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01.09.2007 | Original

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

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

Erschienen in: Intensive Care Medicine | Ausgabe 9/2007

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Abstract

Objective

Genetic variants in the NOD2/CARD15 gene resulting in a diminished capacity to activate NF-κB in response to bacterial cell wall products have been associated with Crohn's disease (CD). Recently, we found an association between the variant Leu1007fsinsC of the NOD2/CARD15 gene (SNP13) and a significantly increased rate of transplant related mortality (TRM) due to intestinal and pulmonary complications in stem cell transplantation (SCT). To assess a possible contribution of variants in the NOD2/CARD15 gene to sepsis related mortality (SRM) we investigated 132 prospectively characterised, consecutive patients with sepsis.

Design and patients

The three most common NOD2/CARD15 variants (Arg702Trp, Gly908Arg, and Leu1007fsinsC) were determined in 132 prospectively characterised patients with sepsis attended to three intensive care units at the University of Regensburg by Taqman PCR. NOD2/CARD15 genotype and major patients' characteristics were correlated with SRM.

Results

Patient groups with and without NOD2/CARD15 variants did not differ in their clinical characteristics such as median age, gender, reason for admission or APACHE score; however, SRM (day 30) was increased in patients with NOD2/CARD15 coding variants (42 vs. 31%) and was highest (57%) in 8 patients carrying the Leu1007fsinsC variant (p < 0.05). Multivariate analysis demonstrated the Leu1007fsinsC genetic variant as an independent risk factor for SRM.

Conclusion

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.

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Calandra T, Cohen J (2005) The international sepsis forum consensus conference on definitions of infection in the intensive care unit. Crit Care Med 33:1538–1548PubMedCrossRef

Jacobi J (2002) Pathophysiology of sepsis. Am J Health Syst Pharm 59(Suppl 1):S3–S8PubMed

Abraham E, Matthay MA, Dinarello CA, Vincent JL, Cohen J, Opal SM, Glauser M, Parsons P, Fisher CJ Jr, Repine JE (2000) Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: time for a reevaluation. Crit Care Med 28:232–235PubMedCrossRef

Gluck T, Opal SM (2004) Advances in sepsis therapy. Drugs 64:837–859PubMedCrossRef

Liu SF, Malik AB (2006) NF-κB activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol 290:L622–L645PubMedCrossRef

Kobayashi M, Tsuda Y, Yoshida T, Takeuchi D, Utsunomiya T, Takahashi H, Suzuki F (2006) Bacterial sepsis and chemokines. Curr Drug Targets 7:119–134PubMedCrossRef

Hoesel LM, Gao H, Ward PA (2006) New insights into cellular mechanisms during sepsis. Immunol Res 34:133–141PubMedCrossRef

Johnson GB, Brunn GJ, Samstein B, Platt JL (2005) New insight into the pathogenesis of sepsis and the sepsis syndrome. Surgery 137:393–395PubMedCrossRef

Cavaillon JM, Adib-Conquy M (2005) Monocytes/macrophages and sepsis. Crit Care Med 33:S506–S509PubMedCrossRef

10.

Angus DC, Wax RS (2001) Epidemiology of sepsis: an update. Crit Care Med 29:S109–S116PubMedCrossRef

11.

Tabrizi AR, Zehnbauer BA, Freeman BD, Buchman TG (2001) Genetic markers in sepsis. J Am Coll Surg 192:106–117; quiz 145–146PubMedCrossRef

12.

Sipahi T, Pocan H, Akar N (2006) Effect of various genetic polymorphisms on the incidence and outcome of severe sepsis. Clin Appl Thromb Hemost 12:47–54PubMedCrossRef

13.

Dahmer MK, Randolph A, Vitali S, Quasney MW (2005) Genetic polymorphisms in sepsis. Pediatr Crit Care Med 6:S61–S73PubMedCrossRef

14.

Imahara SD, O'Keefe GE (2004) Genetic determinants of the inflammatory response. Curr Opin Crit Care 10:318–324PubMedCrossRef

15.

Wunderink RG, Waterer GW (2003) Genetics of sepsis and pneumonia. Curr Opin Crit Care 9:384–389PubMedCrossRef

16.

Holmes CL, Russell JA, Walley KR (2003) Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy. Chest 124:1103–1115PubMedCrossRef

17.

Gordon AC, Lagan AL, Aganna E, Cheung L, Peters CJ, McDermott MF, Millo JL, Welsh KI, Holloway P, Hitman GA, Piper RD, Garrard CS, Hinds CJ (2004) TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study. Genes Immun 5:631–640PubMedCrossRef

18.

Fang XM, Schroder S, Hoeft A, Stuber F (1999) Comparison of two polymorphisms of the interleukin-1 gene family: interleukin-1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis. Crit Care Med 27:1330–1334PubMedCrossRef

19.

Arnalich F, Lopez-Maderuelo D, Codoceo R, Lopez J, Solis-Garrido LM, Capiscol C, Fernandez-Capitan C, Madero R, Montiel C (2002) Interleukin-1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis. Clin Exp Immunol 127:331–336PubMedCrossRef

20.

Stassen NA, Leslie-Norfleet LA, Robertson AM, Eichenberger MR, Polk HC Jr (2002) Interferon-gamma gene polymorphisms and the development of sepsis in patients with trauma. Surgery 132:289–292PubMedCrossRef

21.

Fink MP (2003) Intestinal epithelial hyperpermeability: update on the pathogenesis of gut mucosal barrier dysfunction in critical illness. Curr Opin Crit Care 9:143–151PubMedCrossRef

22.

Rowlands BJ, Soong CV, Gardiner KR (1999) The gastrointestinal tract as a barrier in sepsis. Br Med Bull 55:196–211PubMedCrossRef

23.

Souza DA de, Greene LJ (2005) Intestinal permeability and systemic infections in critically ill patients: effect of glutamine. Crit Care Med 33:1125–1135CrossRef

24.

Wells CL, Juni BA, Cameron SB, Mason KR, Dunn DL, Ferrieri P, Rhame FS (1995) Stool carriage, clinical isolation, and mortality during an outbreak of vancomycin-resistant enterococci in hospitalized medical and/or surgical patients. Clin Infect Dis 21:45–50PubMed

25.

Forchielli ML, Walker WA (2005) The role of gut-associated lymphoid tissues and mucosal defence. Br J Nutr 93(Suppl 1):S41–S48PubMedCrossRef

26.

Yuan Q, Walker WA (2004) Innate immunity of the gut: mucosal defense in health and disease. J Pediatr Gastroenterol Nutr 38:463–473PubMedCrossRef

27.

Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411:599–603PubMedCrossRef

28.

Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411:603–606PubMedCrossRef

29.

Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson AJ, Bridger S, van Deventer S, Forbes A, Nikolaus S, Lennard-Jones JE, Foelsch UR, Krawczak M, Lewis C, Schreiber S, Mathew CG (2001) Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 357:1925–1928PubMedCrossRef

30.

Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, Fukase K, Inamura S, Kusumoto S, Hashimoto M, Foster SJ, Moran AP, Fernandez-Luna JL, Nunez G (2003) Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J Biol Chem 278:5509–5512PubMedCrossRef

31.

Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ (2003) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278:8869–8872PubMedCrossRef

32.

Bonen DK, Cho JH (2003) The genetics of inflammatory bowel disease. Gastroenterology 124:521–536PubMedCrossRef

33.

Barnich N, Aguirre JE, Reinecker HC, Xavier R, Podolsky DK (2005) Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor-κB activation in muramyl dipeptide recognition. J Cell Biol 170:21–26PubMedCrossRef

34.

Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G (2001) Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κB. J Biol Chem 276:4812–4818PubMedCrossRef

35.

Chamaillard M, Girardin SE, Viala J, Philpott DJ (2003) Nods, Nalps and Naip: intracellular regulators of bacterial-induced inflammation. Cell Microbiol 5:581–592PubMedCrossRef

36.

Holler E, Rogler G, Herfarth H, Brenmoehl J, Wild PJ, Hahn J, Eissner G, Scholmerich J, Andreesen R (2004) Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood 104:889–894PubMedCrossRef

37.

Rogler G, Holler E (2004) Can NOD2/CARD15 mutations predict intestinal graft-versus-host disease and aid our understanding of Crohn's disease? Nat Clin Pract Gastroenterol Hepatol 1:62–63PubMedCrossRef

38.

Holler E, Rogler G, Brenmoehl J, Hahn J, Herfarth H, Greinix H, Dickinson AM, Socie G, Wolff D, Fischer G, Jackson G, Rocha V, Steiner B, Eissner G, Marienhagen J, Schoelmerich J, Andreesen R (2006) Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination. Blood 107:4189–4193PubMedCrossRef

39.

Gutierrez O, Pipaon C, Inohara N, Fontalba A, Ogura Y, Prosper F, Nunez G, Fernandez-Luna JL (2002) Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-κB activation. J Biol Chem 277:41701–4175PubMedCrossRef

40.

Ogura Y, Lala S, Xin W, Smith E, Dowds TA, Chen FF, Zimmermann E, Tretiakova M, Cho JH, Hart J, Greenson JK, Keshav S, Nunez G (2003) Expression of NOD2 in Paneth cells: a possible link to Crohn's ileitis. Gut 52:1591–1597PubMedCrossRef

41.

Eckmann L (2004) Innate immunity and mucosal bacterial interactions in the intestine. Curr Opin Gastroenterol 20:82–88PubMedCrossRef

42.

Brenmoehl J, Herfarth H, Glück T, Audebert F, Barlage S, Schmitz G, Froehlich D, Schreiber S, Hampe J, Schölmerich J, Holler E, Rogler G (2005) Genetic variants in the NOD2/CARD15 gene are associated with early mortality in sepsis patients. Gastroenterology 128:T1020 (abstract)

43.

Bone RC, Sprung CL, Sibbald WJ (1992) Definitions for sepsis and organ failure. Crit Care Med 20:724–726PubMedCrossRef

44.

Goldhill DR, Sumner A (1998) APACHE II, data accuracy and outcome prediction. Anaesthesia 53:937–943PubMedCrossRef

45.

Hurr H, Hawley HB, Czachor JS, Markert RJ, McCarthy MC (1999) APACHE II and ISS scores as predictors of nosocomial infections in trauma patients. Am J Infect Control 27:79–83PubMedCrossRef

46.

Lockrem JD, Lopez E, Gallagher J, Church GE, Estafanous FG (1991) Severity of illness: APACHE II analysis of an ICU population. Cleve Clin J Med 58:477–486PubMed

47.

Taylor SL, Morgan DL, Denson KD, Lane MM, Pennington LR (2005) A comparison of the Ranson, Glasgow, and APACHE II scoring systems to a multiple organ system score in predicting patient outcome in pancreatitis. Am J Surg 189:219–222PubMedCrossRef

48.

McNelis J, Marini C, Kalimi R, Jurkiewicz A, Ritter G, Nathan I (2001) A comparison of predictive outcomes of APACHE II and SAPS II in a surgical intensive care unit. Am J Med Qual 16:161–165PubMedCrossRef

49.

Aegerter P, Boumendil A, Retbi A, Minvielle E, Dervaux B, Guidet B (2005) SAPS II revisited. Intensive Care Med 31:416–423PubMedCrossRef

50.

Andrews P, Azoulay E, Antonelli M, Brochard L, Brun-Buisson C, Dobb G, Fagon JY, Gerlach H, Groeneveld J, Mancebo J, Metnitz P, Nava S, Pugin J, Pinsky M, Radermacher P, Richard C, Tasker R (2006) Year in review in intensive care medicine, 2005. II. Infection and sepsis, ventilator-associated pneumonia, ethics, haematology and haemostasis, ICU organisation and scoring, brain injury. Intensive Care Med 32:380–390PubMedCrossRef

51.

Andrews P, Azoulay E, Antonelli M, Brochard L, Brun-Buisson C, Dobb G, Fagon JY, Gerlach H, Groeneveld J, Mancebo J, Metnitz P, Nava S, Pugin J, Pinsky M, Radermacher P, Richard C, Tasker R, Vallet B (2005) Year in review in intensive care medicine, 2004. I. Respiratory failure, infection, and sepsis. Intensive Care Med 31:28–40PubMedCrossRef

52.

Andrews P, Azoulay E, Antonelli M, Brochard L, Brun-Buisson C, Dobb G, Fagon JY, Gerlach H, Groeneveld J, Mancebo J, Metnitz P, Nava S, Pugin J, Pinsky M, Radermacher P, Richard C, Tasker R, Vallet B (2005) Year in review in intensive care medicine, 2004. III. Outcome, ICU organisation, scoring, quality of life, ethics, psychological problems and communication in the ICU, immunity and hemodynamics during sepsis, pediatric and neonatal critical care, experimental studies. Intensive Care Med 31:356–372PubMedCrossRef

53.

Brooks SG, May J, Sedman P, Tring I, Johnstone D, Mitchell CJ, MacFie J (1993) Translocation of enteric bacteria in humans. Br J Surg 80:901–902PubMedCrossRef

54.

Sedman PC, Macfie J, Sagar P, Mitchell CJ, May J, Mancey-Jones B, Johnstone D (1994) The prevalence of gut translocation in humans. Gastroenterology 107:643–649PubMed

55.

D'Amico R, Pifferi S, Leonetti C, Torri V, Tinazzi A, Liberati A (1998) Effectiveness of antibiotic prophylaxis in critically ill adult patients: systematic review of randomised controlled trials. Br Med J 316:1275–1285

56.

Wiest R, Rath HC (2003) Gastrointestinal disorders of the critically ill. Bacterial translocation in the gut. Best Pract Res Clin Gastroenterol 17:397–425PubMedCrossRef

57.

Desai MH, Herndon DN, Rutan RL, Abston S, Linares HA (1991) Ischemic intestinal complications in patients with burns. Surg Gynecol Obstet 172:257–261PubMed

58.

Rogler G (2004) Update in inflammatory bowel disease pathogenesis. Curr Opin Gastroenterol 20:311–317PubMedCrossRef

59.

Dickinson AM, Middleton PG, Rocha V, Gluckman E, Holler E (2004) Genetic polymorphisms predicting the outcome of bone marrow transplants. Br J Haematol 127:479–490PubMedCrossRef

Titel: Genetic variants in the NOD2/CARD15 gene are associated with early mortality in sepsis patients
verfasst von: Julia Brenmoehl
Hans Herfarth
Thomas Glück
Franz Audebert
Stefan Barlage
Gerd Schmitz
Dieter Froehlich
Stefan Schreiber
Jochen Hampe
Jürgen Schölmerich
Ernst Holler
Gerhard Rogler
Publikationsdatum: 01.09.2007
Verlag: Springer-Verlag
Erschienen in: Intensive Care Medicine / Ausgabe 9/2007
Print ISSN: 0342-4642
Elektronische ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-007-0722-z

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

Abstract

Objective

Design and patients

Results

Conclusion

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Springer Medizin

Abstract

Objective

Design and patients

Results

Conclusion

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