Genetic variability of CYP2C19 in a Mexican population: contribution to the knowledge of the inheritance pattern of CYP2C19*17 to develop the ultrarapid metabolizer phenotype

Abstract

CYP2C19 is a polymorphic enzyme that metabolizes a wide variety of therapeutic drugs that has been associated with altered enzymatic activity and adverse drug reactions. Differences in allele frequencies of the CYP2C19 gene have been detected in populations worldwide. Thus, we analysed the alleles CYP2C19*2, CYP2C19*3, CYP2C19*4 and CYP2C19*5 related to the poor metabolizer (PM) phenotype in a Mexican population sample (n = 238), as well as CYP2C19*17, unique allele related to ultrarapid metabolizer phenotype (UMs). Genotypes were determined using SNaPshot and TaqManqPCR assays. In addition to the wild-type CYP2C19*1 allele (77.1%), we only found CYP2C19*17 (14.3%) and CYP2C19*2 (8.6%). Comparison with previous population reports demonstrated that these two SNPs are homogeneously distributed in Latin America (P > 0.05). Based on comparison with a previous pharmacokinetic study that determined the frequency of CYP2C19 phenotypes in the same population (western Mexican), we obtained the following findings: (i) based on the difference between the frequency of genotypes CYP2C19*2/*2 (presumably PM) versus the observed prevalence of PM phenotypes (0.4 versus 6.3%; Χ(2) = 9.58, P = 0.00196), we inferred the plausible presence of novel CYP2C19 alleles related to the PM phenotype; (ii) the prevalence of UMs was in disagreement with the dominant inheritance pattern suggested for CYP2C19*17 (23.1 versus 4%; P < 0.00001); (iii) the apparent recessive inheritance pattern of CYP2C19*17, based on the agreement between homozygous CYP2C19*17/*17 (presumably UMs) and the observed prevalence of UMs (2.1 versus 4%; (Χ(2) = 1.048; P = 0.306).

CYP2C9, CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy

“…[29][30][31][32] In both our patient and volunteer MM samples, we observed a predominance of the wild-type CYP2C19*1 allele, a low frequency of CYP2C19*2 and an absence of CYP2C19*3 allele, as it has been previously reported. [33][34][35][36][37][38] The frequency of CYP2C19*17 allele found in the present study (MM from Central Mexico) shows a minor nonsignificant difference from that found in a recent report in MM from the state of Jalisco (0.09 and 0.14, respectively). 38 The frequency of ABCB1 3435C4T in the MM population studied here is similar to that found in previous reports.…”

“…[33][34][35][36][37][38] The frequency of CYP2C19*17 allele found in the present study (MM from Central Mexico) shows a minor nonsignificant difference from that found in a recent report in MM from the state of Jalisco (0.09 and 0.14, respectively). 38 The frequency of ABCB1 3435C4T in the MM population studied here is similar to that found in previous reports. 39,40 Also comparable with our results were the frequencies of the three ABCB1 polymorphisms reported among individuals with Mexican ancestry living in Los Angeles, California (ABCB1 1236C = 0.540, 2677G = 0.570 and 3435C = 0.540; data from HapMap project consulted in NCBI dbSNP).…”

Correspondence between the CYP2C19 and CYP3A4 genotypes with the inferred metabolizer phenotype by omeprazole administration in Mexican healthy children

“…Among the studied SNPs, only CYP3A4*1B, CYP2C19*2 and CYP2C19* 17 were polymorphic and in agreement with Hardy‐Weinberg expectations; the remaining SNPs were monomorphic (Table ). Comparison with other populations demonstrated homogeneity throughout Latin America for CYP2C19 (data not shown), as previously indicated . The estimated distribution for CYP3A4*1B was similar to Mexican, Tepehuano (Mexican indigenous), Caucasian and Spanish American populations (data not shown; P > .05) .…”

“…Comparison with other populations demonstrated homogeneity throughout Latin America for CYP2C19 (data not shown), as previously indicated. 21 The estimated distribution for CYP3A4*1B was similar to Mexican, Tepehuano (Mexican indigenous), Caucasian and Spanish American populations (data not shown; P > .05). [9][10][11][12][13] Conversely, it was different from Colombian, Central American and one Caucasian population (data not shown; P < .05).…”

Analysis of CYP2C19 Genetic Polymorphism in a Large Ethnic Hakka Population in Southern China

“…Recent data demonstrate significant alteration in the enzyme activity result in variable drug responses and increased rates of thrombotic events in patients harboring hepatic cytochrome gene variants [ 10 , 17 – 19 ]. CYP2C19*2 and CYP2C19*3 alleles, which result in the aberrant splicing and a premature stop codon, respectively, have been extensively studied in populations of different ethnicities and geographic origin [ 20 – 23 ]. Since CYP2C19*2 and *3 cover >90% of the poor metabolism population, the mutation genotype contained *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3.…”