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.

Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease

“…Taken together, these findings identify a large number of CpG sites that are differentially methylated across the microbiota-defined clusters, whereof many in proximity to genes known to play a role in IBD. Based on the mucosal DNA of all subjects, we investigated whether the 264 reported gene loci associated with IBD [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] in the present study. While the sample size was insufficient for a Genome-Wide Association Study, a principal component analysis on nominal categorical data of the known IBD loci indicated a significant overlap of the three cohorts, albeit with a slight shift along the second component for UC ( Supplementary Fig.…”

Activity of SHIP, Which Prevents Expression of Interleukin 1β, Is Reduced in Patients With Crohn’s Disease

“…1,[15][16][17] A gene variant in ATG16L1 (rs2241880), which has been associated with CD and high IL1b production, and a second intronic gene variant (rs12994997), which has traditionally been associated with ATG16L1, are located adjacent to the human gene encoding SH2 domain-containing inositolphosphate 5 0phosphatase (SHIP), INPP5D, and may impact disease by affecting ATG16L1 and/or INPP5D. [18][19][20] IL1b antagonism has been used effectively to treat some genetically defined forms of very early onset IBD 21 and may be more broadly applicable for the treatment of subgroups of IBD.…”

Analysis of SHIP1 expression and activity in Crohn’s disease patients

“…The role of SHIP1 in human disease is as yet unclear. While enhanced SHIP1 mRNA expression was observed in biopsies from CD patients [ 8 ], Ngoh and colleagues recently demonstrated decreased SHIP1 protein expression and activity in peripheral blood mononuclear cells (PBMCs) and biopsies in a cohort consisting mainly of treatment-naive subjects with ileal CD [ 9 , 10 ]. Interestingly, this downregulation was correlated with the presence of a single nucleotide polymorphism (SNP) in the ATG16L1 gene, one of the best described CD risk genes, which lies adjacent to the SHIP1 gene, INPP5D .…”