Pre-miR-146a (rs2910164 G>C) single nucleotide polymorphism is genetically and functionally associated with leprosy.
Pre-miR-146a (rs2910164 G>C) single nucleotide polymorphism is genetically and functionally associated with leprosy.
复制标题
DOI：
10.1371/journal.pntd.0003099
复制
发表时间：
2014-09
影响因子：
3.8
通讯作者：
Moraes MO
中科院分区：
文献类型：
--
作者：
Cezar-de-Mello PF;Toledo-Pinto TG;Marques CS;Arnez LE;Cardoso CC;Guerreiro LT;Antunes SL;Jardim MM;Covas Cde J;Illaramendi X;Dias-Baptista IM;Rosa PS;Durães SM;Pacheco AG;Ribeiro-Alves M;Sarno EN;Moraes MO
麻风分枝杆菌感染巨噬细胞和雪旺细胞，诱导基因表达程序以促进其复制和疾病进展。microRNA（miRNAs）是基因表达的关键调节因子，可能参与感染过程。为了解决miRNAs在麻风病中的遗传影响，我们招募了1，098名个体并进行了病例对照分析，以研究含有单核苷酸多态性（miRSNP）的四种miRNAs基因。我们测试了miRSNP-125 a（rs 12975333 G>T）、miRSNP-223（rs34952329 *>T）、miRSNP-196 a-2（rs 11614913 C>T）和miRSNP-146 a（rs 2910164 G>C）。其中，miRSNP-146 a是与麻风本身风险相关的唯一基因（GC OR = 1.44，p = 0.04; CC OR = 2.18，p = 0.0091）。 我们重复了这一发现，表明C-等位基因是过度传播（p = 0.003），使用传输不平衡检验。 功能分析表明，活M.麻风（MOI 100∶1）可诱导THP-1细胞表达miR-146 a（p<0.05）。此外，与来自与麻风无关的神经病变的活检样本相比，纯神经麻风活检表达增加的miRNA水平（p = 0.001）。 有趣的是，风险变体（C等位基因）的携带者在神经中产生更高水平的成熟miR-146 a（p = 0.04）。 从皮肤活检中，虽然我们观察到miR-146 a的水平增加，但我们无法将其与特定的临床形式或宿主基因型相关联。已知miR-146 a调节TNF水平，因此我们评估了用BCG Moreau感染的外周血单核细胞的TNF表达（神经活检）和释放。在这两种情况下，较低的TNF水平与携带风险C等位基因的受试者相关（分别为p= 0.0453和p =0.0352），这与该miRNA在麻风中的免疫调节作用一致。 尽管药物治疗取得了成功，但麻风病仍然影响着世界各地的人们。众所周知，宿主的遗传背景影响麻风病的发展，遗传变异与该病有关。因此，我们进行了一项研究，以评估microRNAs（miRNAs）多态性在麻风病中的作用。我们观察到miR-146 a的多态性与巴西人患麻风病的风险相关。基于对临床标本的分析，我们发现该遗传变异与miR-146 a水平升高相关，并且它也是肿瘤坏死因子（TNF）的负调节因子，肿瘤坏死因子是麻风病背景下的重要炎症介质。这些发现为miR-146 a在M.麻风感染，也可能有助于麻风的发展，通过控制TNF水平。
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. In spite of the successful drug therapy, leprosy is still affecting people worldwide. It is well known that host genetic background influences leprosy development and that genetic variants have been associated with the disease. Therefore we conducted a study to evaluate the role of microRNAs (miRNAs) polymorphisms in leprosy. We observed that a polymorphism in miR-146a is associated with the risk to develop leprosy in Brazilians. Based on the analysis of clinical specimens, we found that the genetic variant was correlated with elevated levels of miR-146a and it is also a negative regulator of tumor necrosis factor (TNF), an important inflammatory mediator in the leprosy context. These findings provide tenable evidences that miR-146a is important in the control of gene expression during M. leprae infection and also may contribute with leprosy development by controlling TNF levels.
登录
查看更多内容
影响因子：
6.7
作者：
Chatterjee S;Dwivedi VP;Singh Y;Siddiqui I;Sharma P;Van Kaer L;Chattopadhyay D;Das G
通讯作者：
Das G
影响因子：
5.3
作者：
Alter, Andrea;Fava, Vinicius Medeiros;Schurr, Erwin
通讯作者：
Schurr, Erwin
DOI：
10.1073/pnas.0812591106
发表时间：
2009-02-03
影响因子：
11.1
作者：
Jazdzewski, Krystian;Liyanarachchi, Sandya;De la Chapelle, Albert
通讯作者：
De la Chapelle, Albert
DOI：
10.1073/pnas.0802682105
发表时间：
2008-05-20
影响因子：
11.1
作者：
Jazdzewski, Krystian;Murray, Elizabeth L.;de la Chapelle, Albert
通讯作者：
de la Chapelle, Albert
影响因子：
3.7
作者：
Guerreiro LT;Robottom-Ferreira AB;Ribeiro-Alves M;Toledo-Pinto TG;Rosa Brito T;Rosa PS;Sandoval FG;Jardim MR;Antunes SG;Shannon EJ;Sarno EN;Pessolani MC;Williams DL;Moraes MO
通讯作者：
Moraes MO