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008969:Molecular Sequence Data; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*
chemical_list: D000925:Anticoagulants; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol