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Hypothesis-free analysis of ATG16L1 demonstrates gene-wide extent of association with Crohn's disease susceptibility
  1. Johan Van Limbergen1,2,3,
  2. Boyko Kabakchiev4,
  3. Joanne M Stempak4,
  4. Phil Schumm5,
  5. Wei Xu6,
  6. Paul Henderson1,
  7. NIDDK IBD Genetics Consortium,,
  8. Stephen Girardin7,
  9. Anne M Griffiths2,
  10. Dana Philpott2,
  11. Mark Silverberg4
  1. 1Child Life and Health, University of Edinburgh, Edinburgh, UK
  2. 2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada
  3. 3Department of Immunology, University of Toronto, Toronto, Ontario, Canada
  4. 4Inflammatory Bowel Disease (IBD) Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital Toronto, Ontario, Canada
  5. 5Dept of Health Studies, University of Chicago, Chicago, Illinois, USA
  6. 6Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
  7. 7Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  1. 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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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 , …

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