Pre-miR-146a (rs2910164 G>C) Single Nucleotide Polymorphism Is Genetically and Functionally Associated with Leprosy: e3099

Pre-miR-146a (rs2910164 G>C) Single Nucleotide Polymorphism Is Genetically and Functionally Associated with Leprosy e3099

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...

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Bibliographic Details
Published in:PLoS neglected tropical diseases Vol. 8; no. 9
Main Authors: Cezar-de-Mello, Paula FT, Toledo-Pinto, Thiago G, Marques, Carolinne S, Arnez, Lucia EA, Cardoso, Cynthia C, Guerreiro, Luana TA, Antunes, Sérgio LG, Jardim, Márcia M, Covas, de JF, Illaramendi, Ximena, Dias-Baptista, Ida M, Rosa, Patrícia S, Durães, Sandra MB, Pacheco, Antonio G, Ribeiro-Alves, Marcelo, Sarno, Euzenir N, Moraes, Milton O
Format: Journal Article
Language:English
Published: San Francisco Public Library of Science 01-09-2014
Subjects:
Age
Biopsy
Gene expression
Immune system
Infections
Leprosy
MicroRNAs
Population
Studies
Tropical diseases
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Summary: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.
ISSN:1935-2727
1935-2735
DOI:10.1371/journal.pntd.0003099