Original ResearchFull Report: Basic and Translational—Alimentary TractGenetic Variants Synthesize to Produce Paneth Cell Phenotypes That Define Subtypes of Crohn's Disease
Section snippets
Description and Genotyping of Patient Cohort
Full methods are provided in the Supplementary Detailed Methods. Patients were recruited at Barnes-Jewish Hospital, St Louis between 2005 and 2013 or at Cedars-Sinai Medical Center, Los Angeles between 1999 and 2013. Patient DNA samples were genotyped for ATG16L1 T300A and the CD-associated NOD2 variants.10, 20, 21 Patients from the Barnes-Jewish Hospital cohort were genotyped by the Digestive Disease Research Core Center using matrix-assisted laser desorption ionization-time of flight mass
Association of NOD2 CD Susceptibility Variants With Abnormal Paneth Cell Phenotype
We performed a retrospective analysis of Paneth cell phenotypes in genotyped CD patients (N = 119) using resection specimens. In order to study tissue that might exhibit early pathologic and molecular changes associated with disease pathogenesis, we examined ileal tissue samples that demonstrated no evidence of active/chronic disease. Paneth cell analysis was performed using our previously developed system for robust, quantitative scoring of Paneth cell phenotypes based on high-resolution
Discussion
Here we have provided the first evidence that a defined cellular phenotype (in Paneth cells) is linked to multiple CD genetic susceptibility loci and subdivides patients into 2 groups. In addition, we defined the molecular consequences of this phenotype in human Paneth cells and found an association with immune activation. We demonstrated that Paneth cell phenotypes are associated with the presence of granuloma, a classic histological finding associated with CD. We also showed that the Paneth
Acknowledgments
Transcript Profiling: Microarray data are deposited at ArrayExpress http://www.ebi.ac.uk/arrayexpress/ (accession number E-MTAB-1281).
References (41)
- et al.
Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review
Gastroenterology
(2012) - et al.
Metagenomics and personalized medicine
Cell
(2011) Paneth cell development, differentiation, and function: new molecular cues
Gastroenterology
(2009)- et al.
Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine
Cell
(2010) - et al.
Crohn's disease
Lancet
(2012) - et al.
Inflammatory bowel disease: clinical aspects and established and evolving therapies
Lancet
(2007) - et al.
Paneth's disease
J Crohns Colitis
(2010) - et al.
Crohn's disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan
Gastroenterology
(2003) - et al.
Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease
J Biol Chem
(2003) - et al.
Granulomas do not affect postoperative recurrence rates in Crohn's disease
Gastroenterology
(1982)
Inflammatory bowel disease epidemiology
Curr Opin Gastroenterol
Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin
Nature
Enteric defensins are essential regulators of intestinal microbial ecology
Nat Immunol
Paneth cells and innate mucosal immunity
Curr Opin Gastroenterol
A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells
Nature
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease
Nature
Genetics and pathogenesis of inflammatory bowel disease
Nature
Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease
Nature
A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease
Nature
NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression
Gut
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Author names in bold designate shared co-first authorship.
Conflicts of interest The authors disclose no conflicts.
Funding K.L.V. was supported by a National Institutes of Health training grant (T32 AI007163). The research was funded by a Washington University Institute of Clinical and Translational Sciences Pilot Award (CTSA308). The Washington University Digestive Disease Research Core Center is supported by a grant from the National Institute of Diabetes and Digestive and Kidney Disease (P30DK052574). IBD Research at Cedars-Sinai is supported by US Public Health Service grant PO1DK046763 and the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds. Genotyping at Cedars-Sinai Medical Center is supported in part by the National Center for Research Resources grant M01-RR00425, UCLA/Cedars-Sinai/Harbor/Drew Clinical and Translational Science Institute grant (UL1 TR000124-01), the Southern California Diabetes and Endocrinology Research grant (DK063491). Project investigators are supported by The Helmsley Charitable Trust (D.P.B.M.), The European Union (D.P.B.M.), The Crohn's and Colitis Foundation of America (CCFA) (D.P.B.M.), The Feintech Family Chair in IBD (S.R.T.), The Joshua L. and Lisa Z. Greer Chair in IBD Genetics (D.P.B.M.), and grants DK043351, DK097485, DK092405 (R.J.X.), DK062413, DK046763-19, AI067068, HS021747 (D.P.B.M.), and AI084887 (T.S.S.). T.S.S. and R.J.X. are supported by the CCFA Genetics initiative.
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Authors share co-first authorship