Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis

By J. Rioux, Ramnik J. Xavier, K. Taylor, M. Silverberg, P. Goyette, A. Huett, Todd Green, Petric Kuballa, M. Barmada, L. Datta and 15 more. Nature Genetics, 2007

1,900 citations recorded by the source corpus.

We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10−10) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.

Subfields: Epidemiology, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4fa2cc6197341c81e6f933c3b46165d74b2f2431

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Citations in the corpus

The genetics and immunopathogenesis of inflammatory bowel disease (2008, background): “ATG16L1 is broadly expressed by intestinal epithelial cells, antigen-presenting cells, CD4 + , CD8 + and CD19 + primary human T cell”
Virus-Plus-Susceptibility Gene Interaction Determines Crohn’s Disease Gene Atg16L1 Phenotypes in Intestine (2010, background): “One Crohn’s disease susceptibility allele is in the autophagy gene ATG16L1 (The Wellcome Trust Case Control Consortium, 2007; Rioux et al., 2007; Hampe et al., 2007).”
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”
Common disorders are quantitative traits (2009, background): “Recently, GWA research has implicated autophagy as a previously unsuspected quantitative mechanism in CD pathogenesi”
STrengthening the REporting of Genetic Association Studies (STREGA)— An Extension of the STROBE Statement (2009, neutral): “org 0158 February 2009 | Volume 6 | Issue 2 | e1000022 association studies [85,87–105].”