title: The Crohn's disease-associated polymorphism in ATG16L1 (rs2241880) reduces SHIP gene expression and activity in human subjects.
abstract: Crohn's disease (CD) is a polygenic immune-mediated disease characterized by gastrointestinal inflammation. Mice deficient in the hematopoietic-restricted SH2 domain-containing inositolpolyphosphate 5'-phosphatase (SHIP) develop spontaneous CD-like ileal inflammation. Intriguingly, SHIP mRNA is not upregulated in biopsies from patients with ileal CD despite immune cell infiltration, but SHIP's role in human CD remains unknown. We analyzed SHIP mRNA expression and activity in biopsies and peripheral blood mononuclear cells (PBMCs) from control and treatment-naive subjects with ileal CD, and demonstrated that SHIP mRNA and activity were lower in hematopoietic cells in ileal biopsies and PBMCs from subjects with CD. In all tissues from our patient cohort and in PBMCs from a second healthy control cohort, subjects homozygous for the autophagy-related 16-like protein (ATG16L1) CD-associated gene variant (rs2241880), had low SHIP mRNA expression and activity. SHIP protein expression increased during autophagy and SHIP upregulation was dependent on ATG16L1 and/or autophagy, as well as the ATG16L1 CD-associated gene variant. Finally, homozygosity for the ATG16L1 risk variant and low SHIP mRNA expression is inversely related to increased (LPS+ATP)-induced IL-1β production by PBMCs in our cohorts and was regulated by increased transcription of ILIB. These data suggest a novel mechanism by which the ATG16L1 CD-associated gene variant may predispose people to develop intestinal inflammation.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children's Hospital, Child and Family Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: E N
authors.initials: EN
authors.lastname: Ngoh
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children's Hospital, Child and Family Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: H K
authors.initials: HK
authors.lastname: Brugger
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children's Hospital, Child and Family Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Monajemi
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children's Hospital, Child and Family Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: S C
authors.initials: SC
authors.lastname: Menzies
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, BC Children's Hospital, Child and Family Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: A F
authors.initials: AF
authors.lastname: Hirschfeld
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, BC Children's Hospital, Child and Family Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: K L
authors.initials: KL
authors.lastname: Del Bel
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children's Hospital, Child and Family Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Jacobson
authors.affiliation: Division of Neonatology, Department of Pediatrics, BC Children's Hospital, Child and Family Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: P M
authors.initials: PM
authors.lastname: Lavoie
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, BC Children's Hospital, Child and Family Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: S E
authors.initials: SE
authors.lastname: Turvey
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children's Hospital, Child and Family Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: L M
authors.initials: LM
authors.lastname: Sly
mesh_terms: D000328:Adult; D000818:Animals; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D003424:Crohn Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D008297:Male; D051379:Mice; D010744:Phosphoric Monoester Hydrolases / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018909:src Homology Domains
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D012333:RNA, Messenger; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases