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

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 IRGM1,2, but coding-sequence variation has been excluded as a source of this association2. 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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Figure 1: A common, 20-kb deletion polymorphism upstream of IRGM.
Figure 2: Differential expression of IRGM from the deletion (CD risk) and reference (CD protective) haplotypes.
Figure 3: IRGM expression levels affect the autophagy of Salmonella typhimurium in human epithelial cells.

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Acknowledgements

The current work was funded by a US National Institute of Allergy and Infection Diseases grant, AI062773, HL088297, DK43351, and CCIB developmental funds to R.J.X. and by a Lilly Life Sciences Research Fellowship to S.A.M. The National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) IBD Genetics Consortium is funded by the following grants: DK62431 (S.R.B.), DK62422 (J.H.C.), DK62420 (R.H.D.), DK62432 and DK064869 (J.D.R.), DK62423 (M.S.S.), DK62413 (K.D.T.), and DK62429 (J.H.C.). Additional support was provided by the Burroughs Wellcome Foundation (J.H.C.), the Crohn's and Colitis Foundation of America (S.R.B., J.H.C., J.D.R.), and the NIDDK, DK064869 (J.D.R.). M. Garber and C. Bekpen provided helpful discussion; C. Patil and J. Korn provided thoughtful comments on the manuscript. LC3-GFP lentiviral vector was a gift from C. Münz (The Rockefeller University).

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Correspondence to Mark J Daly or Ramnik J Xavier.

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Supplementary Figures 1–3, Supplementary Table 1, Supplementary Note, Supplementary Methods (PDF 398 kb)

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McCarroll, S., Huett, A., Kuballa, P. et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat Genet 40, 1107–1112 (2008). https://doi.org/10.1038/ng.215

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