Variants in TRIM22 That Affect NOD2 Signaling Are Associated With Very-Early-Onset Inflammatory Bowel Disease

Abstract

Background & Aims Severe forms of inflammatory bowel disease (IBD) that develop in very young children can be caused by variants in a single gene. We performed whole-exome sequence (WES) analysis to identify genetic factors that might cause granulomatous colitis and severe perianal disease, with recurrent bacterial and viral infections, in an infant of consanguineous parents. Methods We performed targeted WES analysis of DNA collected from the patient and her parents. We validated our findings by a similar analysis of DNA from 150 patients with very early onset IBD not associated with known genetic factors analyzed in Toronto, Oxford, and Munich. We compared gene expression signatures in inflamed vs. non-inflamed intestinal and rectal tissues collected from patients with treatment-resistant Crohn's disease who participated in a trial of ustekinumab. We performed functional studies of identified variants in primary cells from patients and cell culture. Results We identified a homozygous variant in the tripartite motif containing 22 gene (TRIM22) of the patient, as well as in 2 patients with a disease similar phenotype. Functional studies showed that the variant disrupted the ability of TRIM22 to regulate nucleotide binding oligomerization domain containing 2 (NOD2)-dependent activation of interferon-beta signaling and NF-κB. Computational studies demonstrated a correlation between the TRIM22–NOD2 network and signaling pathways and genetic factors associated very early onset and adult-onset IBD. The network also associated with antiviral and mycobacterial effectors and markers of inflammation such as fecal calprotectin, c-reactive protein, and Crohn's disease activity index scores. Conclusion In WES and targeted exome sequence analyses of an infant with severe IBD, characterized by granulomatous colitis and severe perianal disease, we identified a homozygous variant of TRIM22 that affect the ability of its product to regulate NOD2. Combined computational and functional studies showed that the TRIM22–NOD2 network regulates antiviral and anti-bacterial signaling pathways that contribute to inflammation. Further study of this network could lead to new disease markers and therapeutic targets for patients with very early and adult-onset IBD.

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

“…We constructed an IBD Bayesian network using previously described methodology (20), from gene expression data for 8,382 genes. The expression data were collected in 203 intestinal biopsies that included ileum, ascending colon, descending colon and transverse colon, and inflamed and non-inflamed sigmoid and rectum, all collected at baseline from 54 anti-TNFα resistant CD patients enrolled in the Ustekinumab (anti-IL12/IL23) clinical trial (21, 22). Among the full set of genes, we defined a specific subset, located within IBD-associated loci previously defined in an Immunochip-based large-scale genetic analysis (1) with the goal of projecting these genes onto the intestinal network and identifying co-expressed genes that act together.…”

Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease

“…We know that in the IL-10 pathway, upon binding of IL-10 to cell receptors IL10RA and IL10RB, the IL-10 receptor complex members JAK1 and Tyk2 are activated and catalyze phosphorylation of themselves and then of IL10RA[3,4], thereby forming a docking site for STAT3. STAT3 is phosphorylated by JAK1 and Tyk2, and this phosphorylation causes STAT3 dimerization and translocation to the nucleus where it can induce expression of its target genes including HO-1 .…”

Advances in Evaluation of Chronic Diarrhea in Infants

“…Recent genetics studies have rapidly increased the number of monogenic disorders, including FOXP3, 70,71 ICOS, 72 IL10R, 73 TRIM22, 74 and ARPC1B, 38 which cause dysregulation of the immune system and subsequently inflammation and enteropathy in the intestine. Immune-mediated intestinal disorders present with a wide variety of manifestations, but all have bloody or watery diarrhea, and are frequently associated with systemic disease and multi-organ involvement.…”