An update on pharmacogenetic factors influencing the metabolism and toxicity of artemisinin-based combination therapy in the treatment of malaria

Funding Information: This paper was funded by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) (404067/2012-3 and 2020/00433-8), the European and Developing Countries Clinical Trials Partnership (EDCTP) (RIA2017T-2018), the Fundação de Amparo *a Pesquisa do Estado de mInas Gerais (FAPEMIG) (CBB-APQ 00952-16) and the Fundação para a Ciência e Tecnologia (FCT, Portugal) (SFRH/BD/142860/2018). Funding Information: L Pernaute-Lau is a recipient of a fellowship from BioSys PhD program PD65‐2012 (Ref SFRH/BD/142860/2018) from Fundação para a Ciência e Tecnologia (FCT, Portugal). JP Gil, M Camara and U Morris were partially supported by the European Developing Countries Clinical Trial Partnership (EDCTP2) programme supported by the European Union (Grant number RIA2017T-2018 – WANECAM 2). T Nóbrega de Sousa is a recipient of a Senior Research Scholarships from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil). Funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPqants number 404,067/2012-3, 2020/00433-8), and the Fundação de Amparo à Pesquisa do Estado de mInas Gerais (FAPEMIG), grant number CBB-APQ 00952-16). MU Ferreira was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPqants number 404,067/2012-3, 2020/00433-8), and the Fundação de Amparo à Pesquisa do Estado de mInas Gerais (FAPEMIG), grant number CBB-APQ 00952-16). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Publisher Copyright: © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.Introduction: Artemisinin-based combination therapies (ACTs) are recommended first-line antimalarials for uncomplicated Plasmodium falciparum malaria. Pharmacokinetic/pharmacodynamic variation associated with ACT drugs and their effect is documented. It is accepted to an extent that inter-individual variation is genetically driven, and should be explored for optimized antimalarial use. Areas covered: We provide an update on the pharmacogenetics of ACT antimalarial disposition. Beyond presently used antimalarials, we also refer to information available for the most notable next-generation drugs under development. The bibliographic approach was based on multiple Boolean searches on PubMed covering all recent publications since our previous review. Expert opinion: The last 10 years have witnessed an increase in our knowledge of ACT pharmacogenetics, including the first clear examples of its contribution as an exacerbating factor for drug–drug interactions. This knowledge gap is still large and is likely to widen as a new wave of antimalarial drug is looming, with few studies addressing their pharmacogenetics. Clinically useful pharmacogenetic markers are still not available, in particular, from an individual precision medicine perspective. A better understanding of the genetic makeup of target populations can be valuable for aiding decisions on mass drug administration implementation concerning region-specific antimalarial drug and dosage options.publishersversionpublishe

Worldwide Genetic Variability of the Duffy Binding Protein: Insights into Plasmodium vivax Vaccine Development

The dependence of Plasmodium vivax on invasion mediated by Duffy binding protein (DBP) makes this protein a prime candidate for development of a vaccine. However, the development of a DBP-based vaccine might be hampered by the high variability of the protein ligand (DBPII), known to bias the immune response toward a specific DBP variant. Here, the hypothesis being investigated is that the analysis of the worldwide DBPII sequences will allow us to determine the minimum number of haplotypes (MNH) to be included in a DBP-based vaccine of broad coverage. For that, all DBPII sequences available were compiled and MNH was based on the most frequent nonsynonymous single nucleotide polymorphisms, the majority mapped on B and T cell epitopes. A preliminary analysis of DBPII genetic diversity from eight malaria-endemic countries estimated that a number between two to six DBP haplotypes (17 in total) would target at least 50% of parasite population circulating in each endemic region. Aiming to avoid region-specific haplotypes, we next analyzed the MNH that broadly cover worldwide parasite population. The results demonstrated that seven haplotypes would be required to cover around 60% of DBPII sequences available. Trying to validate these selected haplotypes per country, we found that five out of the eight countries will be covered by the MNH (67% of parasite populations, range 48–84%). In addition, to identify related subgroups of DBPII sequences we used a Bayesian clustering algorithm. The algorithm grouped all DBPII sequences in six populations that were independent of geographic origin, with ancestral populations present in different proportions in each country. In conclusion, in this first attempt to undertake a global analysis about DBPII variability, the results suggest that the development of DBP-based vaccine should consider multi-haplotype strategies; otherwise a putative P. vivax vaccine may not target some parasite populations

Duffy Binding Protein: Análise da diversidade genética em isolados do Plasmodium vivax da Amazônia Brasileira.

Submitted by Nuzia Santos ([email protected]) on 2017-08-31T12:35:39Z No. of bitstreams: 1 Taís Nóbrega de Sousa.pdf: 31165167 bytes, checksum: a081fe445280b96929490a032cf0f67e (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2017-08-31T12:41:57Z (GMT) No. of bitstreams: 1 Taís Nóbrega de Sousa.pdf: 31165167 bytes, checksum: a081fe445280b96929490a032cf0f67e (MD5)Made available in DSpace on 2017-08-31T12:41:57Z (GMT). No. of bitstreams: 1 Taís Nóbrega de Sousa.pdf: 31165167 bytes, checksum: a081fe445280b96929490a032cf0f67e (MD5) Previous issue date: 2009CNPqFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brasil.A invasão dos eritrócitos pelos merozoítos de Plasmodium vivax requer a interação da Duffy binding protein (PvDBP) com o receptor DARC na superfície dos eritrócito s humanos. Esta interação parece ser essencial na formação d e uma junção irreversível entre as membranas do merozoíto e da cé lula do hospedeiro, uma etapa chave no processo de invasão dos eritrócitos. Diante disso, a PvDBP é considerada uma das mais importantes candidatas para compor uma vacin a anti- P. vivax . O domínio de ligação da PvDBP (região II, PvDBP II ) ao seu receptor é rico em resíduos de cisteína e constitui a região mais polimórfica da prot eína. Embora a maioria dos aminoácidos envolvidos na interação PvDBP II -DARC seja invariável, a resposta imune que parece ser direcionada principalmente contra regiões polimórficas da PvDBP II é capaz de bloquear a interação proteína-receptor. C omo esta diversidade genética pode comprometer a eficácia de uma vacina que inclua este antígeno, o objetivo principal deste trabalho foi caracterizar o pa drão de diversidade do domínio de ligação da Duffy binding protein de isolados de P. vivax de várias regiões da Amazônia Legal brasileira. Utilizando ferramentas esta tísticas adequadas, evidenciou-se o papel da recombinação e da seleção natura l na geração e manutenção da diversidade genética na PvDBP II . Em adição, a seleção positiva parece agir em codons individuais da proteína, preferen cialmente nos epitopos de células T e B da PvDBP II . Em geral, estas regiões apresentam uma diversidade genética maior do que toda a região II da proteína. Em conjunto, os resultados obtidos sugerem que o sistema imune do hospedeiro é um i mportante fator de seleção de mutações relacionadas ao escape do parasito. Adici onalmente, avaliou- se a associação entre prevalência dos alelos DARC e suscetibi lidade à infecção por P. vivax na Amazônia Legal brasileira. Com este objetivo foi desenvolvida uma nova metodologia de genotipagem de DARC baseada no PCR em tempo real. Este foi um dos primeiros estudos a evidenciar uma associação significati va entre indivíduos que expressam dois alelos DARC funcionais e maior suscetibilid ade à infecção por P. vivax e o primeiro a caracterizar o padrão de variabilidad e genética da DBP II em isolados de P. vivax do BrasilPlasmodium vivax requires interaction of the Duffy binding protein (P vDBP) with the Duffy antigen/receptor for chemokines (DARC) to enable its invasion of human erythrocytes, making PvDBP an important vaccine candidate . This interaction seems to be essential for junction formation, which is a key st ep in the erythrocyte invasion process. The receptor-binding domain of PvDBP maps to a conserved cysteine-rich region, referred to as region II (PvDBP II ). Most of the allelic diversity observed in PvDBP is due to the high rate of nonsynonymous polymor phisms in this critical domain for receptor recognition. Although contact resid ues that form the DARC- recognition site within PvDBP II appear to be invariant, host immune responses that target mainly against polymorphic regions are able to inhibit binding of PvDBP II to DARC. As the PvDBP II allelic diversity may represent a major obstacle for v accine development, this study undertook a comprehensive analysi s of the genetic diversity of the DBP II from P. vivax isolates obtained from different sites across the Brazili an Amazon region. Using appropriate statistical tests, we found evidence that allelic diversity within the Brazilian population of parasite s is maintained by recombination and natural selection at PvDBP II locus. In addition, we conclude that positive natural selection preferentially acts on B- and T-cell epitopes. Overall, these regions also showed higher nucleotide diversity compared to the whol e PvDBP II . Our results suggest that the host immune system is an important select ion factor for mutations related to escape of the parasite. In this study, we also evaluated the relationship between DARC alleles and malaria susceptibility. For t his aim we developed a new DARC genotyping assay based on multiplex real-time PC R. Our findings provided one of the first evidences that the presence of two fu nctional alleles increases the risk of P. vivax infection. Indeed, the current investigation presented the first comprehensive analysis of genetic diversity across PvDBP II gene from Brazilian parasite isolates

The Duffy binding protein as a key target for a Plasmodium vivax vaccine: lessons from the Brazilian Amazon

Submitted by Nuzia Santos ([email protected]) on 2015-03-02T17:27:49Z No. of bitstreams: 1 2014_122.pdf: 663626 bytes, checksum: 7afde180dcee5a1505fac1672960c98d (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-03-02T17:27:56Z (GMT) No. of bitstreams: 1 2014_122.pdf: 663626 bytes, checksum: 7afde180dcee5a1505fac1672960c98d (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-03-02T17:30:52Z (GMT) No. of bitstreams: 1 2014_122.pdf: 663626 bytes, checksum: 7afde180dcee5a1505fac1672960c98d (MD5)Made available in DSpace on 2015-03-02T17:30:52Z (GMT). No. of bitstreams: 1 2014_122.pdf: 663626 bytes, checksum: 7afde180dcee5a1505fac1672960c98d (MD5) Previous issue date: 2014Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratorio de Malária. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratorio de Malária. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratorio de Malária. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratorio de Malária. Belo Horizonte, MG, BrasilPlasmodium vivax infects human erythrocytes through a major pathway that requires interaction between an apical parasite protein, the Duffy binding protein (PvDBP) and its receptor on reticulocytes, the Duffy antigen/receptor for chemokines (DARC). The importance of the interaction between PvDBP (region II, DBPII) and DARC to P. vivax infection has motivated our malaria research group at Oswaldo Cruz Foundation (state of Minas Gerais, Brazil) to conduct a number of immunoepidemiological studies to characterise the naturally acquired immunity to PvDBP in populations living in the Amazon rainforest. In this review, we provide an update on the immunology and molecular epidemiology of PvDBP in the Brazilian Amazon - an area of markedly unstable malaria transmission - and compare it with data from other parts of Latin America, as well as Asia and Oceania

[PROVISIONAL] A systematic scoping review of the genetic ancestry of the Brazilian population

Abstract The genetic background of Brazilian population is mainly characterized by three parental populations: European, African and Native American. The aim of this study is to overview the genetic ancestry estimates for different Brazilian geographic regions and analyzed factors involved in these estimates. In a systematic scoping review were included fifty-one studies, comprehending 81 populations of 19 states from five regions of Brazil. To reduce the potential bias of studies with different sampling, we calculated the mean of genetic ancestry weighted by the number of individuals. The weighted mean proportions of European, African and Native American ancestries were 68.1%, 19.6% and 11.6%, respectively. At the regional level, the highest European contribution occurred in the South, while the highest African and Native American contributions occurred in the Northeastern and Northern regions, respectively. Among states in the Northeast region, Bahia and Ceará showed significant differences among them, suggesting distinct demographic histories. This review contributes for a broader understanding of the Brazilian ancestry estimates and also identify that the ancestry estimates were influenced by the type of molecular marker and the sampling

The Duffy binding protein as a key target for a Plasmodium vivax vaccine: lessons from the Brazilian Amazon

Plasmodium vivax infects human erythrocytes through a major pathway that requires interaction between an apical parasite protein, the Duffy binding protein (PvDBP) and its receptor on reticulocytes, the Duffy antigen/receptor for chemokines (DARC). The importance of the interaction between PvDBP (region II, DBPII) and DARC to P. vivax infection has motivated our malaria research group at Oswaldo Cruz Foundation (state of Minas Gerais, Brazil) to conduct a number of immunoepidemiological studies to characterise the naturally acquired immunity to PvDBP in populations living in the Amazon rainforest. In this review, we provide an update on the immunology and molecular epidemiology of PvDBP in the Brazilian Amazon - an area of markedly unstable malaria transmission - and compare it with data from other parts of Latin America, as well as Asia and Oceania

Assessing the mitochondrial DNA diversity of the Chagas disease vector Triatoma sordida (Hemiptera: Reduviidae)

Submitted by Nuzia Santos ([email protected]) on 2016-08-24T17:46:49Z No. of bitstreams: 1 ve_Pessoa_Grasielle_Assessing_CPqRR_2016.pdf: 862246 bytes, checksum: 83c92e6ad9287a3fdd0fbc3c95d3ddb3 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2016-08-24T17:53:31Z (GMT) No. of bitstreams: 1 ve_Pessoa_Grasielle_Assessing_CPqRR_2016.pdf: 862246 bytes, checksum: 83c92e6ad9287a3fdd0fbc3c95d3ddb3 (MD5)Made available in DSpace on 2016-08-24T17:53:31Z (GMT). No. of bitstreams: 1 ve_Pessoa_Grasielle_Assessing_CPqRR_2016.pdf: 862246 bytes, checksum: 83c92e6ad9287a3fdd0fbc3c95d3ddb3 (MD5) Previous issue date: 2016Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Referência em Triatomíneos e Epidemiologia da Doença de Chagas. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Malária. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Referência em Triatomíneos e Epidemiologia da Doença de Chagas. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Referência em Triatomíneos e Epidemiologia da Doença de Chagas. Belo Horizonte, MG, BrasilTriatoma sordida is a species that transmits Trypanosoma cruzi to humans. In Brazil, T. sordida currently deserves special attention because of its wide distribution, tendency to invade domestic environments and vectorial competence. For the planning and execution of control protocols to be effective against Triatominae, they must consider its population structure. In this context, this study aimed to characterise the genetic variability of T. sordida populations collected in areas with persistent infestations from Minas Gerais, Brazil. Levels of genetic variation and population structure were determined in peridomestic T. sordida by sequencing a polymorphic region of the mitochondrial cytochrome b gene. Low nucleotide and haplotype diversity were observed for all 14 sampled areas; π values ranged from 0.002-0.006. Most obtained haplotypes occurred at low frequencies, and some were exclusive to only one of the studied populations. Interpopulation genetic diversity analysis revealed strong genetic structuring. Furthermore, the genetic variability of Brazilian populations is small compared to that of Argentinean and Bolivian specimens. The possible factors related to the reduced genetic variability and strong genetic structuring obtained for studied populations are discussed in this paper

Assessment of copy number variation in genes related to drug resistance in Plasmodium vivax and Plasmodium falciparum isolates from the Brazilian Amazon and a systematic review of the literature

Abstract Background Parasite resistance to anti-malarials represents a great obstacle for malaria elimination. The majority of studies have investigated the association between single-nucleotide polymorphisms (SNPs) and drug resistance; however, it is becoming clear that the copy number variation (CNV) is also associated with this parasite phenotype. To provide a baseline for molecular surveillance of anti-malarial drug resistance in the Brazilian Amazon, the present study characterized the genetic profile of both markers in the most common genes associated with drug resistance in Plasmodium falciparum and Plasmodium vivax isolates. Additionally, these data were compared to data published elsewhere applying a systematic review of the literature published over a 20-year time period. Methods The genomic DNA of 67 patients infected by P. falciparum and P. vivax from three Brazilian States was obtained between 2002 and 2012. CNV in P. falciparum multidrug resistance gene-1 (pfmdr1), GTP cyclohydrolase 1 (pfgch1) and P. vivax multidrug resistance gene-1 (pvmdr1) were assessed by real-time PCR assays. SNPs in the pfmdr1 and pfcrt genes were assessed by PCR–RFLP. A literature search for studies that analysed CNP in the same genes of P. falciparum and P. vivax was conducted between May 2014 and March 2017 across four databases. Results All analysed samples of P. falciparum carried only one copy of pfmdr1 or pfgch1. Although the pfcrt K76T polymorphism, a determinant of CQ resistance, was present in all samples genotyped, the pfmdr1 N86Y was absent. For P. vivax isolates, an amplification rate of 20% was found for the pvmdr1 gene. The results of the study are in agreement with the low amplification rates for pfmdr1 gene evidenced in the Americas and Africa, while higher rates have been described in Southeast Asia. For P. vivax, very low rates of amplification for pvmdr1 have been described worldwide, with exceptions in French Guiana, Cambodia, Thailand and Brazil. Conclusions The present study was the first to evaluate gch1 CNV in P. falciparum isolates from Brazil, showing an absence of amplification of this gene more than 20 years after the withdrawal of the Brazilian antifolates therapeutic scheme. Furthermore, the rate of pvmdr1 amplification was significantly higher than that previously reported for isolates circulating in Northern Brazil