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Characterization of a novel CYP2C9 gene mutation and structural bioinformatic protein analysis in a warfarin hypersensitive patient.

TitleCharacterization of a novel CYP2C9 gene mutation and structural bioinformatic protein analysis in a warfarin hypersensitive patient.
Publication TypeJournal Article
Year of Publication2011
AuthorsCiccacci, C, Falconi, M, Paolillo, N, Oteri, F, Forte, V, Novelli, G, Desideri, A, Borgiani, P
JournalPharmacogenet Genomics
Volume21
Issue6
Pagination344-6
Date Published2011 Jun
ISSN1744-6880
KeywordsAnticoagulants, Aryl Hydrocarbon Hydroxylases, Computational Biology, Cytochrome P-450 CYP2C9, Cytochrome P-450 Enzyme System, Genotype, Humans, Mixed Function Oxygenases, Mutation, Vitamin K Epoxide Reductases, Warfarin
Abstract

Warfarin (coumadin) is a worldwide-prescribed anticoagulant for the long-term treatment and prevention of thromboembolic events, presenting a great interindividual variability in the required dose. It is known that both environmental and genetic factors influence the dose necessary for the therapeutic effect. Herein we describe a pharmacogenetic study conducted on an Italian patient with warfarin hypersensitivity, who required a very low dosage to achieve therapeutic anticoagulation effect. We genotyped common polymorphisms in VKORC1, CYP2C9, and CYP4F2 genes, known to be involved in warfarin dosing. As the patient resulted in a mixture of low-dosing and high-dosing polymorphic variants, we searched for rare mutations by direct sequencing of the same genes. We identified in the CYP2C9 gene, a novel mutation in heterozygote status, c.374G>T, which produces the Arg125Leu substitution. We have observed, through an electrostatic analysis, that the new mutation produces an electrostatic alteration on the cytochrome surface.

DOI10.1097/FPC.0b013e328344c340
Alternate JournalPharmacogenet. Genomics
PubMed ID21451434