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The Crohn’s disease-associated polymorphism in ATG16L1 (rs2241880) reduces SHIP gene expression and activity in human subjects

Genes & Immunity volume 16, pages 452–461 (2015)Cite this article

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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.

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Acknowledgements

We would like to thank members of the Divisions of Anesthesiology and Gastroenterology at BC Children’s Hospital for support with acquiring blood and biopsy samples. We are grateful for salary support for ENN and MM from the Transplantation Training Program at the University of British Columbia, which is funded by Canadian Institutes of Health Research (CIHR); for ENN from the Child & Family Research Institute studentship and the MITACs Accelerate fellowship programs; and LMS from the Canadian Association of Gastroenterology/Crohn’s and Colitis Canada/CIHR New Investigator Salary Award and the Michael Smith Foundation for Health Research Scholar Award. This work was funded by a grant from the CIHR (MOP-133607) to LMS.

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Authors and Affiliations

  1. Division of Gastroenterology, Hepatology and Nutrition,

    E N Ngoh, H K Brugger, M Monajemi, S C Menzies, K Jacobson & L M Sly

  2. Department of Pediatrics, BC Children’s Hospital, Child and Family Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada

    E N Ngoh, H K Brugger, M Monajemi, S C Menzies, K Jacobson & L M Sly

  3. 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

    A F Hirschfeld, K L Del Bel & S E Turvey

  4. Division of Neonatology, Department of Pediatrics, BC Children's Hospital, Child and Family Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada

    P M Lavoie

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  1. E N Ngoh
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Correspondence to L M Sly.

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Ngoh, E., Brugger, H., Monajemi, M. et al. The Crohn’s disease-associated polymorphism in ATG16L1 (rs2241880) reduces SHIP gene expression and activity in human subjects. Genes Immun 16, 452–461 (2015). https://doi.org/10.1038/gene.2015.30

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