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

Jamila Alessandra Perini; Paulo Cesar Basta; Guilherme Suarez-Kurtz

doi:10.3389/fphar.2024.1359570

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

Front Pharmacol. 2024 Feb 6:15:1359570. doi: 10.3389/fphar.2024.1359570. eCollection 2024.

Authors

Jamila Alessandra Perini¹, Paulo Cesar Basta², Guilherme Suarez-Kurtz³

Affiliations

¹ Laboratório de Pesquisa de Ciências Farmacêuticas (LAPESF), Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, Brazil.
² Departamento de Endemias Samuel Pessoa, Escola Nacional de Saúde Pública, Fundação Oswaldo Cruz (ENSP/Fiocruz), Rio de Janeiro, Brazil.
³ Divisão de Pesquisa Clínica e Desenvolvimento Tecnológico, Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.

Abstract

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

Keywords: Brazilian Amazon; NUDT15; TPMT; genetic polymorphism; native ancestry; pharmacogenetics; population diversity; thiopurine drug.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Fieldwork in the Sawré Muybu Indigenous Land was carried out with financial support from the Vice-Presidency of Environment, Care and Health Promotion (VPAAPS) of the Oswaldo Cruz Foundation (Fiocruz), Brazilian Ministry of Health. In the Yanomami Indigenous Land, fieldwork was carried out with financial support from the Parliamentary Amendment of the Federal Deputy for Roraima, Joênia Wapichana. In the Sete de Setembro Indigenous Land, fieldwork was supported by the Non-Governmental Organization WWF-Brazil. JP and GS-K are supported by the Brazilian agencies Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).