Produção Nacional
Revisado por pares
Pre-miR-146a (rs2910164 G>C) Single Nucleotide Polymorphism Is Genetically and Functionally Associated with Leprosy
2014; Public Library of Science; Volume: 8; Issue: 9 Linguagem: Inglês
10.1371/journal.pntd.0003099
ISSN1935-2735
AutoresPaula Fernandes Tavares Cezar de Mello, Thiago Gomes de Toledo-Pinto, Carolinne de Sales Marques, Lucia Elena Alvarado-Arnez, Cynthia Chester Cardoso, Luana Tatiana Albuquerque Guerreiro, Sérgio Luiz Gomes Antunes, Márcia Rodrigues Jardim, Claúdia Covas, Ximena Illaramendi, Ida Maria Foschiani Dias‐Baptista, Patrícia Sammarco Rosa, Sandra Maria Barbosa Durães, Antônio Guilherme Pacheco, Marcelo Ribeiro‐Alves, Euzenir Nunes Sarno, Milton Ozório Moraes,
Tópico(s)Infectious Diseases and Tuberculosis
ResumoMycobacterium 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.
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