Deletion Polymorphism Upstream of IRGM Associated with Altered IRGM Expression and Crohn's Disease

Overview

Journal Nat Genet

Specialty Genetics

Date 2009 Jan 24

PMID 19165925

Citations 354

Authors

Steven A McCarroll

Alan Huett

Petric Kuballa

Shannon D Chilewski

Aimee Landry

Philippe Goyette

Michael C Zody

Jennifer L Hall

Steven R Brant

Judy H Cho

Richard H Duerr

Mark S Silverberg

Kent D Taylor

John D Rioux

David Altshuler

Mark J Daly

Ramnik J Xavier

Affiliations

Soon will be listed here.

Abstract

Following recent success in genome-wide association studies, a critical focus of human genetics is to understand how genetic variation at implicated loci influences cellular and disease processes. Crohn's disease (CD) is associated with SNPs around IRGM, but coding-sequence variation has been excluded as a source of this association. We identified a common, 20-kb deletion polymorphism, immediately upstream of IRGM and in perfect linkage disequilibrium (r2 = 1.0) with the most strongly CD-associated SNP, that causes IRGM to segregate in the population with two distinct upstream sequences. The deletion (CD risk) and reference (CD protective) haplotypes of IRGM showed distinct expression patterns. Manipulation of IRGM expression levels modulated cellular autophagy of internalized bacteria, a process implicated in CD. These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant.

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