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

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 - 2014/5/1

Y1 - 2014/5/1

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 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.

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 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.

U2 - 10.1007/s10048-014-0396-y

DO - 10.1007/s10048-014-0396-y

M3 - SCORING: Journal article

C2 - 24638856

VL - 15

SP - 129

EP - 134

JO - NEUROGENETICS

JF - NEUROGENETICS

SN - 1364-6745

IS - 2

ER -