Genetic variants in the NOD2/CARD15 gene are associated with early mortality in sepsis patients

Brenmoehl, Julia; Herfarth, Hans H; Glück, Thomas; Audebert, Franz; Barlage, Stefan; Schmitz, Gerd; Froehlich, Dieter; Schreiber, Stefan; Hampe, Jochen; Schölmerich, Jürgen; Holler, Ernst; Rogler, Gerhard

doi:10.1007/s00134-007-0722-z

Cited by 58 publications

(50 citation statements)

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“…Thus, we can speculate that, in CARD15 wild-type patients, endogenous antimicrobial activity may synergize with antibiotics to enhance their action, while in patients with CARD15 mutations this synergy does not occur. This speculation is reinforced by some recent data that support an association between CARD15 mutations and increased risk of several infectious complications [45][46][47].…”

Section: Discussionmentioning

confidence: 83%

CARD15 Mutations and Perianal Fistulating Crohn’s Disease: Correlation and Predictive Value of Antibiotic Response

et al. 2010

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Background CARD15 mutations alter bowel immunity and increase susceptibility to Crohn 0 s disease (CD). However, the relation between these mutations and Crohn 0 s perianal fistulas has not been fully clarified. Aims To assess whether CARD15 mutations are associated with risk of developing Crohn's perianal fistulas and whether these mutations are predictors of the response of perianal fistulas to antibiotics. Methods CARD15 mutations were investigated in 203 consecutive CD patients. Presence/absence of history of perianal fistula was recorded. Patients with history of perianal fistula were divided into two groups (with/without CARD15 mutations), and response to antibiotics was evaluated in both groups. Results Of the 203 patients, 60 (29.6%) showed at least one CARD15 mutation and 55 (27.1%) had history of perianal fistula. History of perianal fistula was identified in 13 (21.7%) patients with mutations and in 42 (29.4%) patients without mutations (P = 0.260). Mean age at diagnosis of first perianal fistula was similar in patients with/without CARD15 mutations (28.7 ± 9.8 versus 29.7 ± 10.1 years, P = 0.758). Average time between disease onset and diagnosis of first perianal fistula was also similar in the two groups (4.6 ± 5.1 versus 5.0 ± 5.9 years, P = 0.816). Response of perianal fistulas to antibiotics (metronidazole alone or combined with ciprofloxacin) was significantly higher in patients without CARD15 mutations (7.7% versus 40.5%, P = 0.041). Conclusions In CD, CARD15 mutations are not associated with risk of developing perianal fistulas or with time of their outbreak. Nevertheless, patients with perianal fistulas and CARD15 mutations showed worse response to antibiotics.

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Section: Discussionmentioning

confidence: 83%

CARD15 Mutations and Perianal Fistulating Crohn’s Disease: Correlation and Predictive Value of Antibiotic Response

et al. 2010

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“…3 The expression of NF-jB was increased after 72 h stimulation by MDP and Af conidia; the effect was interrupted by RNA interference of NOD2. *p \ 0.05 versus control (CON), # p \ 0.05 versus without RNAi factors of bacterial infection and are associated with early mortality in sepsis patients [13,14]. Meanwhile, the effect of NOD2 in detecting microorganisms and induction of innate immune response was shown in Toxoplasma gondii [15], virals [16], Streptococcus pneumonia, Mycobacterium tuberculosis, Staphylococcus aureus [17,18], Listeria monocytogenes [19], and recently in the intracellular pathogens Legionella pneumophila [20] and Chlamydophila pneumonia [21].…”

Section: Discussionmentioning

confidence: 99%

Role of NOD2 in regulating the immune response to Aspergillus fumigatus

Tao

Zhang

et al. 2012

Inflamm. Res.

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“…MDP can activate several immunological signaling pathways, including the nucleotide oligomerization domain 2 (NOD2, a NLR member) dependent pathway via specific interaction between NOD2 and MDP; resulting in activation of nuclear factor-κB (NF-κB), a ubiquitous transcription factor which induces expression of pro-inflammatory cytokines [2]. Multiple studies have linked NOD2 to several severe immunological dysfunctions such as graft-versus-host disease [3], enhanced mortality during sepsis [4,5] , and Crohn's disease (CD) [6,7], indicating that MDP might play a pathophysiological role in these disorders. The NOD2 gene, which initially was identified as NOD1-related gene, was found to have a highly restricted expression in monocytes [8].…”

Section: Introductionmentioning

confidence: 99%

Muramyl dipeptide responsive pathways in Crohn’s disease: from NOD2 and beyond

Salem

Seidelin

Rogler

et al. 2012

Cell. Mol. Life Sci.

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Crohn's disease (CD) is one of main disease entities under the umbrella term chronic inflammatory bowel disease. The etiology of CD involves alterations in genetic, microbiological, and immunological factors. This review is devoted to the role of the bacterial wall compound muramyl dipeptide (MDP) for the activation of inflammatory pathways involved in the pathogenesis of CD. The importance of this molecule is underscored by the fact that (1) MDP, which is found in most Gram-negative and -positive bacteria, is able to trigger several immunological responses in the intestinal system, and (2) that alterations in several mediators of the MDP response including-but not restricted to-nucleotide oligomerization domain 2 (NOD2) are associated with CD. The normalization of MDP signaling is one of several important factors that influence the intestinal inflammatory response, a fact which emphasizes the pathogenic importance of MDP signaling for the pathogenesis of CD. The important aspects of NOD2 and non-NOD2 mediated effects of MDP for the development of CD are highlighted, as well as how alterations in these pathways might translate into the development of new therapeutic strategies.

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Genetic variants in the NOD2/CARD15 gene are associated with early mortality in sepsis patients

Abstract: Our findings indicate a major role of NOD2/CARD15 coding variants for SRM. This may be indicative for a role of impaired barrier function and bacterial translocation in the pathophysiology of early sepsis related death.

Cited by 58 publications

References 58 publications

CARD15 Mutations and Perianal Fistulating Crohn’s Disease: Correlation and Predictive Value of Antibiotic Response

CARD15 Mutations and Perianal Fistulating Crohn’s Disease: Correlation and Predictive Value of Antibiotic Response

Role of NOD2 in regulating the immune response to Aspergillus fumigatus

Muramyl dipeptide responsive pathways in Crohn’s disease: from NOD2 and beyond

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