miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS.
miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS.
复制标题
从 GWAS 推断 miRNA 对儿童多发性硬化症的贡献。
DOI：
10.1002/acn3.786
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发表时间：
2019
影响因子：
5.3
通讯作者：
Hart,Jan
中科院分区：
文献类型：
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作者：
Rhead,Brooke;Shao,Xiaorong;Graves,JenniferS;Chitnis,Tanuja;Waldman,AmyT;Lotze,Timothy;Schreiner,Teri;Belman,Anita;Krupp,Lauren;Greenberg,BenjaminM;Weinstock-Guttman,Bianca;Aaen,Gregory;Tillema,JanM;Rodriguez,Moses;Hart,Jan
多发性硬化症（MS）在儿童期发病，约有5%的病例（儿科MS或ped-MS）。表观遗传学的影响在成人MS发病机制中有很大的影响，包括来自microRNA（miRNAs）的贡献，miRNAs是通过结合靶基因mRNA影响基因表达的小的非编码RNA。很少有研究专门研究ped-MS中的miRNAs，但早期发展MS的个体可能携带相对较高的遗传风险因素负担，因此，miRNA失调可能在ped-MS的发展中发挥更大的作用，而不是在成人发病的MS。这项研究旨在寻找证据的miRNA参与ped-MS pathogeneticsMethodsGWAS结果从486 ped-MS病例和1362对照来自美国。研究了儿科MS网络和Kaiser Permanente北方加州成员的miRNA特异性信号。首先，使用MIGWAS软件评估miRNA-靶基因网络信号的富集。其次，检测miRNA基因和靶基因结合位点（miR−SNPs）中的SNPs与ped-MS的相关性，并对相关靶基因进行通路分析。结果MIGWAS分析显示，miRNA-靶基因信号在GWAS中富集（P= 0.038），并确定了39个候选生物标志物miRNA-靶基因对，包括免疫和神经元信号传导基因。miR-SNP分析提示miRNAs与靶基因结合的5条途径中存在失调，主要涉及免疫信号传导。来自GWAS的证据表明，miRNAs通过影响免疫信号传导和其他途径在ped-MS发病机制中发挥作用。候选生物标志物miRNA-靶基因对应进一步研究以用于诊断、预后和/或治疗用途。
ObjectiveOnset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatric MS, or ped‐MS). Epigenetic influences are strongly implicated in MS pathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped‐MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA dysregulation may therefore play a larger role in the development of ped‐MS than in adult‐onset MS. This study aimed to look for evidence of miRNA involvement in ped‐MS pathogenesis.MethodsGWAS results from 486 ped‐MS cases and 1362 controls from the U.S. Pediatric MS Network and Kaiser Permanente Northern California membership were investigated for miRNA‐specific signals. First, enrichment of miRNA‐target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR−SNPs) were tested for association with ped‐MS, and pathway analysis was performed on associated target genes.ResultsMIGWAS analysis showed that miRNA‐target gene signals were enriched in GWAS (P= 0.038) and identified 39 candidate biomarker miRNA‐target gene pairs, including immune and neuronal signaling genes. The miR‐SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling.InterpretationEvidence from GWAS suggests that miRNAs play a role in ped‐MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA‐target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.