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Ann Clin Transl Neurol. 2019 May 15;6(6):1053-1061. doi: 10.1002/acn3.786. eCollection 2019 Jun.

miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS.

Author information

1
Division of Epidemiology School of Public Health University of California Berkeley California.
2
Computational Biology Graduate Group University of California Berkeley California.
3
Department of Neurology University of California San Francisco California.
4
Department of Neurosciences University of California San Diego California.
5
Partners Pediatric Multiple Sclerosis Center Massachusetts General Hospital for Children Boston Massachusetts.
6
Division of Neurology Children's Hospital of Philadelphia Philadelphia Pennsylvania.
7
Blue Bird Circle Multiple Sclerosis Center Baylor College of Medicine Houston Texas.
8
Children's Hospital Colorado University of Colorado Denver Colorado.
9
Lourie Center for Pediatric MS Stony Brook Children's Hospital Stony Brook New York.
10
Department of Neurology and Neurotherapeutics University of Texas Southwestern Dallas Texas.
11
Pediatric Multiple Sclerosis Center Jacobs Neurological Institute SUNY Buffalo Buffalo New York.
12
Pediatric MS Center at Loma Linda University Children's Hospital Loma Linda California.
13
Mayo Clinic's Pediatric MS Center Rochester Minnesota.
14
University of California, San Francisco Regional Pediatric MS Center Neurology San Francisco California.
15
University of Alabama Center for Pediatric-onset Demyelinating Disease Children's Hospital of Alabama Birmingham Alabama.
16
Department of Pediatric Neurology Northwestern Feinberg School of Medicine Chicago Illinois.
17
Division of Pediatric Neurology University of Utah Primary Children's Hospital Salt Lake City Utah.
18
Boston Children's Hospital Boston Massachusetts.
19
Pediatric-onset Demyelinating Diseases and Autoimmune Encephalitis Center St. Louis Children's Hospital Washington University School of Medicine St. Louis Missouri.
20
Children's National Medical Center Washington District of Columbia.
21
Department of Neurology University of Utah School of Medicine Salt Lake City Utah.
22
Department of Pediatrics University of Utah School of Medicine Salt Lake City Utah.
23
Kaiser Permanente Division of Research Oakland California.
24
Research Program on Genes, Environment and Health Kaiser Permanente Oakland California.

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.

Conflict of interest statement

E. Waubant is site PI for a Novartis and Roche trial. She has volunteered on an advisory board for a Novartis trial. She is a nonremunerated advisor for clinical trial design to Novartis, Biogen‐IDEC, Sanofi, Genentech, Serono, and Celgene. She has funding from the NMSS, PCORI, and the Race to Erase MS. She is the section editor for Annals of Clinical and Translational Neurology, and co‐Chief editor for MS And Related Disorders. A. Waldman reports grants from NIH (NINDS) NS071463 and from NMSS during the conduct of the study, as well as funds for investigator‐initiated study from Ionis Pharmaceuticals and Biogen Idec and grants from United Leukodystrophy Foundation outside the submitted work. She is a consultant for Optum and has received royalties from UpToDate. B. Greenberg has received grant funding from Chugai, Medimmune, Medday, National Institutes of Health (NIH), NMSS, Guthy Jackson Charitable Foundation, and Transverse Myelitis Association. He has received consulting fees from Novartis, EMD Serono, Celgene, and Alexion. L. Benson reports BG12 clinical trial support from Biogen, grants from Boston Children's Hospital Office of Faculty Development, travel funds from National MS Society, and personal fees from National Vaccine Compensation Program outside the submitted work. T.C. Casper reports grants from National MS Society. J. Graves reports speaking honoraria from Novartis outside the submitted work. B. Weinstock‐Guttman reports grants and personal fees from Biogen, EMD Serono, Novartis, and Genentech, and personal fees from Mallinckrodt outside the submitted work.

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