Faculty Collaboration Database

Assessment of microRNA-related SNP effects in the 3' untranslated region of the IL22RA2 risk locus in multiple sclerosis. Neurogenetics 2014 May;15(2):129-34

Date

03/19/2014

Pubmed ID

24638856

DOI

10.1007/s10048-014-0396-y

Scopus ID

2-s2.0-84900496324 (requires institutional sign-in at Scopus site)   15 Citations

Abstract

Recent large-scale association studies have identified over 100 MS risk loci. One of these MS risk variants is single-nucleotide polymorphism (SNP) rs17066096, located ~14 kb downstream of IL22RA2. IL22RA2 represents a compelling MS candidate gene due to the role of IL-22 in autoimmunity; however, rs17066096 does not map into any known functional element. We assessed whether rs17066096 or a nearby proxy SNP may exert pathogenic effects by affecting microRNA-to-mRNA binding and thus IL22RA2 expression using comprehensive in silico predictions, in vitro reporter assays, and genotyping experiments in 6,722 individuals. In silico screening identified two predicted microRNA binding sites in the 3'UTR of IL22RA2 (for hsa-miR-2278 and hsa-miR-411-5p) encompassing a SNP (rs28366) in moderate linkage disequilibrium with rs17066096 (r (2) = 0.4). The binding of both microRNAs to the IL22RA2 3'UTR was confirmed in vitro, but their binding affinities were not significantly affected by rs28366. Association analyses revealed significant association of rs17066096 and MS risk in our independent German dataset (odds ratio  = 1.15, P = 3.48 × 10(-4)), but did not indicate rs28366 to be the cause of this signal. While our study provides independent validation of the association between rs17066096 and MS risk, this signal does not appear to be caused by sequence variants affecting microRNA function.

Author List

Lill CM, Schilling M, Ansaloni S, Schröder J, Jaedicke M, Luessi F, Schjeide BM, Mashychev A, Graetz C, Akkad DA, Gerdes LA, Kroner A, Blaschke P, Hoffjan S, Winkelmann A, Dörner T, Rieckmann P, Steinhagen-Thiessen E, Lindenberger U, Chan A, Hartung HP, Aktas O, Lohse P, Buttmann M, Kümpfel T, Kubisch C, Zettl UK, Epplen JT, Zipp F, Bertram L

Author

Antje Kroner-Milsch MD, PhD Associate Professor in the Neurosurgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

3' Untranslated Regions
Binding Sites
Female
Gene Expression Regulation
Genetic Association Studies
Genetic Predisposition to Disease
HEK293 Cells
Humans
Male
MicroRNAs
Multiple Sclerosis
Polymorphism, Single Nucleotide
RNA, Messenger
Receptors, Interleukin
Risk Factors