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

Article Details

Citation

Copy to clipboard

Ciccacci C, Falconi M, Paolillo N, Oteri F, Forte V, Novelli G, Desideri A, Borgiani P

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

Pharmacogenet Genomics. 2011 Jun;21(6):344-6. doi: 10.1097/FPC.0b013e328344c340.

PubMed ID

21451434 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Phenytoin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*35	Not Available	374G>T 430C>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Celecoxib	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*35	Not Available	374G>T 430C>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Warfarin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*35	Not Available	374G>T 430C>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Clopidogrel	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*35	Not Available	374G>T 430C>T	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for drug-drug interactions	Details
Acetylsalicylic acid	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*35	Not Available	374G>T 430C>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Glipizide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*35	Not Available	374G>T 430C>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Tolbutamide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*35	Not Available	374G>T 430C>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Acenocoumarol	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*35	Not Available	374G>T 430C>T	Effect Inferred	Poor drug metabolizer, associated with lower dose requirement.	Details
Phenprocoumon	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*35	Not Available	374G>T 430C>T	ADR Inferred	Associated with delayed stabilization. If carrier of rs9934438 as well, increased risk of severe overanticoagulation.	Details