Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease

By Steven A. McCarroll, A. Huett, Petric Kuballa, S. Chilewski, Aimee L Landry, P. Goyette, M. Zody, Jennifer L. Hall, S. Brant, Judy H. Cho and 7 more. Nature Genetics, 2008

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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.

Subfields: Epidemiology, Immunology, Surgery

View Paper: https://www.semanticscholar.org/paper/bbc570de8e077da1d7aa85bd2ddce54c63a29ec1

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Citations in the corpus

Autophagy: Renovation of Cells and Tissues (2011, positive): “Later studies also identified an association between Crohn disease and IRGM (immunity-related GTPase family, M), which has also been implicated in autophagy against intracellular pathogens (McCarroll et al., 2008; Parkes et al., 2007).”
Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut (2015, background): “As a matter of fact several defects in bacterial recognition and processing have been documented in CD patients carrying particular genetic polymorphisms, chiefly of pattern-recognition receptors such as NOD2/CARD15 [68, 69] and genes involved in autophagy like ATG16L1 and IRGM [70–72].”
Autophagy, Immunity, and Microbial Adaptations (2009, background): “Interestingly, several risk loci identified through GWAS are common to ulcerative colitis and CD, but autophagy genes ATG16L1 and IRGM, along with NOD2, appear to be more specific for CD (Fisher et al., 2008), and IRGM risk alleles may predispose even more specifically to the ileal form of CD (Rober”
Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants (2011, methodology): “and analysis of data from genome-wide association studie”
DELLY: structural variant discovery by integrated paired-end and split-read analysis (2012, background): “…Page: i333 i333–i339 Motivation: The discovery of genomic structural variants (SVs) at high sensitivity and specificity is an essential requirement for characterizing naturally occurring variation and for understanding pathological somatic rearrangements in personal genome sequencing data.”
Genetics and pathogenesis of inflammatory bowel disease (2011, background): “Autophagy and IBD Genetic analyses have shown an unsuspected role for autophagy in innate immunity and IBD, implicating two component genes, ATG16L1 and IRGM , in IBD pathogenesi”