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Assessment of microRNA-related SNP effects in the 3′ untranslated region of the IL22RA2 risk locus in multiple sclerosis

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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.

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We are grateful to the patients and controls participating in this study. This project was funded by grants from the Hans and Ilse Breuer Foundation for Alzheimer’s Research, the Cure Alzheimer's Fund, and the Brain and Behavior Research Foundation (formerly NARSAD; all to L.B.), the German Ministry for Education and Research (BMBF; grant 16SV5538 to L.B., KKNMS to F.Z., grant NBL3 to U.K.Z., grant 01GM1203A to H.-P.H. and O.A., grant 01UW0808 to U.L. and E.S.-T.), the Johannes Gutenberg University Mainz (grants MAIFOR and “Inneruniversitäre Forschungsförderung Stufe I” to F.L.), the Walter- and Ilse-Rose-Stiftung (to H.-P.H. and O.A.), and the Innovation Fund of the Max Planck Society (M.FE.A.LD0002 to U.L.). S.A. and J.S. were supported by fellowships of the Max Planck International Research Network on Aging (MaxNetAging).

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Correspondence to Christina M. Lill.

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Lill, C.M., Schilling, M., Ansaloni, S. et al. Assessment of microRNA-related SNP effects in the 3′ untranslated region of the IL22RA2 risk locus in multiple sclerosis. Neurogenetics 15, 129–134 (2014).

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