title: Assessment of microRNA-related SNP effects in the 3' untranslated region of the IL22RA2 risk locus in multiple sclerosis.
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.
authors.affiliation: Neuropsychiatric Genetics Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, Berlin, Germany, lill@molgen.mpg.de.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Lill
authors.forename: Marcel
authors.initials: M
authors.lastname: Schilling
authors.forename: Sara
authors.initials: S
authors.lastname: Ansaloni
authors.forename: Julia
authors.initials: J
authors.lastname: Schröder
authors.forename: Marian
authors.initials: M
authors.lastname: Jaedicke
authors.forename: Felix
authors.initials: F
authors.lastname: Luessi
authors.forename: Brit-Maren M
authors.initials: BM
authors.lastname: Schjeide
authors.forename: Andriy
authors.initials: A
authors.lastname: Mashychev
authors.forename: Christiane
authors.initials: C
authors.lastname: Graetz
authors.forename: Denis A
authors.initials: DA
authors.lastname: Akkad
authors.forename: Lisa-Ann
authors.initials: LA
authors.lastname: Gerdes
authors.forename: Antje
authors.initials: A
authors.lastname: Kroner
authors.forename: Paul
authors.initials: P
authors.lastname: Blaschke
authors.forename: Sabine
authors.initials: S
authors.lastname: Hoffjan
authors.forename: Alexander
authors.initials: A
authors.lastname: Winkelmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Dörner
authors.forename: Peter
authors.initials: P
authors.lastname: Rieckmann
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Steinhagen-Thiessen
authors.forename: Ulman
authors.initials: U
authors.lastname: Lindenberger
authors.forename: Andrew
authors.initials: A
authors.lastname: Chan
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.forename: Orhan
authors.initials: O
authors.lastname: Aktas
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.forename: Mathias
authors.initials: M
authors.lastname: Buttmann
authors.forename: Tania
authors.initials: T
authors.lastname: Kümpfel
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.forename: Uwe K
authors.initials: UK
authors.lastname: Zettl
authors.forename: Joerg T
authors.initials: JT
authors.lastname: Epplen
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
mesh_terms: D020413:3' Untranslated Regions; D001665:Binding Sites; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics*; D012307:Risk Factors
chemical_list: D020413:3' Untranslated Regions; C433253:IL22RA2 protein, human; D035683:MicroRNAs; D012333:RNA, Messenger; D018123:Receptors, Interleukin