title: Cutting edge: a variant of the IL-23R gene associated with inflammatory bowel disease induces loss of microRNA regulation and enhanced protein production.
abstract: IL-23R gene variants have been identified as risk factors for two major inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, but how they contribute to disease is poorly understood. In this study, we show that the rs10889677 variant in the 3'-untranslated region of the IL-23R gene displays enhanced levels of both mRNA and protein production of IL-23R. This can be attributed to a loss of binding capacity for the microRNAs (miRNAs) Let-7e and Let-7f by the variant allele. Indeed, inhibition and overexpression of these miRNAs influenced the expression of the wild type but not the variant allele. Our data clearly demonstrate a role for miRNA-mediated dysregulation of IL-23R signaling, correlated with a single nucleotide polymorphism in the IL-23R strongly associated with IBD susceptibility. This implies that this mutation, in combination with other genetic risk factors, can lead to disease through sustained IL-23R signaling, contributing to the chronicity of IBD.
authors.affiliation: Department of Gastroenterology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands. a.zwiers@vumc.nl
authors.forename: Antonie
authors.initials: A
authors.lastname: Zwiers
authors.forename: Laurens
authors.initials: L
authors.lastname: Kraal
authors.forename: Tineke C T M
authors.initials: TC
authors.lastname: van de Pouw Kraan
authors.forename: Thomas
authors.initials: T
authors.lastname: Wurdinger
authors.forename: Gerd
authors.initials: G
authors.lastname: Bouma
authors.forename: Georg
authors.initials: G
authors.lastname: Kraal
mesh_terms: D020413:3' Untranslated Regions; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D053759:Interleukin-23 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D053759:Interleukin-23; D035683:MicroRNAs; D012333:RNA, Messenger; C487931:mirnlet7 microRNA, human