Polymorphisms of ADME-related genes and their implications for drug safety and efficacy in Amazonian Amerindians

Rodrigues, Juliana Carla Gomes; Fernandes, Marianne Rodrigues; Guerreiro, João Farias; Silva, Artur da Costa da Luiz; Ribeiro-dos-Santos, Ândrea; Santos, Sidney Emanuel Batista dos; Santos, Ney Pereira Carneiro dos

doi:10.1038/s41598-019-43610-y

Cited by 26 publications

(23 citation statements)

References 41 publications

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“…The Brazilian population is one of the populations with the broadest genetic diversity in the world due to the high degree of miscegenation in its formation [26][27][28]. Different regions of Brazil have significant genetic variations in the contribution of their ancestry.…”

Section: Analyses In Amazon Natives and Admixed Populationmentioning

confidence: 99%

ACE2 polymorphisms as potential players in COVID-19 outcome

et al. 2020

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The clinical condition COVID-19, caused by SARS-CoV-2, was declared a pandemic by the WHO in March 2020. Currently, there are more than 5 million cases worldwide, and the pandemic has increased exponentially in many countries, with different incidences and death rates among regions/ethnicities and, intriguingly, between sexes. In addition to the many factors that can influence these discrepancies, we suggest a biological aspect, the genetic variation at the viral S protein receptor in human cells, ACE2 (angiotensin I-converting enzyme 2), which may contribute to the worse clinical outcome in males and in some regions worldwide. We performed exomics analysis in native and admixed South American populations, and we also conducted in silico genomics databank investigations in populations from other continents. Interestingly, at least ten polymorphisms in coding, noncoding and regulatory sites were found that can shed light on this issue and offer a plausible biological explanation for these epidemiological differences. In conclusion, there are ACE2 polymorphisms that could influence epidemiological discrepancies observed among ancestry and, moreover, between sexes.

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Section: Analyses In Amazon Natives and Admixed Populationmentioning

confidence: 99%

ACE2 polymorphisms as potential players in COVID-19 outcome

et al. 2020

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“…The analysis of the polymorphisms of the Drug Absorption, Distribution, Metabolism, and Excretion (ADME) genes has been commonly employed in personalized medicine as a diagnostic tool for the selection of the most appropriate drugs and/or dosage for the treatment of a range of diseases. A number of recent studies [1,2,3] have identified varying frequencies in many genetic polymorphisms in genetically distinct populations, which may modulate the prognosis of patients and the therapeutic efficacy of treatments.…”

Section: Introductionmentioning

confidence: 99%

Identification of NUDT15 gene variants in Amazonian Amerindians and admixed individuals from northern Brazil

et al. 2020

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Introduction The nudix hydrolase 15 (NUDT15) gene acts in the metabolism of thiopurine, by catabolizing its active metabolite thioguanosine triphosphate into its inactivated form, thioguanosine monophosphate. The frequency of alternative NUDT15 alleles, in particular those that cause a drastic loss of gene function, varies widely among geographically distinct populations. In the general population of northern Brazilian, high toxicity rates (65%) have been recorded in patients treated with the standard protocol for acute lymphoblastic leukemia, which involves thiopurine-based drugs. The present study characterized the molecular profile of the coding region of the NUDT15 gene in two groups, non-admixed Amerindians and admixed individuals from the Amazon region of northern Brazil. Methods The entire NUDT15 gene was sequenced in 64 Amerindians from 12 Amazonian groups and 82 admixed individuals from northern Brazil. The DNA was extracted using phenol-chloroform. The exome libraries were prepared using the Nextera Rapid Capture Exome (Illumina) and SureSelect Human All Exon V6 (Agilent) kits. The allelic variants were annotated in the ViVa ® (Viewer of Variants) software. Results Four NUDT15 variants were identified: rs374594155, rs1272632214, rs147390019, andrs116855232. The variants rs1272632214 and rs116855232 were in complete linkage disequilibrium, and were assigned to the NUDT15*2 genotype. These variants had high

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“…Several studies have shown large genetic variation for important PGx biomarkers between distinct populational groups. [20][21][22] The knowledge obtained to date in PGx genes in Native American populations is very limited to specific genes, failing to reach a wider genome context. 23,24 The investigation of important PGx polymorphisms in the genes selected by our panel has the potential to provide powerful information regarding the predictivity of therapeutic response to the use of different drugs and xenobiotics in Amazonian Native Americans and/or admixed populations with this ethnic group.…”

Section: Discussionmentioning

confidence: 99%

Genetic Diversity of Drug-Related Genes in Native Americans of the Brazilian Amazon

Fernandes¹,

Rodrigues²,

Maroñas³

et al. 2021

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Introduction: The genetic admixture of the Brazilian population has considerable relevance to the implementation of the principles of pharmacogenomics (PGx), as it may compromise the extrapolation of data obtained in more homogeneous world populations. Purpose: This study aims to investigate a panel of 117 polymorphisms in 35 pharmacogenes, which contains label recommendations or clinical evidence by international drug regulatory agencies, in Amazonian Native American populations, and compare the results obtained with continental population data from the 1000 Genomes Project Consortium. Patients and Methods: The study population is composed of 109 Native American individuals from three Brazilian Amazon groups. The genotyping of the PGx polymorphisms was performed by allelic discrimination using TaqMan ® OpenArray Genotyping with a panel of 120 customized assays on the QuantStudio™ 12K Flex Real-Time PCR System. Results: Statistical differences within the Native American populations were observed regarding both genotypes and phenotypes of some genes of the CYP family. The discriminant analysis of principal components (DAPCs) between the NAM group and the continental populations of the 1000 Genomes Project resulted in the clustering of the three Native American populations. Additionally, in general, the NAM group was determined to be closely situated between East Asia, America, and South Asia groups, which enabled us to infer a genetic similarity between these populations. The DAPC analysis further demonstrated that eight polymorphisms and six polymorphisms were more relevant in differentiating the NAM from the continental populations and the NAM populations among themselves, respectively. Conclusion: Some investigated polymorphisms show differences among world populations, particularly with populations of European origin, for whom precision medicine protocols are primarily designed. The accumulated knowledge regarding these variations may assist in the design of specific protocols for Native American populations and populations admixed with them.

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Polymorphisms of ADME-related genes and their implications for drug safety and efficacy in Amazonian Amerindians

Cited by 26 publications

References 41 publications

ACE2 polymorphisms as potential players in COVID-19 outcome

ACE2 polymorphisms as potential players in COVID-19 outcome

Identification of NUDT15 gene variants in Amazonian Amerindians and admixed individuals from northern Brazil

Genetic Diversity of Drug-Related Genes in Native Americans of the Brazilian Amazon

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