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Pre-miR-146a (rs2910164 G>C) Single Nucleotide Polymorphism Is Genetically and Functionally Associated with Leprosy
Mycobacterium leprae infects macrophages and Schwann cells inducing a gene expression program to facilitate its replication and progression to disease. MicroRNAs (miRNAs) are key regulators of gene expression and could be involved during the infection. To address the genetic influence of miRNAs in l...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154665/ https://www.ncbi.nlm.nih.gov/pubmed/25187983 http://dx.doi.org/10.1371/journal.pntd.0003099 |
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author | Cezar-de-Mello, Paula F. T. Toledo-Pinto, Thiago G. Marques, Carolinne S. Arnez, Lucia E. A. Cardoso, Cynthia C. Guerreiro, Luana T. A. Antunes, Sérgio L. G. Jardim, Márcia M. Covas, Claudia de J. F. Illaramendi, Ximena Dias-Baptista, Ida M. Rosa, Patrícia S. Durães, Sandra M. B. Pacheco, Antonio G. Ribeiro-Alves, Marcelo Sarno, Euzenir N. Moraes, Milton O. |
author_facet | Cezar-de-Mello, Paula F. T. Toledo-Pinto, Thiago G. Marques, Carolinne S. Arnez, Lucia E. A. Cardoso, Cynthia C. Guerreiro, Luana T. A. Antunes, Sérgio L. G. Jardim, Márcia M. Covas, Claudia de J. F. Illaramendi, Ximena Dias-Baptista, Ida M. Rosa, Patrícia S. Durães, Sandra M. B. Pacheco, Antonio G. Ribeiro-Alves, Marcelo Sarno, Euzenir N. Moraes, Milton O. |
author_sort | Cezar-de-Mello, Paula F. T. |
collection | PubMed |
description | Mycobacterium leprae infects macrophages and Schwann cells inducing a gene expression program to facilitate its replication and progression to disease. MicroRNAs (miRNAs) are key regulators of gene expression and could be involved during the infection. To address the genetic influence of miRNAs in leprosy, we enrolled 1,098 individuals and conducted a case-control analysis in order to study four miRNAs genes containing single nucleotide polymorphism (miRSNP). We tested miRSNP-125a (rs12975333 G>T), miRSNP-223 (rs34952329 *>T), miRSNP-196a-2 (rs11614913 C>T) and miRSNP-146a (rs2910164 G>C). Amongst them, miRSNP-146a was the unique gene associated with risk to leprosy per se (GC OR = 1.44, p = 0.04; CC OR = 2.18, p = 0.0091). We replicated this finding showing that the C-allele was over-transmitted (p = 0.003) using a transmission-disequilibrium test. A functional analysis revealed that live M. leprae (MOI 100∶1) was able to induce miR-146a expression in THP-1 (p<0.05). Furthermore, pure neural leprosy biopsies expressed augmented levels of that miRNA as compared to biopsy samples from neuropathies not related with leprosy (p = 0.001). Interestingly, carriers of the risk variant (C-allele) produce higher levels of mature miR-146a in nerves (p = 0.04). From skin biopsies, although we observed augmented levels of miR-146a, we were not able to correlate it with a particular clinical form or neither host genotype. MiR-146a is known to modulate TNF levels, thus we assessed TNF expression (nerve biopsies) and released by peripheral blood mononuclear cells infected with BCG Moreau. In both cases lower TNF levels correlates with subjects carrying the risk C-allele, (p = 0.0453 and p = 0.0352; respectively), which is consistent with an immunomodulatory role of this miRNA in leprosy. |
format | Online Article Text |
id | pubmed-4154665 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-41546652014-09-08 Pre-miR-146a (rs2910164 G>C) Single Nucleotide Polymorphism Is Genetically and Functionally Associated with Leprosy Cezar-de-Mello, Paula F. T. Toledo-Pinto, Thiago G. Marques, Carolinne S. Arnez, Lucia E. A. Cardoso, Cynthia C. Guerreiro, Luana T. A. Antunes, Sérgio L. G. Jardim, Márcia M. Covas, Claudia de J. F. Illaramendi, Ximena Dias-Baptista, Ida M. Rosa, Patrícia S. Durães, Sandra M. B. Pacheco, Antonio G. Ribeiro-Alves, Marcelo Sarno, Euzenir N. Moraes, Milton O. PLoS Negl Trop Dis Research Article Mycobacterium leprae infects macrophages and Schwann cells inducing a gene expression program to facilitate its replication and progression to disease. MicroRNAs (miRNAs) are key regulators of gene expression and could be involved during the infection. To address the genetic influence of miRNAs in leprosy, we enrolled 1,098 individuals and conducted a case-control analysis in order to study four miRNAs genes containing single nucleotide polymorphism (miRSNP). We tested miRSNP-125a (rs12975333 G>T), miRSNP-223 (rs34952329 *>T), miRSNP-196a-2 (rs11614913 C>T) and miRSNP-146a (rs2910164 G>C). Amongst them, miRSNP-146a was the unique gene associated with risk to leprosy per se (GC OR = 1.44, p = 0.04; CC OR = 2.18, p = 0.0091). We replicated this finding showing that the C-allele was over-transmitted (p = 0.003) using a transmission-disequilibrium test. A functional analysis revealed that live M. leprae (MOI 100∶1) was able to induce miR-146a expression in THP-1 (p<0.05). Furthermore, pure neural leprosy biopsies expressed augmented levels of that miRNA as compared to biopsy samples from neuropathies not related with leprosy (p = 0.001). Interestingly, carriers of the risk variant (C-allele) produce higher levels of mature miR-146a in nerves (p = 0.04). From skin biopsies, although we observed augmented levels of miR-146a, we were not able to correlate it with a particular clinical form or neither host genotype. MiR-146a is known to modulate TNF levels, thus we assessed TNF expression (nerve biopsies) and released by peripheral blood mononuclear cells infected with BCG Moreau. In both cases lower TNF levels correlates with subjects carrying the risk C-allele, (p = 0.0453 and p = 0.0352; respectively), which is consistent with an immunomodulatory role of this miRNA in leprosy. Public Library of Science 2014-09-04 /pmc/articles/PMC4154665/ /pubmed/25187983 http://dx.doi.org/10.1371/journal.pntd.0003099 Text en © 2014 Cezar-de-Mello et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Cezar-de-Mello, Paula F. T. Toledo-Pinto, Thiago G. Marques, Carolinne S. Arnez, Lucia E. A. Cardoso, Cynthia C. Guerreiro, Luana T. A. Antunes, Sérgio L. G. Jardim, Márcia M. Covas, Claudia de J. F. Illaramendi, Ximena Dias-Baptista, Ida M. Rosa, Patrícia S. Durães, Sandra M. B. Pacheco, Antonio G. Ribeiro-Alves, Marcelo Sarno, Euzenir N. Moraes, Milton O. Pre-miR-146a (rs2910164 G>C) Single Nucleotide Polymorphism Is Genetically and Functionally Associated with Leprosy |
title | Pre-miR-146a (rs2910164 G>C) Single Nucleotide Polymorphism Is Genetically and Functionally Associated with Leprosy |
title_full | Pre-miR-146a (rs2910164 G>C) Single Nucleotide Polymorphism Is Genetically and Functionally Associated with Leprosy |
title_fullStr | Pre-miR-146a (rs2910164 G>C) Single Nucleotide Polymorphism Is Genetically and Functionally Associated with Leprosy |
title_full_unstemmed | Pre-miR-146a (rs2910164 G>C) Single Nucleotide Polymorphism Is Genetically and Functionally Associated with Leprosy |
title_short | Pre-miR-146a (rs2910164 G>C) Single Nucleotide Polymorphism Is Genetically and Functionally Associated with Leprosy |
title_sort | pre-mir-146a (rs2910164 g>c) single nucleotide polymorphism is genetically and functionally associated with leprosy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154665/ https://www.ncbi.nlm.nih.gov/pubmed/25187983 http://dx.doi.org/10.1371/journal.pntd.0003099 |
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