Perini Jamila Alessandra, Basta Paulo Cesar, Suarez-Kurtz Guilherme
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.
Front Pharmacol. 2024 Feb 6;15:1359570. doi: 10.3389/fphar.2024.1359570. eCollection 2024.
This is the first report of the distribution of and single nucleotide polymorphisms and metabolic phenotypes associated with cytotoxicity of thiopurine drugs, in indigenous groups of Brazilian Amazon: Munduruku, Paiter-Suruí and Yanomami. The minor allele frequency (MAF) of rs116855232 did not differ significantly across the groups; rs1800462 was absent, while rs1800460 and rs1142345 were in strong linkage disequilibrium, and 10- and 30-fold more common in Paiter-Suruí. Indeed, the MAFs in Paiter-Surui (0.193 and 0.188) are the largest report globally. The distribution of combined NUDT15/TPMT metabolic phenotypes differed significantly ( < 0.0001) and largely (Cramér´s V = 0.37) across cohorts. This has important pharmacogenetic implications: the Clinical Pharmacogenetics Implementation Consortium recommendations to reduce or consider reduction of thiopurine dose applies to 4.4% Yanomami, 5.6% Munduruku, 41% Paiter-Suruí. The proportion of Paiter-Suruí at risk of thiopurine intolerance is 3- to 4-fold higher than any other population worldwide.
这是关于巴西亚马逊地区原住民群体（蒙杜鲁库人、派特-苏瑞人和雅诺马马人）中硫嘌呤类药物细胞毒性相关的NUDT15和TPMT单核苷酸多态性分布及代谢表型的首份报告。rs116855232的次要等位基因频率（MAF）在各群体间无显著差异；rs1800462不存在，而rs1800460和rs1142345处于强连锁不平衡状态，且在派特-苏瑞人中的出现频率高出10倍和30倍。实际上，派特-苏瑞人中的MAF（0.193和0.188）是全球报告中的最高值。联合NUDT15/TPMT代谢表型的分布在各队列间存在显著差异（P<0.0001）且差异较大（克莱姆V系数=0.37）。这具有重要的药物遗传学意义：临床药物遗传学实施联盟关于降低或考虑降低硫嘌呤剂量的建议适用于4.4%的雅诺马马人、5.6%的蒙杜鲁库人、41% 的派特-苏瑞人。派特-苏瑞人中硫嘌呤不耐受风险的比例比世界上任何其他人群高出3至4倍。
