RESUMO
This study was designed to investigate the potential differences between Spaniards and Ecuadorian Mestizo people regarding CYP2C8, CYP2C9, and CYP2C19 genetic polymorphisms. DNA from 282 Spaniard and 297 Ecuadorian subjects were analyzed by either a previously reported pyrosequencing method (CY2C8*3, CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3) or a nested PCR technique (CYP2C19*17). Whereas CYP2C19*17 allele distribution was higher in Ecuadorians than in Spaniards (P < 0.001) and the frequency of CYP2C19*3 was similar in these two populations (P > 0.05), the other allelic variants were detected at significantly lower frequencies in Ecuadorians than in Spaniards (P < 0.05). According to the diplotype distributions, the prevalence of the presumed CYP2C9 and CYP2C8 extensive metabolizers was higher in Ecuadorians than in Spaniards (P < 0.05). Individuals genotyped CYP2C19*1/*17 and *17/*17 who were considered as ultrarapid metabolizers were overrepresented in Ecuadorians in relation to Spaniards (P < 0.001). By contrast, among Ecuadorians no poor metabolizers (PMs) of either CYP2C8 or CYP2C9 were found and only two individuals were CYP2C19 PMs. These data are compatible with a higher CYP2C8, CYP2C9, and CYP2C19 activity in Mestizo Ecuadorians as opposed to Spaniards, which could imply differences in dosage requirements for drugs metabolized by these cytochromes and should also be considered in allele-disease association studies.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Genética Populacional , Adulto , Alelos , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP2C9 , Equador , Feminino , Humanos , Inativação Metabólica/genética , Indígenas Sul-Americanos/genética , Masculino , Polimorfismo Genético , População Branca/genéticaRESUMO
This study was designed to investigate the potential differences between Spaniards and Ecuadorian Mestizo people regarding CYP2A6*1A, CYP2A6*1B1, CYP2A6*1x2A, CYP2A6*9A, and CYP2A6*4A variant alleles at the CYP2A6 gene and also to compare the observed frequencies with those previously reported in different ethnic groups. DNA from 234 Spaniard and 300 Ecuadorian subjects were analyzed by either PCR or PCR-restriction fragment length polymorphism. Differences between Spaniards and Mestizo Ecuadorians were detected in relation to the frequencies of the alleles linked to either absent enzyme activity, CYP2A6*4A (4 and 7.1%, respectively), or reduced CYP2A6 enzyme activity, CYP2A6*9A (6.4 and 10.3%, respectively). CYP2A6*4A and CYP2A6*9A frequencies in Ecuadorians were higher than those in Africans or Caucasian groups and lower than those in Asians. This study provides, for the first time, the result of the analysis of CYP2A6 allele frequency in a South American population and demonstrates the presence of ethnic differences in CYP2A6 genetic variants between Spaniards and Mestizo Ecuadorians, which should be considered in allele-disease association studies and, in particular, in those involving CYP2A6 genetic polymorphisms and tobacco-related cancer.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Frequência do Gene , Adolescente , Adulto , Alelos , Hidrocarboneto de Aril Hidroxilases/metabolismo , Povo Asiático/genética , População Negra/genética , Citocromo P-450 CYP2A6 , DNA , Equador/etnologia , Etnicidade/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Nicotina , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único/fisiologia , Fumar/patologia , Espanha/etnologia , Tabaco sem Fumaça/toxicidade , População Branca/genética , Adulto JovemRESUMO
This study was aimed to investigate the potential differences in allele frequencies of the CYP2B6 gene between Spaniards and Central Americans. Three single nucleotide polymorphisms of the CYP2B6 gene 516 G>T, 785 A>G and 1459 C>T were assayed by a polymerase chain reaction in 180 Spaniards and 182 Central Americans. The allele frequencies for CYP2B6*1, CYP2B6*4, CYP2B6*5, CYP2B6*6, CYP2B6*9 in Spaniards and Central Americans were 0.593 and 0.642, 0.062 and 0.073, 0.113 and 0.030, 0.215 and 0.230, 0.014 and 0.023, respectively. CYP2B6*5 was less prevalent among Central Americans than in Spaniards (P < 0.001). In comparison to other previously studied populations, the CYP2B6*5 allele frequency among Spaniards was similar to other Caucasian or African groups, and higher than that in Asian populations. The CYP2B6*5 allele frequency in Central Americans was lower than that in Africans or Caucasian groups and higher than in Asians. The results indicate the presence of ethnic differences in CYP2B6 genetic variants between Spaniards and Central Americans, and support the need for further investigations to explore whether these differences significantly alter the efficacy or toxicity of CYP2B6 substrate drugs.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Etnicidade/genética , Oxirredutases N-Desmetilantes/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , América Central , Citocromo P-450 CYP2B6 , Feminino , Frequência do Gene , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Espanha , População Branca/genética , Adulto JovemRESUMO
Polymorphisms in CYP3A genes, such as CYP3A5} and CYP3A4, as well as in the MDR1 gene, which encodes for P-glycoprotein, have been implicated as genetic markers in several disorders. Differences in the frequency distribution of the allelic variants CYP3A5 3, CYP3A4 1B, and MDR1 3435T have been demonstrated between distinct ethnic groups. In this study we examined the frequency of these allelic variants in 317 healthy Mestizo individuals from Ecuador and made comparisons with results reported in the literature. The genotypes were determined by PCR-RFLP. Allele and genotype differences were studied by chi-square test. The MDR1 T allele frequency was similar to that of Spaniard or Asian populations, which is consistent with the ethnic origin of Ecuadorian Mestizo individuals (Amerindian and Spaniard Caucasians). By contrast, the CYP3A5 3 allele frequency was significantly lower in Ecuadorians than in Spaniards and other white populations and higher than in Central Americans, Asians and blacks. CYP3A4 1B was more common in Ecuadorians than in Caucasian or Asian populations but less present than in blacks. The differences in the polymorphism found in this work should be considered in allele-disease association studies.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Citocromo P-450 CYP3A/genética , Etnicidade/genética , Polimorfismo Genético/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adolescente , Adulto , Povo Asiático/genética , População Negra/genética , Equador/epidemiologia , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , População Branca/genéticaRESUMO
The human multidrug resistance gene (MDR1) encodes for P-glycoprotein (P-gp) which is a transmembrane transporter protein that acts as an efflux pump for a number of lypophilic compounds. It plays a protective role for cells against DNA damage. The wobble C3435T polymorphism at exon 26 has been associated with different expression levels and activity. Differences in allele frequency of the C3435T polymorphism have been demonstrated between distinct ethnic groups. In our study we examined these polymorphisms in 433 healthy individuals. From these, 229 were Central American mestizos from Nicaragua (n = 117) and El Salvador (n = 112) to be compared with a group of 204 North Spaniards, with the aim of detecting potential genotypic differences between these populations. The genotypes were determined by PCR-RFLP. The frequencies of the C allele were very similar among Central Americans (0.53) and Spaniards (0.52), which is consistent with the ethnic origin of Central American individuals (Amerindians and European Caucasians). In comparison to other previously studied populations, the C allele frequency in Central Americans was significantly lower than that found in African populations and higher than that observed in the Indian and Southwest Asian populations. These data may be relevant for dose recommendation of P-gp substrate drugs and also for studies of allele disease association in the Central American population.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Polimorfismo Genético/genética , Alelos , América Central/etnologia , Citidina/genética , Genótipo , Humanos , Espanha/etnologia , Timidina/genéticaRESUMO
The aim of this study was to detect genotypic differences between three populations of healthy volunteers from Northern Spain (204 subjects), Nicaragua (120 subjects), and El Salvador (112 subjects) regarding CYP3A4*1B and CYP3A5*3 polymorphisms. No significant differences were found by comparing allelic frequencies between the two Central American populations. The CYP3A5*3 allele frequency was significantly different (P < 0.01) between Central Americans (76%) and Spaniards (91%). By contrast, CYP3A4*1B allele was more prevalent among Central Americans (12.5%) than among North Spaniards (4%) (P < 0.01). Analysis of CYP3A4-3A5 genotype combinations revealed that individuals carrying CYP3A4*1B/CYP3A5*1 were more represented in Central Americans (16.9%) than in Spaniards (5.4%), suggesting a marked linkage disequilibrium. These data are compatible with a higher CYP3A enzyme activity in Central Americans as opposed to Spaniards and other white groups, which could imply differences in dose requirements for drugs metabolized by CYP3A and should be considered in allele-disease association studies.