miRNAcontributions to pediatric‐onset multiple sclerosis inferred fromGWAS

Abstract

Objective Onset 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. Methods GWAS 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. Results MIGWAS 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. Interpretation Evidence 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.

Emerging Biomarkers of Multiple Sclerosis in the Blood and the CSF: A Focus on Neurofilaments and Therapeutic Considerations

“…The analysis has shown the aberrant regulation of 5 genes in the histamine H 1 receptor, five genes in the MHC protein complex, five genes present on the inner part of the ER lumen, six genes in the 5-HT 2 type receptor-mediated signalling pathway, and nine genes in the interferon-gamma signalling pathways. Furthermore, as expected, pedMS patients were shown to have more copies of the HLA-DRB1*15:01 allele than controls [ 387 ].…”

“…The relative sparsity of CNS and immune-system related genes, especially in adolescents, proven to be associated with MS, might raise the question that epigenetic changes may play a pivotal role in the pathogenesis of pediatric-onset MS (pedMS). To explore this option, a large scale miRNA genome-wide association study (MIGWAS) and an miR-SNP analysis were conducted on 486 pedMS patients and 1362 control subjects [ 387 ]. The MIGWAS method first integrates the results of genome-wide association studies of cell- and tissue-type specific expression profiles of miRNAs.…”

“…Additionally, it has shown the enrichment of miRNA-target genes in 25 separate examined tissues without accounting for tissue-specific miRNA profiles. Of all the identified tissues, the highest enrichment was found in the keratinised cells of the oral mucosa of the gastrointestinal tract [ 387 ]. This is a somewhat expected result, as there is a mounting body of evidence of a bidirectional, proinflammatory relationship between MS and the gut microbiome.…”

Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells

“…Likewise, miRNAs are important regulatory coordinators of inflammatory processes and mitochondrial function as shown in pediatric MS [180], at least in part via the regulation of the mitochondrial melatonergic pathway [9]. Given the proposed important role of increased gut permeability in the etiology and course of MS, it is notable that miRNAs can significantly regulate gut permeability and physiological response [181], with the effects of butyrate at least partly mediated via miRNA regulation [182].…”

The Role of microRNA in the Development of Ischemic Heart Disease

“…Поэтому уровень отдельной микроРНК в биологических образцах может служить высокочувствительным маркером того или иного заболевания и использоваться в его диагностике. Показано, что изменение экспрессии или функционирования ряда микроРНК сопряжено с развитием многих болезней человека, включая сердечнососудистые (ССЗ), онкологические, инфекционные, нейродегенеративные и аутоиммунные заболевания [9][10][11].…”