Assessment of microRNA-related SNP effects in the 3' untranslated region of the IL22RA2 risk locus in multiple sclerosis
| Autor: | Elisabeth Steinhagen-Thiessen, Joerg T. Epplen, Christiane Graetz, Marian Jaedicke, Andrew T. Chan, Alexander Winkelmann, Mathias Buttmann, Paul Blaschke, Sabine Hoffjan, Lars Bertram, Brit-Maren M. Schjeide, Felix Luessi, Orhan Aktas, Ulman Lindenberger, Tania Kümpfel, Marcel Schilling, Julia Schröder, Lisa-Ann Gerdes, Christian Kubisch, Frauke Zipp, Antje Kroner, Denis A. Akkad, Thomas Dörner, Andriy Mashychev, Sara Ansaloni, Uwe K. Zettl, Peter Lohse, Peter Rieckmann, Hans-Peter Hartung, Christina M. Lill |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Linkage disequilibrium Candidate gene Multiple Sclerosis In silico Locus (genetics) Biology Polymorphism Single Nucleotide Cellular and Molecular Neuroscience Risk Factors Genetics SNP Humans Genetic Predisposition to Disease RNA Messenger Genotyping 3' Untranslated Regions Genetics (clinical) Genetic Association Studies Genetic association Binding Sites Three prime untranslated region Receptors Interleukin MicroRNAs HEK293 Cells Gene Expression Regulation Female |
| Zdroj: | Neurogenetics |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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