1. Pharmacogenomics of thiopurines: distribution of TPMT and NUDT15 polymorphisms in the Brazilian Amazon
- Author
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Marcus V. G. Lacerda, Guilherme Motta Antunes Ferreira, Guilherme Suarez-Kurtz, Gisely Cardoso de Melo, Joabi Nascimento, Anna Beatriz Ribeiro Elias, Djane Clarys Baia-da-Silva, and Wuelton Marcelo Monteiro
- Subjects
0301 basic medicine ,Male ,Adolescent ,030226 pharmacology & pharmacy ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Azathioprine ,Genetics ,Distribution (pharmacology) ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,1000 Genomes Project ,Allele ,Pyrophosphatases ,Child ,Molecular Biology ,Genetics (clinical) ,Thiopurine methyltransferase ,biology ,Amazon rainforest ,Indians, South American ,Methyltransferases ,Healthy Volunteers ,Pharmacogenomic Testing ,030104 developmental biology ,Phenotype ,Pharmacogenomics ,biology.protein ,Molecular Medicine ,Dose reduction ,Pharmacogenetics ,Brazil - Abstract
Reduced function alleles in the TPMT and NUDT15 genes are risk factors for thiopurine toxicity. This study evaluated the influence of Native ancestry on the distribution of TPMT (rs1142345, rs1800460 and rs1800462) and NUDT15 (rs116855232) polymorphisms and compound metabolic phenotypes in 128 healthy males from the Brazilian Amazon. The average proportion of Native and European ancestry differed greatly and significantly between self-declared Amerindians and non-Amerindians, although extensive admixture in both groups was evident. Native ancestry was not significantly associated with the frequency distribution of the TPMT or NUDT15 polymorphisms investigated. The apparent discrepancy with our previous results for NUDT15 rs116855232 in the Ad Mixed American superpopulation of the 1000 Genomes Project is ascribed to the diversity of the Native populations of the Americas. Based on the inferred TPMT/NUDT15 compound metabolic phenotypes, the Clinical Pharmacogenetics Implementation Consortium recommendations for starting thiopurine therapy with reduced doses or to consider dose reduction applied respectively to 3-5% and to 12-20% of the study cohorts.
- Published
- 2020