TY - JOUR
T1 - Assessment of microRNA-related SNP effects in the 3′ untranslated region of the IL22RA2 risk locus in multiple sclerosis
AU - Lill, Christina M.
AU - Schilling, Marcel
AU - Ansaloni, Sara
AU - Schröder, Julia
AU - Jaedicke, Marian
AU - Luessi, Felix
AU - Schjeide, Brit Maren M.
AU - Mashychev, Andriy
AU - Graetz, Christiane
AU - Akkad, Denis A.
AU - Gerdes, Lisa Ann
AU - Kroner, Antje
AU - Blaschke, Paul
AU - Hoffjan, Sabine
AU - Winkelmann, Alexander
AU - Dörner, Thomas
AU - Rieckmann, Peter
AU - Steinhagen-Thiessen, Elisabeth
AU - Lindenberger, Ulman
AU - Chan, Andrew
AU - Hartung, Hans Peter
AU - Aktas, Orhan
AU - Lohse, Peter
AU - Buttmann, Mathias
AU - Kümpfel, Tania
AU - Kubisch, Christian
AU - Zettl, Uwe K.
AU - Epplen, Joerg T.
AU - Zipp, Frauke
AU - Bertram, Lars
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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 3UTR 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 3UTR 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.
AB - 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 3UTR 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 3UTR 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.
UR - http://www.scopus.com/inward/record.url?scp=84900496324&partnerID=8YFLogxK
U2 - 10.1007/s10048-014-0396-y
DO - 10.1007/s10048-014-0396-y
M3 - Journal articles
C2 - 24638856
AN - SCOPUS:84900496324
SN - 1364-6745
VL - 15
SP - 129
EP - 134
JO - Neurogenetics
JF - Neurogenetics
IS - 2
ER -
