Genetic variations and haplotypes of CYP2C19 in a Japanese population.

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Fukushima-Uesaka H, Saito Y, Maekawa K, Ozawa S, Hasegawa R, Kajio H, Kuzuya N, Yasuda K, Kawamoto M, Kamatani N, Suzuki K, Yanagawa T, Tohkin M, Sawada J

Genetic variations and haplotypes of CYP2C19 in a Japanese population.

Drug Metab Pharmacokinet. 2005 Aug;20(4):300-7.

PubMed ID

16141610 [ View in PubMed

]

Abstract

Forty-eight single nucleotide variations, including 27 novel ones, were found in the 5'- regulatory region, all of the exons and their surrounding introns of CYP2C19 in 253 Japanese subjects (134 diabetic patients and 119 healthy volunteers). Identified novel variations were as follows: -2772G>A, 2767_-2760delGGTGAACA, -2720T>C, -2547delG, -2545G>T, -2545_-2544 delGC, and -2040C>T in the enhancer region; -778C>T, -777G>A, -529G>C, -189C>A, and -185A>G in the promoter region; 151A>G (S51G), 481G>C (A161P), 986G>A (R329H), 1078G>A (D360N), and 1119C>T (D373D) in the exons, and IVS1+128T>A, IVS3+163G>A, IVS4+271A>G, IVS5-49A>G, IVS6-210C>T, IVS6-196T>A, IVS6-32T>A, IVS7+84G>A, IVS7-174C>T, and IVS8+64C>T in the introns. Since we found no significant differences in the variation frequencies between healthy volunteers and diabetic patients, the data for all subjects were treated as one group in further analysis. The allele frequencies were 0.265 for IVS6-196T>A, 0.045 for -2772G>A and -2720T>C, 0.024 for -2040C>T, 0.014 for IVS7-174C>T, 0.010 for -529G>C, 0.006 for IVS1+128T>A and 481G>C (A161P), 0.004 for -2767_-2760delGGTGAACA and IVS6-210C>T, and 0.002 for the other 17 variations. In addition, the two known nonsynonymous single nucleotide polymorphisms, 681G>A (splicing defect, (*)2 allele) and 636G>A (W212X; (*)3 allele) were detected at 0.267 and 0.128 frequencies, respectively. No variation was detected in the known binding sites for constitutive androstane receptor and glucocorticoid receptor. Linkage disequilibrium analysis showed several close linkages of variations throughout the gene. By using the variations, thirty-one haplotypes of CYP2C19 and their frequencies were estimated. Our results would provide fundamental and useful information for genotyping CYP2C19 in the Japanese and probably other Asian populations.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Cytochrome P450 2C19	P33261	Details

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Amitriptyline	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2A	Not Available	681G>A (rs4244285)	ADR Inferred	Those with the AA or AG genotype are poor metabolizers of amitriptyline	Details
Amitriptyline	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*3	Not Available	636G>A (rs4986893)	ADR Inferred	Those with the AA or AG genotype are poor metabolizers of amitriptyline	Details
Omeprazole	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2A	Not Available	681G>A (rs4244285)	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Clobazam	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2A	Not Available	681G>A (rs4244285)	ADR Inferred	Clobazem is metabolized into N-desmethylclobazem (NCLB) mostly by CYP3A4. NCLB is primarily metabolized by 2C19. Those with one 2C192 allele mutation (1/2) are intermediate metabolizers of NCLB. Those with two (2/2) mutations will metabolize NCLB poorly in comparisone to extensive metabolizers (1/1). Levels of NCLB can be five times higher in poor metabolizers, and two times higher in intermediate metabolizers as compared to individuals who are extensive metabolizers. The safety and efficacy of clobazem may be affected by polymorphic expression of CYP2C192.	Details
Clobazam	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*3	Not Available	636G>A (rs4986893)	ADR Inferred	Clobazem is metabolized into N-desmethylclobazem (NCLB) mostly by CYP3A4. NCLB is primarily metabolized by 2C19. Those with one 2C192 allele mutation (1/2) are intermediate metabolizers of NCLB. Those with two (2/2) mutations will metabolize NCLB poorly in comparisone to extensive metabolizers (1/1). Levels of NCLB can be five times higher in poor metabolizers, and two times higher in intermediate metabolizers as compared to individuals who are extensive metabolizers. The safety and efficacy of clobazem may be affected by polymorphic expression of CYP2C192.	Details
Lansoprazole	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2A	Not Available	681G>A (rs4244285)	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Mephenytoin	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2A	Not Available	681G>A (rs4244285)	Effect Inferred	Poor metabolizer, lower dose requirement	Details
Esomeprazole	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2A	Not Available	681G>A (rs4244285)	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Clopidogrel	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2A	Not Available	681G>A (rs4244285)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for drug-drug interactions	Details
Clopidogrel	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*3	Not Available	636G>A (rs4986893)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for drug-drug interactions	Details
Proguanil	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2A	Not Available	681G>A (rs4244285)	Effect Inferred	Poor metabolizer, lower dose requirement	Details
Gliclazide	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2A	Not Available	681G>A (rs4244285)	Effect Inferred	Poor drug metabolizer.	Details