This allelic variant is also known as CYP2C19*2 and CYP2C19m1.
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.
Using PCR, Kaneko et al. (1997) determined the distribution of the CYP2C19*2 and CYP2C19*3 (124020.0003) 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. Further studies showed that homozygosity or compound heterozygosity for the mutations were associated with poor metabolism of proguanil, which is recommended for malaria chemoprophylaxis. 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.
Among 1,419 patients with acute coronary syndrome on dual antiplatelet treatment, including clopidogrel and aspirin, Giusti et al. (2007) found an association between carriers of the CYP2C19*2 polymorphism and increased residual platelet reactivity, as evaluated by platelet aggregation studies. The active metabolite of clopidogrel arises from complex biochemical reactions involving several P450 isoforms, including CYP2C19.
In a population-based study of 359 unrelated mainland Chinese, consisting of 103 Han, 107 Kazakh, and 149 Uygur individuals, Wang et al. (2009) found that the frequency of the CYP2C19*2 allele was significantly lower in the Kazakh and Uygur populations (15.4% and 16.1%, respectively) compared to the Han population (28.8%).
