A Synonymous Variant in IRGM Alters a Binding Site for MiR-196 and Causes Deregulation of IRGM-dependent Xenophagy in Crohn's Disease

Overview

Journal Nat Genet

Specialty Genetics

Date 2011 Feb 1

PMID 21278745

Citations 295

Authors

Patrick Brest

Pierre Lapaquette

Mouloud Souidi

Kevin Lebrigand

Annabelle Cesaro

Valerie Vouret-Craviari

Bernard Mari

Pascal Barbry

Jean-Francois Mosnier

Xavier Hebuterne

Annick Harel-Bellan

Baharia Mograbi

Arlette Darfeuille-Michaud

Paul Hofman

Affiliations

Soon will be listed here.

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.

Citing Articles

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