Influence of polymorphisms in the NOD1/CARD4 and NOD2/CARD15 genes on the clinical outcome of Helicobacter pylori infection.
Host immune response influences the clinical outcome of Helicobacter pylori infection leading to ulcer disease, gastric carcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. A genetic risk profile for gastric cancer has been identified, but genetic susceptibility to develop MALT lymphoma is still unclear. We investigated the role of NOD1 and NOD2 as intracellular recognition molecules for pathogen-associated molecules in H. pylori infection in vitro and analysed the influence of single nucleotide polymorphisms on susceptibility to ulcer disease and MALT lymphoma. Expression of NOD1 and NOD2 significantly sensitized HEK293 cells to H. pylori-induced NF-kappaB activation in a cag pathogenicity island (cagPAI)-dependent manner. In cells carrying the Crohn-associated NOD2 variant R702W the NF-kappaB response was significantly diminished. NOD1/NOD2 expression levels were induced in the gastric epithelium in H. pylori-positive patients. No mutations were found to be associated with gastritis or gastric ulcer development. However, the R702W mutation in the NOD2/CARD15 gene was significantly associated with gastric lymphoma. Carrier of the rare allele T had a more than doubled risk to develop lymphoma than controls [odds ratio (OR): 2.4, 95% confidence interval (CI): 1.2-4.6; P < 0.044]. H. pylori-induced upregulation of NOD1 and NOD2 in vivo may play a critical role in the recognition of this common pathogen. A missense mutation in the leucine-rich region of CARD15 is associated with gastric lymphoma.
Rosenstiel
Philip
P
Institut für Klinische Molekularbiologie, Christian-Albrechts Universität, Kiel, Germany.
Hellmig
Stephan
S
Hampe
Jochen
J
Ott
Stefan
S
Till
Andreas
A
Fischbach
Wolfgang
W
Sahly
Hany
H
Lucius
Ralph
R
Fölsch
Ulrich R
UR
Philpott
Dana
D
Schreiber
Stefan
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000483:Alleles; D001426:Bacterial Proteins / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D002908:Chronic Disease; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005756:Gastritis / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D020022:Genetic Predisposition to Disease; D016481:Helicobacter Infections / Q000175:diagnosis / Q000235:genetics*; D016480:Helicobacter pylori; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics / Q000382:microbiology; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D010437:Peptic Ulcer / Q000235:genetics / Q000382:microbiology; D011110:Polymorphism, Genetic; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D001426:Bacterial Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein