NOD2 Mutations Affect Muramyl Dipeptide Stimulation of Human B Lymphocytes and Interact with Other IBD-Associated Genes View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2013-09

AUTHORS

Zhenwu Lin, John P. Hegarty, Gerrit John, Arthur Berg, Zhong Wang, Rishabh Sehgal, Danielle M. Pastor, Yunhua Wang, Leonard R. Harris, Lisa S. Poritz, Stefan Schreiber, Walter A. Koltun

ABSTRACT

BACKGROUND: Genetic and functional studies have associated variants in the NOD2/CARD15 gene with Crohn's disease. AIMS: This study aims to replicate the association of three common NOD2 mutations with Crohn's disease, study its effect on NOD2 expression in B cells and its interaction with other IBD-associated genes. METHODS: A total of 294 IBD patients (179 familial IBD, 115 sporadic IBD) and 298 unrelated healthy controls were from central Pennsylvania. NOD2 mutations were analyzed by primer-specific amplification, PCR based-RFLP, and validated with the ABI SNPlexM genotyping system. Gene-gene interaction was studied using a statistical model for epistasis analysis. RESULTS: Three common NOD2 mutations are associated with Crohn's disease (p=5.08×10(-7), 1.67×10(-6), and 1.87×10(-2) for 1007fs, R720W, and G908R, respectively), but not with ulcerative colitis (p=0.1046, 0.1269, and 0.8929, respectively). For IBD overall, 1007finsC (p=4.4×10(-5)) and R720W (p=9.24×10(-5)) were associated with IBD, but not G908R (p=0.1198). We revealed significant interactions of NOD2 with other IBD susceptibility genes IL23R, DLG5, and OCTN1. We discovered that NOD2 was expressed in both normal human peripheral blood B cells and in EBV-transformed B cell lines. Moreover, we further demonstrated that muramyl dipeptide (MDP) stimulation of B lymphocytes up-regulated expression of NF-κB-p50 mRNA. CONCLUSION: NOD2 is expressed in peripheral B cells, and the up-regulation of NOD2 expression by MDP was significantly impaired by NOD2 mutations. The finding suggests a possible role of NOD2 in the immunological response in IBD pathogenesis. More... »

PAGES

2599-2607

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10620-013-2696-8

DOI

http://dx.doi.org/10.1007/s10620-013-2696-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1028842226

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23709157


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