A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease

作者：Brest Patrick; Lapaquette Pierre; Souidi Mouloud; Lebrigand Kevin; Cesaro Annabelle; Vouret Craviari Valerie; Mari Bernard; Barbry Pascal; Mosnier Jean Francois; Hebuterne Xavier; Harel Bellan Annick; Mograbi Baharia; Darfeuille Michaud Arlette; Hofman Paul^*

来源：Nature Genetics, 2011, 43(3): 242-U24.

DOI：10.1038/ng.762

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.

• 出版日期2011-3