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Doctoral Thesis
DOI
https://doi.org/10.11606/T.5.2019.tde-09122019-113756
Document
Author
Full name
Lucas Augusto Moysés Franco
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2019
Supervisor
Committee
Sabino, Ester Cerdeira (President)
Costa, Silvia Figueiredo
Paranhos, Glaucia da Silva
Rodrigues, Alice Cristina
Title in Portuguese
Perfil farmacogenômico de pacientes com doença de Chagas em tratamento com benznidazol
Keywords in Portuguese
Benznidazol
Doença de Chagas
Efeitos colaterais e reações adversas relacionados a medicamentos
Farmacogenômica
Genoma humano
Transcriptoma
Abstract in Portuguese
Contexto: A doença de Chagas (DC) continua sendo um grande problema de saúde pública e social na América Latina. O Benznidazol (BZN) é uma das duas drogas antiparasitas disponíveis para o tratamento do agente etiológico Tripanossoma cruzi. Esta droga provoca várias reações adversas ao medicamento (RAM). O objetivo deste estudo foi compreender as bases genéticas associadas às RAMs do BZN. Métodos: Uma coorte prospectiva de 102 pacientes com DC, tratados com BZN, foi estabelecida para entender os biomarcadores de cura e reações adversas. Os pacientes foram classificados em dois grupos: com pelo menos uma manifestação de RAM (n = 73) e sem RAM (n = 29). Análises genômicas em busca de polimorfismos de nucleotídeo único (SNPs) comparando esses grupos foram realizadas usando GeneTitan Axiom 2.0 (Affymetrix, Califórnia, EUA). Dados de transcriptoma foram obtidos utilizando o painel Ion Proton AmpliSeq Transcriptome Human Gene Expression (Thermo Fisher Scientific, Massachusetts, EUA) em busca de genes diferencialmente expressos, antes (T0) e ao final do tratamento (T60) com BZN. Dados de expressão gênica deste painel foram utilizados para avaliar as vias de sinalização envolvidas nas principais manifestações clínicas das RAMs. Resultados e conclusões: Foi detectada uma região do cromossomo 16 altamente associada à reação adversa ao BZN (rs1518601, rs11861761 e rs34091595). Os dados transcriptômicos revelaram vias de sinalização associadas as RAMs do BZN, em concordância com os sintomas clínicos de RAMs mais comuns apresentados pelos pacientes do estudo
Title in English
Pharmacogenomic profile of patients with Chagas' disease on benznidazole
Keywords in English
Benznidazole
Chagas disease
Drug-related side effects and adverse reactions
Genome human
Pharmacogenetics
Transcriptome
Abstract in English
Background: Chagas' disease (CD) remains a major social and public health problem in Latin America. Benznidazole (BZN) is one of the two antiparasite drugs available for treating the etiological agent Tripanossoma cruzi. This drug causes several adverse drug reaction (ADR). The aim of this study was to understand the genetic basis associated with BZN ADRs. Methods: A prospective cohort of 102 patients with CD, treated with BZN was established to understand biomarkers of cure and adverse reaction. Patients were classified in two groups: with at least one ADR manifestation (n= 73), and without ADR (n=29). Genomic analyses in search for single nucleotide polymorphisms (SNPs) comparing these groups was performed using GeneTitan Axiom 2.0 (Affymetrix, California, USA). Transcriptome data was obtained using Ion Proton AmpliSeq Transcriptome Human Gene Expression panel (Thermo Fisher Scientific, Massachusetts, USA) in search for genes differentially expressed, before and at the end of the BZN treatment. Expression data was used to evaluate the signaling pathways involved in the main clinical manifestations of ADR. Results and conclusions: We have detected one region of chromosome 16 highly associated with BZN adverse reaction (rs1518601, rs11861761 and rs34091595). Transcriptomic data reveled signaling pathways associated with BZN ADRs, in agreement with the most common clinical symptoms of ADRs presented by patients in this study
 
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Publishing Date
2019-12-09
 
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