The influence of self-reported “race/color”, geographical origin and genetic ancestry on the distribution of three functional CYP3A5 polymorphisms, their imputed haplotypes and inferred phenotypes was examined in 909 healthy, adult Brazilians, self-identified as White, Brown or Black (“race/color” categories of the Brazilian census). The cohort was genotyped for CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343), CYP3A5 haplotypes were imputed and CYP3A5 metabolizer phenotypes were inferred according to the number of defective CYP3A5 alleles. Estimates of the individual proportions of Amerindian, African and European ancestry were available for the entire cohort. Multinomial log-linear regression models were applied to infer the statistical association between the distribution of CYP3A5 alleles, haplotypes and phenotypes (response variables), and self-reported Color, geographical region and ancestry (explanatory variables). We found that Color per se or in combination with geographical region associates significantly with the distribution of CYP3A5 variant alleles and CYP3A5 metabolizer phenotypes, whereas geographical region per se influences the frequency distribution of CYP3A5 variant alleles. The odds of having the default CYP3A5*3 allele and the poor metabolizer phenotype increases continuously with the increase of European ancestry and decrease of African ancestry. The opposite trend is observed in relation to CYP3A5*6, CYP3A5*7, the default CYP3A5*1 allele, and both the extensive and intermediate phenotypes. No significant effect of Amerindian ancestry on the distribution of CYP3A5 alleles or phenotypes was observed. In conclusion, this study strongly supports the notion that the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of pharmacogenomic studies, and dealt with as a continuous variable, rather than proportioned in arbitrary categories that do not capture the diversity of the population. The relevance of this work extrapolates the Brazilian borders, and extends to other admixed peoples of the Americas, with ancestral roots in Europe, Africa and the American continent.
Programa de Farmacologia, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil;Programa de Farmacologia, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil;Programa de Farmacologia, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil;Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil;Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brazil;Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil;Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Guamá, PA, Brazil;Instituto Nacional de Ciência e Tecnologia de Medicina Molecular, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil;Programa de Computação Científica, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
Recommended Citation:
Guilherme Suarez-Kurtz,Daniela D. Vargens,Ana Beatriz Santoro,et al. Global Pharmacogenomics: Distribution of CYP3A5 Polymorphisms and Phenotypes in the Brazilian Population[J]. PLOS ONE,2014-01-01,9(1)