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

• Published in: Frontiers in pharmacology Vol. 15; p. 1359570
• Main Authors: Perini, Jamila Alessandra, Basta, Paulo Cesar, Suarez-Kurtz, Guilherme
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 06-02-2024
• Subjects: Brazilian Amazon; genetic polymorphism; native ancestry; NUDT15; Pharmacology; population diversity; TPMT; native ancestry; TPMT; population diversity; thiopurine drug; Brazilian Amazon; NUDT15; genetic polymorphism; pharmacogenetics
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2024.1359570

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.