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

Nature Genetics volume 43, pages 242–245 (2011)Cite this article

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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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Figure 1: Allele-specific regulation of IRGM by miR-196.
Figure 2: miR-196 overexpression in inflamed mucosa correlates with decreased expression of the IRGM c.313C variant ex vivo.
Figure 3: IRGM expression and miR-196 affect autophagic flux and AIEC-bacteria–mediated autophagy.

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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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Author notes

  1. Arlette Darfeuille-Michaud and Paul Hofman: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM ERI-21, EA4319, Faculty of Medicine, Nice, France

    Patrick Brest, Annabelle Cesaro, Valérie Vouret-Craviari, Xavier Hébuterne, Baharia Mograbi & Paul Hofman

  2. University of Nice Sophia Antipolis, Nice, France

    Patrick Brest, Kevin Lebrigand, Annabelle Cesaro, Valérie Vouret-Craviari, Bernard Mari, Pascal Barbry, Xavier Hébuterne, Baharia Mograbi & Paul Hofman

  3. Clermont Université, Université d'Auvergne, Jeune Equipe JE 2526, Clermont-Ferrand, France

    Pierre Lapaquette & Arlette Darfeuille-Michaud

  4. INRA, Institut de Recherche Agronomique, Unité sous contrat USC-2018, Clermont-Ferrand, France

    Pierre Lapaquette & Arlette Darfeuille-Michaud

  5. Université Paris-Sud 11, Epigenetics and Cancer, FRE 3239, Villejuif, France

    Mouloud Souidi & Annick Harel-Bellan

  6. Centre National de la Recherche Scientifique (CNRS), Villejuif, France

    Mouloud Souidi & Annick Harel-Bellan

  7. CNRS UMR 6097, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France

    Kevin Lebrigand, Bernard Mari & Pascal Barbry

  8. EA4273, University of Nantes, Nantes, France

    Jean-François Mosnier

  9. Centre Hospitalier Universitaire de Nice, Hôpital de l'Archet, Service de Gastroentérologie, Nice, France

    Xavier Hébuterne

  10. Centre Hospitalier Universitaire de Nice, Hôpital Pasteur, Tumorothèque, Centre de Ressource Biologique INSERM, Nice, France

    Paul Hofman

  11. Centre Hospitalier Universitaire de Nice, Hôpital Pasteur, Laboratoire de Pathologie Clinique et Expérimentale, Nice, France

    Paul Hofman

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  1. Patrick Brest
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Contributions

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.

Corresponding authors

Correspondence to Arlette Darfeuille-Michaud or Paul Hofman.

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The authors declare no competing financial interests.

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Supplementary Figures 1–16, Supplementary Table 1 and Supplementary Note (PDF 1630 kb)

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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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