Departamento de Farmácia, Laboratório de Pesquisa de Ciências Farmacêuticas (LAPESF), Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, Brazil.
Departamento de Endemias Samuel Pessoa, Escola Nacional de Saúde Pública, Fundação Oswaldo Cruz (ENSP/Fiocruz), Rio de Janeiro, Brazil.
Pharmacogenet Genomics. 2024 Dec 1;34(9):269-274. doi: 10.1097/FPC.0000000000000544. Epub 2024 Sep 10.
We report, for the first time, the distribution of four no-function NAT2 single nucleotide polymorphisms and inferred NAT2 acetylator phenotypes in three indigenous groups (Munduruku, Paiter-Suruí, and Yanomami), living in reservation areas in the Brazilian Amazon.
Two hundred and seventy-six participants from three indigenous groups (92 for each group) were included and genotyped for four NAT2 polymorphisms (rs1801279, rs1801280, rs1799930, and rs1799931) by the TaqMan system. Minor Allele Frequency (MAF) was determined and NAT2 acetylator phenotypes were inferred.
NAT2 rs1801279G>A was absent in all cohorts; rs1799930G>A was absent in Yanomami and rare (MAF 0.016) in Munduruku and Paiter-Suruí; MAF of rs1801280T>C ranged five-fold (0.092-0.433), and MAF of rs1799931G>A varied between 0.179 and 0.283, among the three groups. The distribution of NAT2 phenotypes differed significantly across cohorts; the prevalence of the slow acetylator phenotype ranged from 16.3% in Yanomami to 33.3% in Munduruku to 48.9% in Paiter-Suruí. This three-fold range of variation is of major clinical relevance because the NAT2 slow phenotype is associated with higher risk of hepatotoxicity with antituberculosis chemotherapy and high incidence rates of tuberculosis and burden of latent infection among Munduruku, Paiter-Surui, and Yanomami peoples. According to the frequency of the NAT2 slow acetylator phenotype, the estimated number of individuals needed to be genotyped to prevent one additional event of hepatotoxicity range from 31 (Munduruku) to 39 (Paiter-Surui) and to 67 (Yanomami).
The rs1801279 polymorphism was not found in any of the cohorts, while the MAF of the other polymorphisms showed significant variation between the cohorts. The difference in the prevalence of the NAT2 slow acetylator phenotype, which is linked to isoniazid-induced hepatotoxicity, was observed in the different study cohorts.
我们首次报道了四个无功能 NAT2 单核苷酸多态性在三个居住在巴西亚马逊地区保留地的原住民群体（Munduruku、Paiter-Suruí 和 Yanomami）中的分布，并推断了 NAT2 乙酰化表型。
我们纳入了三个原住民群体的 276 名参与者（每个群体 92 名），并通过 TaqMan 系统对四个 NAT2 多态性（rs1801279、rs1801280、rs1799930 和 rs1799931）进行了基因分型。确定了次要等位基因频率（MAF），并推断了 NAT2 乙酰化表型。
NAT2 rs1801279G>A 在所有队列中均不存在；rs1799930G>A 在 Yanomami 中罕见（MAF 0.016），在 Munduruku 和 Paiter-Suruí 中罕见（MAF 0.016）；rs1801280T>C 的 MAF 范围为五倍（0.092-0.433），rs1799931G>A 的 MAF 范围为 0.179 至 0.283，三组之间存在差异。NAT2 表型的分布在队列之间存在显著差异；慢乙酰化表型的患病率在 Yanomami 中为 16.3%，在 munduruku 中为 33.3%，在 Paiter-Suruí 中为 48.9%。这种三倍的变异范围具有重要的临床意义，因为 NAT2 慢表型与抗结核化疗的肝毒性风险增加以及 munduruku、paiter-surui 和 Yanomami 人群中结核病的高发病率和潜伏感染负担有关。根据 NAT2 慢乙酰化表型的频率，估计要进行基因分型以预防额外的肝毒性事件，所需的个体数量在 31（Munduruku）到 39（Paiter-Surui）之间，在 67（Yanomami）之间。
rs1801279 多态性在任何队列中均未发现，而其他多态性的 MAF 在队列之间存在显著差异。在不同的研究队列中观察到 NAT2 慢乙酰化表型的患病率差异，该表型与异烟肼诱导的肝毒性有关。
