Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism.

Article Details

Citation

Copy to clipboard

King BP, Khan TI, Aithal GP, Kamali F, Daly AK

Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism.

Pharmacogenetics. 2004 Dec;14(12):813-22.

PubMed ID

15608560 [ View in PubMed

]

Abstract

OBJECTIVES: To assess whether CYP2C9 alleles other than CYP2C9*2 and *3 are associated with a low-warfarin dose requirement and the relevance of upstream CYP2C9 polymorphisms to dose requirement and metabolism. METHODS: CYP2C9 exons, intron-exon boundaries and 3 kb of upstream sequence in 20 patients requiring or= 0.01, was obtained. In individuals negative for coding region polymorphisms, neither individual genotypes for T-1188C or DeltaG-2664DeltaT-2665 or particular combinations of haplotype pairs were predictive of dose requirement or S-warfarin total clearance, suggesting neither upstream polymorphism was functionally significant. Dose requirements in CYP2C9*11 heterozygotes were not statistically significantly different from homozygous wild-type individuals. CONCLUSIONS: The coding region non-synonymous polymorphisms associated with the CYP2C9*2 and CYP2C9*3 alleles are the major CYP2C9-related factor affecting warfarin dose in UK Caucasians. Upstream CYP2C9 polymorphisms do not appear to be important independent determinants of dose requirement.

DrugBank Data that Cites this Article

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Warfarin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*2	(T;T) / (C;T)	T Allele (rs1799853)	Effect Directly Studied	Patients with this genotype have reduced metabolism of warfarin.	Details
Phenytoin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*2	Not Available	430C>T (rs1799853)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Phenytoin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*11	Not Available	1003C>T (rs28371685)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Celecoxib	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*2	Not Available	430C>T (rs1799853)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Celecoxib	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*11	Not Available	1003C>T (rs28371685)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Warfarin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*3	Not Available	1075A>C (rs1057910)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Warfarin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*11	Not Available	1003C>T (rs28371685)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Clopidogrel	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*2	Not Available	430C>T (rs1799853)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for drug-drug interactions	Details
Clopidogrel	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*11	Not Available	1003C>T (rs28371685)	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*2	Not Available	430C>T (rs1799853)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Acetylsalicylic acid	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*11	Not Available	1003C>T (rs28371685)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Glipizide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*2	Not Available	430C>T (rs1799853)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Glipizide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*11	Not Available	1003C>T (rs28371685)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Tolbutamide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*2	Not Available	430C>T (rs1799853)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Tolbutamide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*11	Not Available	1003C>T (rs28371685)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Acenocoumarol	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*11	Not Available	1003C>T (rs28371685)	Effect Inferred	Poor drug metabolizer, associated with lower dose requirement.	Details
Phenprocoumon	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*3	Not Available	1075A>C (rs1057910)	ADR Inferred	Associated with delayed stabilization. If carrier of rs9934438 as well, increased risk of severe overanticoagulation.	Details
Phenprocoumon	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*11	Not Available	1003C>T (rs28371685)	ADR Inferred	Associated with delayed stabilization. If carrier of rs9934438 as well, increased risk of severe overanticoagulation.	Details