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.
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Acknowledgements
This work was supported by grants from the Ministère de la Recherche et de la Technologie (JE2526, A.D.-M.), by INRA (USC 2018, A.D.-M.) by the Association F. Aupetit (A.D.-M. and V.V.-C.), by the Institut National du Cancer (07/3D1616/Pdoc-110-32/NG-NC (P. Brest), PL0079 (P. Barbry) and INFLACOL (P.H.)), the European Community (P. Barbry and B. Mari; MICROENVIMET, FP7-HEALTH-F2-2008-201279), Association pour la Recherche sur le Cancer (ARC), Villejuif, France (V.V.-C.), Integrated Project SIROCCO LSHG-CT-2006-037900 (A.H.-B.), French clinical research projects funding program 'MUTCROHN' (PHRC-2010) (X.H.) and the Infectiopôle Sud PACA (P.H.). The confocal microscope was the property of the Université d'Auvergne. The authors would like to thank E. Selva, V. Gavric-Tanga, K. Havet, O. Bordone, G. Cane, M. Ohanna and A. Chargui for their excellent technical assistance.
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P. Brest, B. Mograbi, A.D.-M. and P.H. designed the study. P. Brest, P.L., M.S. and A.C. performed the experiments. P. Brest, P.L., M.S., B. Mograbi, A.D.-M. and P.H. collected and analyzed the data. P.H., J.-F.M. and X.H. participated in subject recruitment and in the Tissue Bank. P. Brest, P.L., A.H.-B., B. Mograbi, A.D.-M. and P.H. wrote the manuscript. K.L., V.V.-C., A.H.-B., B. Mari and P. Barbry gave technical support and conceptual advice.
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Brest, P., Lapaquette, P., Souidi, M. et al. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease. Nat Genet 43, 242–245 (2011). https://doi.org/10.1038/ng.762
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DOI: https://doi.org/10.1038/ng.762
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