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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.

SUBMITTER: Cezar-de-Mello PF

PROVIDER: S-EPMC4154665 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Pre-miR-146a (rs2910164 G>C) single nucleotide polymorphism is genetically and functionally associated with leprosy.

Cezar-de-Mello Paula F T PF Toledo-Pinto Thiago G TG Marques Carolinne S CS Arnez Lucia E A LE Cardoso Cynthia C CC Guerreiro Luana T A LT Antunes Sérgio L G SL Jardim Márcia M MM Covas Claudia de J F Cde J Illaramendi Ximena X Dias-Baptista Ida M IM Rosa Patrícia S PS Durães Sandra M B SM Pacheco Antonio G AG Ribeiro-Alves Marcelo M Sarno Euzenir N EN Moraes Milton O MO

PLoS neglected tropical diseases 20140904 9

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> ...[more]

PMID: 25187983

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Project description:To systematically evaluate the association between the miR-146a rs2910164 polymorphism and susceptibility to gastric cancer.A comprehensive electronic search was conducted for articles published up until January 27, 2014 in Medline (PubMed), Excerpta Medica Database (Embase), the Cochrane Library and Google Scholar. Only case-control studies published in English that evaluated the association between the miR-146a rs2910164 polymorphism and susceptibility to gastric cancer were included. Furthermore, only studies with sufficient data allowing for calculation of odds ratio (OR) and corresponding 95% confidence interval (CI) were included. These values were used in the quantitative synthesis to assess the strength of the association between the miR-146a rs2910164 polymorphism and risk of gastric cancer.The database search identified 1002 eligible studies, of which seven (comprising 4112 cases and 5811 controls) were included for the meta-analysis. The results indicate that miR-146a rs2910164 polymorphism is more likely to be associated with gastric cancer risk. In the overall analysis, a significantly increased cancer risk was found in the heterozygote (GG vs GC) comparison (OR = 1.14, 95%CI: 1.03-1.27; P = 0.01 for pooled OR). In the ethnicity subgroup analysis, a similar result was found among Caucasians (OR = 1.36, 95%CI: 1.01-1.85; P = 0.04 for pooled OR). In the stratified analysis by quality of studies, a significantly increased cancer risk was found in the heterozygote comparison among high quality studies (OR = 1.12, 95%CI: 1.01-1.26; P = 0.04 for pooled OR). When stratified on the basis of sample size, a significantly increased cancer risk was found among small sample size subgroups for the allelic (G vs C: OR = 1.16, 95%CI: 1.03-1.30; P = 0.01), homozygote (GG vs CC: OR = 1.33, 95%CI: 1.03-1.73; P = 0.03) and recessive model (GG vs GC + CC: OR = 0.05, 95%CI: 0.00-0.10; P = 0.03) comparisons.The miR-146a rs2910164 polymorphism is associated with increased gastric cancer risk, particularly evident in high quality studies with small sample sized Caucasian populations.

Dataset Information

Pre-miR-146a (rs2910164 G>C) single nucleotide polymorphism is genetically and functionally associated with leprosy.

Publications

Pre-miR-146a (rs2910164 G>C) single nucleotide polymorphism is genetically and functionally associated with leprosy.

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