title: A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in VKORC1 and CYP2C9.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA. rettie@u.washington.edu
authors.forename: Allan E
authors.initials: AE
authors.lastname: Rettie
authors.forename: Frederico M
authors.initials: FM
authors.lastname: Farin
authors.forename: Nitasha G
authors.initials: NG
authors.lastname: Beri
authors.forename: Sengkeo L
authors.initials: SL
authors.lastname: Srinouanprachanh
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Henk H
authors.initials: HH
authors.lastname: Thijssen
mesh_terms: D000074:Acenocoumarol / Q000009:adverse effects*; D000925:Anticoagulants / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004342:Drug Hypersensitivity / Q000209:etiology*; D005260:Female; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000009:adverse effects*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; 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