NOD2 mutations affect muramyl dipeptide stimulation of human B lymphocytes and interact with other IBD-associated genes.

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
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Digestive diseases and sciences
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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.Genetic and functional studies have associated variants in the NOD2/CARD15 gene with Crohn''s disease.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.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.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.