A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in VKORC1 and CYP2C9

Abstract

Aims: To determine the cause of a genotype-phenotype discordancy for acenocoumarol sensitivity. Methods: A patient, highly sensitive to acenocoumarol, and previously determined to carry only a single CYP2C9 *3 allele, was genotyped for additional functionally defective alleles in the CYP2C9 and VKORC1 genes. Family members were also analyzed to trace the pedigree. Results: The acenocoumarol-sensitive patient was found to possess, in addition to CYP2C9 *3 allele, a CYP2C9 *11 allele and the VKORC1 AA diplotype which were all traced back through the parental lines. Conclusions: Acenocoumarol sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the CYP2C9 and VKORC1 genes. The study provides additional data in support of diminished CYP2C9 activity due to the presence of the rare *11 allele. © 2006 The Authors.