Interethnic diversity of NAT2 polymorphisms in Brazilian admixed populations

Abstract

BackgroundN-acetyltransferase type 2 (Nat2) is a phase II drug- metabolizing enzyme that plays a key role in the bioactivation of aromatic and heterocyclic amines. Its relevance in drug metabolism and disease susceptibility remains a central theme for pharmacogenetic research, mainly because of its genetic variability among human populations. In fact, the evolutionary and ethnic-specific SNPs on the NAT2 gene remain a focus for the potential discoveries in personalized drug therapy and genetic markers of diseases. Despite the wide characterization of NAT2 SNPs frequency in established ethnic groups, little data are available for highly admixed populations. In this context, five common NAT2 SNPs (G191A, C481T, G590A, A803G and G857A) were investigated in a highly admixed population comprised of Afro-Brazilians, Whites, and Amerindians in northeastern Brazil. Thus, we sought to determine whether the distribution of NAT2 polymorphism is different among these three ethnic groups.ResultsOverall, there were no statistically significant differences in the distribution of NAT2 polymorphism when Afro-Brazilian and White groups were compared. Even the allele frequency of 191A, relatively common in African descendents, was not different between the Afro-Brazilian and White groups. However, allele and genotype frequencies of G590A were significantly higher in the Amerindian group than either in the Afro-Brazilian or White groups. Interestingly, a haplotype block between G590A and A803G was verified exclusively among Amerindians.ConclusionsOur results indicate that ethnic admixture might contribute to a particular pattern of genetic diversity in the NAT2 gene and also offer new insights for the investigation of possible new NAT2 gene-environment effects in admixed populations.

Expression of NAT2 in immune system cells and the relation of NAT2 gene polymorphisms in the anti-tuberculosis therapy in Mexican mestizo population

“…In this latter study, the authors found frequencies of 10.7 % of rapid acetylators, The slow acetylator phenotype is the most common in European populations (59 %) and is highly heterogeneous in Africa and America, in spite of slight geographic changes [34]. Our population displayed the following phenotypic frequencies: 32-39 % of slow acetylators for groups, 32-45 % of intermediate acetylators and 14-35 % of rapid acetylators; these frequencies representing a significant difference from other Central and South American populations [32,[36][37][38][39]. One explanation would be related with the ancestral origins of the Latino populations, as well as the demographic events that each population has suffered.…”

CYP1A2, CYP2A6, CYP2B6, CYP3A4 and CYP3A5 Polymorphisms in Two Bantu-Speaking Populations from Cameroon and South Africa: Implications for Global Pharmacogenetics

“…Interethnic variability in response to the anti-TB drug rifampicin has been explained by variability in CYP2B6 and N-acetyltransferase type 2 (NAT2) expressions [19,59]. For the realization of global pharmacogenetics, funding and capacity development must be emphasized in low and middle income countries so that the level of genomics research can improve health for African populations.…”

Genetic selection of volunteers and concomitant dose adjustment leads to comparable hydralazine/valproate exposure

“…Generally, SNPs in NAT2 reduce the enzymatic activity, decrease its expression, produce enzyme instability or are silent . As a result, NAT2 activity varies widely and its distribution has been characterized as bimodal (fast and slow acetylators) or trimodal (fast, intermediate and slow acetylators) . As NAT2 is not inducible in vivo , genetic polymorphisms are considered the source of interpersonal variability .…”

“…[30][31][32][33] As a result, NAT2 activity varies widely and its distribution has been characterized as bimodal (fast and slow acetylators) or trimodal (fast, intermediate and slow acetylators). [34][35][36] As NAT2 is not inducible in vivo, genetic polymorphisms are considered the source of interpersonal variability. 31,37 When using the trimodal model, NAT2 genotypes or diplotypes (combinations of two haplotypes) can be grouped into three different phenotypes: 'slow acetylator' (two slow alleles), 'intermediate acetylator' (one slow and one rapid allele) and 'fast acetylator' (two fast alleles).…”