AUTHOR=Perini Jamila Alessandra , Basta Paulo Cesar , Suarez-Kurtz Guilherme 

TITLE=NUDT15 and TPMT polymorphisms in three distinct native populations of the Brazilian Amazon

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1359570

DOI=10.3389/fphar.2024.1359570

ISSN=1663-9812

ABSTRACT=<p>This is the first report of the distribution of <italic>TPMT</italic> and <italic>NUDT15</italic> 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 <italic>NUDT15</italic> rs116855232 did not differ significantly across the groups; <italic>TPMT</italic> 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 (<italic>p</italic> &lt; 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, <italic>versus</italic> 41% Paiter-Suruí. The proportion of Paiter-Suruí at risk of thiopurine intolerance is 3- to 4-fold higher than any other population worldwide.</p>