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.

Division of Colon and Rectal Surgery Department of Surgery Pennsylvania State University College of Medicine H137 500 University Drive Hershey PA 17033 USA

Zobrazit více v PubMed

Hum Mol Genet. 2004 Aug 15;13(16):1715-25 PubMed

J Biol Chem. 2005 Oct 28;280(43):35859-67 PubMed

Nat Genet. 2007 Feb;39(2):207-11 PubMed

Nature. 2001 May 31;411(6837):599-603 PubMed

Gastroenterology. 2002 Jul;123(1):86-91 PubMed

J Crohns Colitis. 2009 Sep;3(3):189-95 PubMed

J Immunol. 2010 Jun 15;184(12):7247-56 PubMed

J Biol Chem. 2003 Mar 14;278(11):8869-72 PubMed

Nature. 2007 Jun 7;447(7145):661-78 PubMed

Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2582-7 PubMed

Trends Mol Med. 2006 Sep;12(9):397-9 PubMed

J Biol Chem. 2002 Nov 1;277(44):41701-5 PubMed

Mutat Res. 2005 Jun 3;573(1-2):111-35 PubMed

Nat Immunol. 2009 May;10(5):471-9 PubMed

PLoS One. 2010 Aug 18;5(8):e11384 PubMed

J Biomol Tech. 2005 Dec;16(4):398-406 PubMed

Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3455-60 PubMed

Clin Gastroenterol Hepatol. 2009 Sep;7(9):972-980.e2 PubMed

Dig Dis Sci. 2007 Aug;52(8):1783-9 PubMed

J Leukoc Biol. 2011 Feb;89(2):177-87 PubMed

Br J Haematol. 2009 Feb;144(4):507-16 PubMed

Inflamm Bowel Dis. 2008 Aug;14(8):1033-40 PubMed

Lancet. 2005 May 21-27;365(9473):1794-6 PubMed

Mol Immunol. 2007 Apr;44(10):2566-77 PubMed

World J Gastroenterol. 2006 Nov 28;12(44):7097-103 PubMed

Br Med Bull. 2008;87:17-30 PubMed

Nat Immunol. 2009 Oct;10(10):1073-80 PubMed

Immunol Rev. 2005 Aug;206:277-95 PubMed

Rev Gastroenterol Disord. 2003;3 Suppl 1:S18-22 PubMed

J Biol Chem. 2001 Feb 16;276(7):4812-8 PubMed

Gastroenterology. 2003 Jan;124(1):140-6 PubMed

Curr Opin Gastroenterol. 2011 Jan;27(1):32-7 PubMed

Gut. 2005 Nov;54(11):1553-7 PubMed

Neth J Med. 2005 Sep;63(8):305-8 PubMed

Science. 2006 Dec 1;314(5804):1461-3 PubMed

J Gastroenterol Hepatol. 2011 Apr;26(4):694-9 PubMed

Nat Rev Immunol. 2008 Aug;8(8):631-43 PubMed

J Biol Chem. 2003 Feb 21;278(8):5509-12 PubMed