title: Pre-miR-146a (rs2910164 G>C) single nucleotide polymorphism is genetically and functionally associated with leprosy.
abstract: 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.
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brasil.
authors.forename: Paula F T
authors.initials: PF
authors.lastname: Cezar-de-Mello
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brasil.
authors.forename: Thiago G
authors.initials: TG
authors.lastname: Toledo-Pinto
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brasil.
authors.forename: Carolinne S
authors.initials: CS
authors.lastname: Marques
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brasil.
authors.forename: Lucia E A
authors.initials: LE
authors.lastname: Arnez
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brasil.
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Cardoso
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brasil.
authors.forename: Luana T A
authors.initials: LT
authors.lastname: Guerreiro
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brasil.
authors.forename: Sérgio L G
authors.initials: SL
authors.lastname: Antunes
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brasil.
authors.forename: Márcia M
authors.initials: MM
authors.lastname: Jardim
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brasil.
authors.forename: Claudia de J F
authors.initials: Cde J
authors.lastname: Covas
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brasil.
authors.forename: Ximena
authors.initials: X
authors.lastname: Illaramendi
authors.affiliation: Instituto Lauro de Souza Lima, Bauru, São Paulo, Brasil.
authors.forename: Ida M
authors.initials: IM
authors.lastname: Dias-Baptista
authors.affiliation: Instituto Lauro de Souza Lima, Bauru, São Paulo, Brasil.
authors.forename: Patrícia S
authors.initials: PS
authors.lastname: Rosa
authors.affiliation: Centro de Ciências Médicas, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brasil.
authors.forename: Sandra M B
authors.initials: SM
authors.lastname: Durães
authors.affiliation: Programa de Computação Científica, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brasil.
authors.forename: Antonio G
authors.initials: AG
authors.lastname: Pacheco
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brasil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Ribeiro-Alves
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brasil.
authors.forename: Euzenir N
authors.initials: EN
authors.lastname: Sarno
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brasil.
authors.forename: Milton O
authors.initials: MO
authors.lastname: Moraes
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007918:Leprosy / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide
chemical_list: C542542:MIRN146 microRNA, human; D035683:MicroRNAs