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Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One

Human T-lymphotropic virus 1 (HTLV-1) was the first recognized human retrovirus. Infection can lead to two main symptomatologies: adult T-cell lymphoma/leukemia (ATLL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Each manifestation is associated with distinct characterist...

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Autores principales: Fukutani, Eduardo Rocha, Ramos, Pablo Ivan Pereira, Kasprzykowski, José Irahe, Azevedo, Lucas Gentil, Rodrigues, Moreno Magalhães de Souza, Lima, João Victor de Oliveira Pimenta, de Araújo Junior, Helton Fábio Santos, Fukutani, Kiyoshi Ferreira, de Queiroz, Artur Trancoso Lopo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857459/
https://www.ncbi.nlm.nih.gov/pubmed/31781157
http://dx.doi.org/10.3389/fgene.2019.01056
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author Fukutani, Eduardo Rocha
Ramos, Pablo Ivan Pereira
Kasprzykowski, José Irahe
Azevedo, Lucas Gentil
Rodrigues, Moreno Magalhães de Souza
Lima, João Victor de Oliveira Pimenta
de Araújo Junior, Helton Fábio Santos
Fukutani, Kiyoshi Ferreira
de Queiroz, Artur Trancoso Lopo
author_facet Fukutani, Eduardo Rocha
Ramos, Pablo Ivan Pereira
Kasprzykowski, José Irahe
Azevedo, Lucas Gentil
Rodrigues, Moreno Magalhães de Souza
Lima, João Victor de Oliveira Pimenta
de Araújo Junior, Helton Fábio Santos
Fukutani, Kiyoshi Ferreira
de Queiroz, Artur Trancoso Lopo
author_sort Fukutani, Eduardo Rocha
collection PubMed
description Human T-lymphotropic virus 1 (HTLV-1) was the first recognized human retrovirus. Infection can lead to two main symptomatologies: adult T-cell lymphoma/leukemia (ATLL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Each manifestation is associated with distinct characteristics, as ATLL presents as a leukemia-like disease, while HAM/TSP presents as severe inflammation in the central nervous system, leading to paraparesis. Previous studies have identified molecules associated with disease development, e.g., the downregulation of Foxp3 in Treg cells was associated with increased risk of HAM/TSP. In addition, elevated levels of CXCL10, CXCL9, and Neopterin in cerebrospinal fluid also present increased risk. However, these molecules were only associated with specific patient groups or viral strains. Furthermore, the majority of studies did not jointly compare all clinical manifestations, and robust analysis entails the inclusion of both ATLL and HAM/TSP. The low numbers of samples also pose difficulties in conducting gene expression analysis to identify specific molecular relationships. To address these limitations and increase the power of manifestation-specific gene associations, meta-analysis was performed using publicly available gene expression data. The application of supervised learning techniques identified alterations in two genes observed to act in tandem as potential biomarkers: GBP2 was associated with HAM/TSP, and CD40LG with ATLL. Together, both molecules demonstrated high sample-classification accuracy (AUC values: 0.88 and 1.0, respectively). Next, other genes with expression correlated to these genes were identified, and we attempted to relate the enriched pathways identified with the characteristic of each clinical manifestation. The present findings contribute to knowledge surrounding viral progression and suggest a potentially powerful new tool for the molecular classification of HTLV-associated diseases.
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spelling pubmed-68574592019-11-28 Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One Fukutani, Eduardo Rocha Ramos, Pablo Ivan Pereira Kasprzykowski, José Irahe Azevedo, Lucas Gentil Rodrigues, Moreno Magalhães de Souza Lima, João Victor de Oliveira Pimenta de Araújo Junior, Helton Fábio Santos Fukutani, Kiyoshi Ferreira de Queiroz, Artur Trancoso Lopo Front Genet Genetics Human T-lymphotropic virus 1 (HTLV-1) was the first recognized human retrovirus. Infection can lead to two main symptomatologies: adult T-cell lymphoma/leukemia (ATLL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Each manifestation is associated with distinct characteristics, as ATLL presents as a leukemia-like disease, while HAM/TSP presents as severe inflammation in the central nervous system, leading to paraparesis. Previous studies have identified molecules associated with disease development, e.g., the downregulation of Foxp3 in Treg cells was associated with increased risk of HAM/TSP. In addition, elevated levels of CXCL10, CXCL9, and Neopterin in cerebrospinal fluid also present increased risk. However, these molecules were only associated with specific patient groups or viral strains. Furthermore, the majority of studies did not jointly compare all clinical manifestations, and robust analysis entails the inclusion of both ATLL and HAM/TSP. The low numbers of samples also pose difficulties in conducting gene expression analysis to identify specific molecular relationships. To address these limitations and increase the power of manifestation-specific gene associations, meta-analysis was performed using publicly available gene expression data. The application of supervised learning techniques identified alterations in two genes observed to act in tandem as potential biomarkers: GBP2 was associated with HAM/TSP, and CD40LG with ATLL. Together, both molecules demonstrated high sample-classification accuracy (AUC values: 0.88 and 1.0, respectively). Next, other genes with expression correlated to these genes were identified, and we attempted to relate the enriched pathways identified with the characteristic of each clinical manifestation. The present findings contribute to knowledge surrounding viral progression and suggest a potentially powerful new tool for the molecular classification of HTLV-associated diseases. Frontiers Media S.A. 2019-11-08 /pmc/articles/PMC6857459/ /pubmed/31781157 http://dx.doi.org/10.3389/fgene.2019.01056 Text en Copyright © 2019 Fukutani, Ramos, Kasprzykowski, Azevedo, Rodrigues, Lima, Araújo Junior, Fukutani and Queiroz http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Fukutani, Eduardo Rocha
Ramos, Pablo Ivan Pereira
Kasprzykowski, José Irahe
Azevedo, Lucas Gentil
Rodrigues, Moreno Magalhães de Souza
Lima, João Victor de Oliveira Pimenta
de Araújo Junior, Helton Fábio Santos
Fukutani, Kiyoshi Ferreira
de Queiroz, Artur Trancoso Lopo
Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One
title Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One
title_full Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One
title_fullStr Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One
title_full_unstemmed Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One
title_short Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One
title_sort meta-analysis of htlv-1-infected patients identifies cd40lg and gbp2 as markers of atll and ham/tsp clinical status: two genes beat as one
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857459/
https://www.ncbi.nlm.nih.gov/pubmed/31781157
http://dx.doi.org/10.3389/fgene.2019.01056
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