Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose.

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Zhao F, Loke C, Rankin SC, Guo JY, Lee HS, Wu TS, Tan T, Liu TC, Lu WL, Lim YT, Zhang Q, Goh BC, Lee SC

Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose.

Clin Pharmacol Ther. 2004 Sep;76(3):210-9.

PubMed ID

15371982 [ View in PubMed

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Abstract

BACKGROUND: Commonly occurring genetic variants in CYP2C9 are known to reduce catalytic activity and are associated with enhanced patient sensitivity to warfarin. Interethnic differences in warfarin dose requirement have been described in the Asian population, and we postulate that this could be related to genetic variants of CYP2C9 that are unique to ethnic groups. METHODS: We prospectively genotyped 125 patients who were receiving a stable daily warfarin dose to maintain international normalized ratio values between 2 and 3 through comprehensive sequencing of the promoter and coding regions of the CYP2C9 gene. RESULTS: The mean weight-adjusted warfarin maintenance dose was significantly lower for Malay and Chinese subjects than Indian subjects ( P <.001 and.014, respectively). Warfarin dose negatively correlated with age (r = -0.4, P <.001) but not with sex. Multiple variants were detected in the promoter, exonic, intronic, and 3'-untranslated regions of CYP2C9, of which 16 were novel, including 7 nonsynonymous exonic variants ( 208G>C, 374G>A, 485C>A, 895A>G, 1144C>T, 1190A>C, and 1362G>C ). CYP2C9*3, but not CYP2C9*2, was found in Chinese and Malay patients, and carriers of the CYP2C9*3 variant in Chinese ( P <.01) and Indian ( P <.01) patients, but not Malay patients ( P =.77), required less warfarin. The influence of the novel exonic variants on warfarin dose requirement was unclear, because they were rare, but the lower warfarin dose requirement for Chinese and Malay patients existed despite omission of individuals with any coding region variants from analysis. CONCLUSIONS: Interethnic differences in warfarin dosing in Asian subjects may result from other genetic, dietary, or environmental influences; however, these novel variants in the gene warrant further characterization through functional studies.

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*15	Not Available	485C>A (rs72558190)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Phenytoin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*14	Not Available	374G>A (rs72558189)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Phenytoin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*16	Not Available	895A>G (rs72558192)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Phenytoin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*18	Not Available	1075A>C 1190A>C 1425A>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Celecoxib	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*15	Not Available	485C>A (rs72558190)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Celecoxib	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*14	Not Available	374G>A (rs72558189)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Celecoxib	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*16	Not Available	895A>G (rs72558192)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Celecoxib	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*18	Not Available	1075A>C 1190A>C 1425A>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Warfarin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*15	Not Available	485C>A (rs72558190)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Warfarin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*14	Not Available	374G>A (rs72558189)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Warfarin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*16	Not Available	895A>G (rs72558192)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Warfarin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*18	Not Available	1075A>C 1190A>C 1425A>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Clopidogrel	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*15	Not Available	485C>A (rs72558190)	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*14	Not Available	374G>A (rs72558189)	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*16	Not Available	895A>G (rs72558192)	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*18	Not Available	1075A>C 1190A>C 1425A>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*15	Not Available	485C>A (rs72558190)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Acetylsalicylic acid	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*14	Not Available	374G>A (rs72558189)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Acetylsalicylic acid	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*16	Not Available	895A>G (rs72558192)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Acetylsalicylic acid	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*18	Not Available	1075A>C 1190A>C 1425A>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Glipizide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*15	Not Available	485C>A (rs72558190)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Glipizide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*14	Not Available	374G>A (rs72558189)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Glipizide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*16	Not Available	895A>G (rs72558192)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Glipizide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*18	Not Available	1075A>C 1190A>C 1425A>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Tolbutamide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*15	Not Available	485C>A (rs72558190)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Tolbutamide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*14	Not Available	374G>A (rs72558189)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Tolbutamide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*16	Not Available	895A>G (rs72558192)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Tolbutamide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*18	Not Available	1075A>C 1190A>C 1425A>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Acenocoumarol	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*15	Not Available	485C>A (rs72558190)	Effect Inferred	Poor drug metabolizer, associated with lower dose requirement.	Details
Acenocoumarol	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*14	Not Available	374G>A (rs72558189)	Effect Inferred	Poor drug metabolizer, associated with lower dose requirement.	Details
Acenocoumarol	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*16	Not Available	895A>G (rs72558192)	Effect Inferred	Poor drug metabolizer, associated with lower dose requirement.	Details
Acenocoumarol	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*18	Not Available	1075A>C 1190A>C 1425A>T	Effect Inferred	Poor drug metabolizer, associated with lower dose requirement.	Details
Phenprocoumon	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*15	Not Available	485C>A (rs72558190)	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*14	Not Available	374G>A (rs72558189)	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*16	Not Available	895A>G (rs72558192)	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*18	Not Available	1075A>C 1190A>C 1425A>T	ADR Inferred	Associated with delayed stabilization. If carrier of rs9934438 as well, increased risk of severe overanticoagulation.	Details