title: A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease.
abstract: Susceptibility to Crohn's disease, a complex inflammatory disease, is influenced by common variants at many loci. The common exonic synonymous SNP (c.313C>T) in IRGM, found in strong linkage disequilibrium with a deletion polymorphism, has been classified as non-causative because of the absence of an alteration in the IRGM protein sequence or splice sites. Here we show that a family of microRNAs (miRNAs), miR-196, is overexpressed in the inflammatory intestinal epithelia of individuals with Crohn's disease and downregulates the IRGM protective variant (c.313C) but not the risk-associated allele (c.313T). Subsequent loss of tight regulation of IRGM expression compromises control of intracellular replication of Crohn's disease-associated adherent invasive Escherichia coli by autophagy. These results suggest that the association of IRGM with Crohn's disease arises from a miRNA-based alteration in IRGM regulation that affects the efficacy of autophagy, thereby implicating a synonymous polymorphism as a likely causal variant.
authors.affiliation: INSERM ERI-21, EA4319, Faculty of Medicine, Nice, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Brest
authors.forename: Pierre
authors.initials: P
authors.lastname: Lapaquette
authors.forename: Mouloud
authors.initials: M
authors.lastname: Souidi
authors.forename: Kevin
authors.initials: K
authors.lastname: Lebrigand
authors.forename: Annabelle
authors.initials: A
authors.lastname: Cesaro
authors.forename: Valérie
authors.initials: V
authors.lastname: Vouret-Craviari
authors.forename: Bernard
authors.initials: B
authors.lastname: Mari
authors.forename: Pascal
authors.initials: P
authors.lastname: Barbry
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Mosnier
authors.forename: Xavier
authors.initials: X
authors.lastname: Hébuterne
authors.forename: Annick
authors.initials: A
authors.lastname: Harel-Bellan
authors.forename: Baharia
authors.initials: B
authors.lastname: Mograbi
authors.forename: Arlette
authors.initials: A
authors.lastname: Darfeuille-Michaud
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
mesh_terms: D001343:Autophagy / Q000235:genetics*; D001665:Binding Sites; D003424:Crohn Disease / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide
chemical_list: C542543:MIRN196 microRNA, human; D035683:MicroRNAs; D019204:GTP-Binding Proteins; C513539:IRGM protein, human