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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.    Objectives  To identify new genetic variations in  VKORC1  with relevance for oral anticoagulant therapy.    Methods and 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%).    Conclusion  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.

Novel Associations of VKORC1 Variants with Higher Acenocoumarol Requirements