MAGI2 genetic variation and inflammatory bowel disease

McGovern, Dermot; Taylor, Kent D.; Landers, Carol J.; Derkowski, Carrie; Dutridge, Deb; Dubinsky, Marla; Ippoliti, Andy; Vasiliauskas, Eric A.; Mei, Ling; Mengesha, Emebet; King, Lily; Pressman, Sheila; Targan, Stephan R.; Rotter, Jerome I.

doi:10.1002/ibd.20611

Cited by 46 publications

(33 citation statements)

References 44 publications

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“…[146][147][148] Regulators of E-cadherin have been shown to be associated with UC, and the AJC protein MAGI2 has also been linked to IBD, supporting its role in disease pathogenesis. 149,150 Chimeric mice with impaired E-cadherin function due to expression of dominant-negative N-cadherin developed colitis despite possessing an intact immune system. 146,151 Furthermore, intestinal pathogens like Bacteroides fragilis and Candida albicans are known to cleave E-cadherin, disrupting the adherens junction, which supports its critical gatekeeping role.…”

Section: à4mentioning

confidence: 99%

Genetics of ulcerative colitis

Thompson

Lees

2011

Inflammatory Bowel Diseases

137

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Ulcerative colitis (UC) and Crohn's disease (CD) are related polygenic inflammatory bowel diseases (IBDs), with distinct and overlapping susceptibility loci. Recently, hypothesis-free genome-wide association (GWA) studies have revolutionized the field of complex disease genetics. Substantial advances have been achieved in defining the genetic architecture of IBD. To date, over 60 published IBD susceptibility loci have been discovered and replicated, of which approximately a third are associated with both UC and CD, although 21 are specific to UC and 23 to CD. In CD, the breakthrough identification of NOD2 as a susceptibility gene was followed by a rapid phase of gene discovery from GWA studies between 2006 and 2008. Progress in UC was slower; however, by initially testing hits for CD in UC, and later scanning larger UC cohorts, significant new loci for UC have been discovered, with exciting novel insights into disease pathogenesis. Notably, genes implicated in mucosal barrier function (ECM1, CDH1, HNF4α, and laminin B1) confer risk of UC; furthermore, E-cadherin is the first genetic correlation between colorectal cancer and UC. Impaired IL10 signaling has reemerged as a key pathway in intestinal inflammation, and is perhaps the most amenable to therapeutic intervention in UC. Collaborative international efforts with large meta-analyses of GWA studies and replication will yield many new UC genes. Furthermore, a large effort is required to characterize the loci found. Fine-mapping, deep resequencing, and functional studies will be critical to translating these gene discoveries into pathogenic insights, and ultimately into clinical insights and novel therapeutics.

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Section: à4mentioning

confidence: 99%

Genetics of ulcerative colitis

Thompson

Lees

2011

Inflammatory Bowel Diseases

137

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“…Some of the identified variants have been studied. rs11209026 (or R381Q) SNP was discovered as a protective variant for CD [63] and UC [65] in Jewish and non-Jewish cohorts which was later shown to be a loss of function mutation in IL-23R [66,67]. Arg-381 is located in the cytoplasmic domain of IL-23R protein and is well conserved among species, whereas Gln-381 allele is less frequent [63].…”

Section: Il-23 Receptor Signaling and Down-stream Inflammatory Mediatorsmentioning

confidence: 99%

Interleukin 23 in IBD Pathogenesis

Eken¹,

Oukka²

2016

New Insights Into Inflammatory Bowel Disease

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Interleukin-23 (IL-23) is a cytokine that belongs to the IL-12 cytokine family that is produced mainly by antigen-presenting cells. IL-23 receptor is expressed by various innate and adaptive immune cells, including group 3 innate lymphoid cells (ILC3), neutrophils, γδ T cells, Th17 and natural killer T (NKT) cells. IL-23 regulates various functions of the responding cells critical for host protective responses but is also implicated in many chronic inflammatory diseases including inflammatory bowel diseases (IBD). IL-23 receptor signaling components and downstream effector cytokines IL-17A/F, interferon-gamma (IFN-γ), IL-22, granulocyte macrophage colonystimulating factor (GMCSF) have been shown to impact IBD-like disease development in various animal models; therapeutic approaches targeting the IL-23 pathway in IBD are in clinical trials. In this chapter, we attempt to review the literature on IL-23-mediated IBD pathogenesis. We did this by gathering the current information about the individual IL-23-producing and IL-23-responsive cells as to how they contribute to IBD pathology through various inflammatory mediators.

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“…The gene interacts with Delta proteins in zebrafish, 21 inhibits cell migration and proliferation via PTEN in human hepatocarcinoma cells, 22 and has been associated with inflammatory bowel disease. 23 …”

Section: Genomic Stability Of Mscs With Passagementioning

confidence: 99%

Sox11Is Expressed in Early Progenitor Human Multipotent Stromal Cells and Decreases with Extensive Expansion of the Cells

Larson

Ylöstalo

Lee

et al. 2010

Tissue Engineering Part A

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There has been considerable interest in developing new therapies with adult multipotent progenitor stromal cells or mesenchymal stem cells (MSCs) in organ replacement and repair. To be effectively seeded into scaffolds for therapy, large numbers of cells are needed, but concerns remain regarding their chromatin stability in long-term culture. We therefore expanded four donors of human MSCs (hMSCs) from bone marrow aspirates with a protocol that maintains the cells at low density. MSCs initially proliferated at average doubling times of 24 h and then gradually reached senescence after 8-15 passages (33-55 population doublings) without evidence of immortalization. Comparative genomic hybridization assays of two preparations revealed no abnormalities through 33 population doublings. One preparation had a small amplification of unknown significance in chromosome 7 (7q21:11) after 55 population doublings. Microarray assays demonstrated progressive changes in the transcriptome of the cells. However, the transcriptomes clustered more closely over time within a single passage, rather than with passage number, indicating a partial reversibility of the patterns of gene expression. One of the largest changes was a decrease in mRNA for Sox11, a transcription factor previously identified in neural progenitor cells. Knockdown of Sox11 with siRNA decreased the proliferation and osteogenic differentiation potential of hMSCs. The results suggested that assays for Sox11 may provide a biomarker for early progenitor hMSCs.

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MAGI2 genetic variation and inflammatory bowel disease

Cited by 46 publications

References 44 publications

Genetics of ulcerative colitis

Genetics of ulcerative colitis

Interleukin 23 in IBD Pathogenesis

Sox11Is Expressed in Early Progenitor Human Multipotent Stromal Cells and Decreases with Extensive Expansion of the Cells

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