Cyp2c19 Asian Population

[Brinda]

Shephardet al. (1989) isolated a cDNA encoding CYP2C19, a novel member of the P450IIC subfamily in man. Northern blot hybridization of RNA isolated from human livers showed a 10-fold interindividual variation in the expression of the gene, suggesting that expression may be constitutive and not greatly influenced by environmental factors. The finding is in contrast to that with the CYP2A subfamily (see 122720), in which members exhibit a 1,000-fold interindividual variation in level of expression.

Studies of Wrighton et al. (1993) and of Goldstein et al. (1994) demonstrated a correlation between the levels of CYP2C19 protein and microsomal S-mephenytoin 4-prime-hydroxylase activity in human liver.

Thum and Borlak (2000) investigated the gene expression of major human cytochrome P450 genes in various regions of explanted hearts from 6 patients with dilated cardiomyopathy and 1 with transposition of the arterial trunk and 2 samples of normal heart. mRNA for cytochrome 2C19 was predominantly expressed in the right ventricle. A strong correlation between tissue-specific gene expression and enzyme activity was found. Thum and Borlak (2000) concluded that their findings showed that expression of genes for cytochrome P450 monooxgenases and verapamil metabolism are found predominantly in the right side of the heart, and suggested that this observation may explain the lack of efficacy of certain cardioselective drugs.

By somatic cell hybridization and in situ hybridization, Riddell et al. (1987) and Spurr et al. (1987) assigned a gene for the cytochrome P450 with mephenytoin 4-prime-hydroxylase activity (CYP2C) to chromosome 10q24.1-q24.3. Meehan et al. (1988) mapped the mouse cluster of genes to a region of chromosome 19 that appears to be homologous with the region of human chromosome 10 containing the CYP2C locus. Seven or 8 genes were clustered in a small area of 1 cM. Meehan et al. (1988) found that the CYP2C gene family in the mouse segregates to within 1-2 cM of a locus-controlling constitutive aryl hydrocarbon hydroxylase activity. Although apparent recombination might suggest that the control of AHH activity is mediated by a different but closely linked locus, Meehan et al. (1988) were of the opinion that AHH activity is encoded by the P450-2C genes. Man contains fewer genes in this cluster than do mice and rats. Sequence comparison suggests nonorthology of human cDNA clones to sequenced rat forms of the enzyme, raising an important question as to the appropriateness of the rodent model for human P450 function, in carcinogenesis, for example.

By analysis using Southern blot hybridization of DNA from a panel of 9 independent human-rodent somatic cell hybrids, Shephard et al. (1989) demonstrated that the CYP2C gene is located on human chromosome 10.

Using fluorescence in situ hybridization, Inoue et al. (1994) localized 3 genes of the CYP2C subfamily, CYP2C8 (601129), CYP2C9 (601130), and CYP2C10, to chromosome 10q24.1. Using a combination of STS and restriction mapping to characterize YAC clones, Gray et al. (1995) constructed a 2.4-Mb physical map that incorporated the CYP2C gene cluster. They found that the cluster spans approximately 500 kb on proximal 10q24 and comprises 4 genes arranged in the following order and orientation: Cen--RBP4 (180250)--CYP2C18 (601131)--CYP2C19--CYP2C9--CYP2C8--Tel. Primers specific for CYP2C10 gave no PCR product from either YACs or human genomic DNA, suggesting either PCR failure or that CYP2C10 is either frequently deleted or does not exist in the genome and is a cloning artifact. Subsequent Southern blot analysis implied the latter. Given that the CYP2C9 and CYP2C10 sequences show only 2 base differences in the coding region while showing marked difference in the 3-prime untranslated sequence, it seems likely that CYP2C10 is a cloning artifact derived from CYP2C9. Gray et al. (1995) concluded that there are no other CYP2C genes in the 10q24 cluster than the 4 mentioned. The close proximity of the serum retinol binding protein gene, RBP4, has its counterpart in the mouse where these genes are linked on chromosome 19.

CYP2C19 is the cytochrome P450 enzyme that is the site of the defect in metabolism of mephenytoin and a number of other drugs. Studies of Wrighton et al. (1993) and of Goldstein et al. (1994) had demonstrated a correlation between the levels of CYP2C19 protein and microsomal S-mephenytoin 4-prime-hydroxylase activity in human liver. The molecular defect in CYP2C19 responsible for the poor metabolizer phenotype was identified by de Morais et al. (1994) and is referred to as the CYP2C19*2 allele (124020.0001).

Using direct sequencing and subcloning, Ohkubo et al. (2006) identified a novel mutation in the CYP2C19 gene, a 639C-G transversion which overlaps with the BamHI recognition site and thus was considered to be CYP2C19*3 by PCR-RFLP. Ohkubo et al. (2006) noted that many population studies use only PCR-RFLP, and suggested that alleles that have been identified as CYP2Y19*3 may include other mutations and should be confirmed by sequence analysis.

Proguanil, which is metabolized in the liver to its active form, cycloguanil, is recommended for malaria chemoprophylaxis in the face of chloroquine resistance in Plasmodium falciparum. Kaneko et al. (1997) noted that proguanil and mephenytoin metabolisms cosegregate, suggesting that poor mephenytoin metabolizers would also show poor therapeutic efficacy of proguanil. Using PCR, Kaneko et al. (1997) determined the distribution of the CYP2C19*2 and CYP2C19*3 mutations in 493 individuals from 2 of the 80 islands of Vanuatu, where malaria is endemic. The CYP2C19*2 allele represented 698 of 986 alleles (70.6%), and the CYP2C19*3 allele represented 131 of 986 alleles (13.3%). Only 145 individuals had at least 1 wildtype allele. By analyzing serum concentrations of proguanil and cycloguanil, Kaneko et al. (1997) found that the CYP2C19 genotype predicted the proguanil metabolism phenotype of all 20 patients examined. The data suggested that 348 of the 493 individuals (70.6%) studied had the poor metabolizer phenotype, a finding with major implications for the efficacy of proguanil in this population.

Blaisdell et al. (2002) analyzed genomic DNA obtained from cell lines of 92 healthy individuals from 3 different racial groups of varied ethnic background, including Caucasians, Asians, and Africans, and identified 39 SNPs in the CYP2C19 gene. Expression of those SNPs producing coding changes in a bacterial expression system, followed by S-mephenytoin hydroxylation assays, revealed 3 potentially defective alleles present only in individuals of African descent.

Liou et al. (2006) investigated the frequencies of the poor and ultrarapid metabolizer-associated alleles of 5 cytochrome P450 genes in 180 Han Chinese volunteers in Taiwan and found that more than 50% of the CYP2C19 and CYP2D6 (124030) genotypes were associated with the intermediate metabolizer phenotype. Liou et al. (2006) suggested that this might explain why drug dosages used in clinical trials with east Asian participants are usually lower than those used in trials with western participants.

Clopidogrel, used to inhibit adenosine diphosphate-induced platelet aggregation, is a prodrug that must be metabolized in the liver by several CYP proteins to become active. Mega et al. (2009) tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. The authors then examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1,477 subjects with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38. Mega et al. (2009) found that in healthy subjects who were treated with clopidogrel, carriers of at least 1 CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers (P less than 0.001). Among clopidogrel-treated subjects in TRITON-TIMI 38, carriers had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs 8.0%; hazard ratio for carriers, 1.53; 95% confidence interval, 1.07 to 2.19; p = 0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs 0.8%; hazard ratio, 3.09; 95% confidence interval, 1.19 to 8.00; p = 0.02). Mega et al. (2009) concluded that among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers.

Taubert et al. (2009) found that clopidogrel was not biotransformed into the active 2-oxo-clopidogrel when incubated with CYP2C19 in human microsomes. In contrast, omeprazole was transformed into its active form in the same system. Taubert et al. (2009) concluded that SNPs in the CYP2C19 gene may represent only tags for the true causal gene variant involved in clopidogrel activation.

The principal defect in CYP2C19 responsible for the S-mephenytoin poor metabolizer (PM) phenotype (609535) was found by de Morais et al. (1994) to be a G-to-A mutation at nucleotide 681 in exon 5 that created an aberrant splice site. The change altered the reading frame of the mRNA starting with amino acid 215 and produced a premature stop codon 20 amino acids downstream, resulting in a truncated, nonfunctional protein. De Morais et al. (1994) demonstrated that 7 of 10 Caucasian and 10 of 17 Japanese poor metabolizers were homozygous for this defect. The inheritance of the deficient allele was found to be concordant with that of the PM trait. To determine the nature of the defect, since the genomic sequence of CYP2C19 was not yet known, de Morais et al. (1994) developed primers for the intron 4/exon 5 junction empirically. This involved the use of multiple primers for intron 4 based on the sequence of this region in CYP2C9, a closely related gene that shows 95% similarity to CYP2C19 in the upstream region and several exons, and a specific reverse primer for exon 5 of CYP2C19. Because of the aberrant splice site, a 40-bp deletion occurred at the beginning of exon 5 (from bp 643 to bp 682), resulting in deletion of amino acids 215 to 227. The truncated protein had 234 amino acids and would be catalytically inactive because it lacked the heme-binding region. De Morais et al. (1994) developed a simple PCR-based test for the defective CYP2C19 allele.

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