Hypothesis-free analysis of ATG16L1 demonstrates gene-wide extent of association with Crohn's disease susceptibility
- Johan Van Limbergen1,2,3,
- Boyko Kabakchiev4,
- Joanne M Stempak4,
- Phil Schumm5,
- Wei Xu6,
- Paul Henderson1,
- NIDDK IBD Genetics Consortium,,
- Stephen Girardin7,
- Anne M Griffiths2,
- Dana Philpott2,
- Mark Silverberg4
- 1Child Life and Health, University of Edinburgh, Edinburgh, UK
- 2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada
- 3Department of Immunology, University of Toronto, Toronto, Ontario, Canada
- 4Inflammatory Bowel Disease (IBD) Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital Toronto, Ontario, Canada
- 5Dept of Health Studies, University of Chicago, Chicago, Illinois, USA
- 6Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
- 7Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Correspondence to Dr Johan Van Limbergen, Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Sciennes Road, Edinburgh EH9 1LF, UK; johanvanlimbergen{at}hotmail.com
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Contributors JVL, BK, DP, SG, AMG, MS: design, conduct of study, data analysis, preparation of manuscript. JMS, WX, PS, PH, NIDDK IBD Genetics Consortium: recruitment of subjects, data analysis.
- Accepted 23 June 2012
- Published Online First 24 July 2012
- Genetics
- inflammatory bowel disease
- paediatric gastroenterology
- IBD—genetics
- Crohn's disease
- disease
- infliximab
- enteral nutrition
- genotype
- genetic testing
We read with interest the recent paper by Plantinga et al showing a role for the threonine to alanine (T300A)-variant of ATG16L1 in regulating the expression of ATG16L1 and cytokine production in response to a NOD2-ligand.1 ATG16L1, notably T300A (rs2241880) in exon 9, was first implicated in Crohn's disease (CD) susceptibility in a non-synonymous single nucleotide polymorphism (SNP) study, followed by a tagging SNP study and regression analysis.2 These authors were unable to demonstrate differences in ATG16L1 expression based on T300A-genotype or intestinal inflammation.
ATG16L1 consists of a N-terminal Atg5-interacting domain, a coiled-coil domain (involved in self-dimerisation, containing the T300A variant) and seven WD-domains (putatively interacting with NOD2) at the C-terminus. In ATG16L1-deficient and hypomorphic mice, canonical and bacteria-induced autophagy, Paneth-cell homeostasis and interleukin-1β secretion were dependent on ATG16L1.3 ,4 By contrast, studies focusing on T300A have shown conflicting results.1 , …
