Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: An observational study in three cohorts

Oliver Kumpf; Evangelos J. Giamarellos-Bourboulis; Alexander Koch; Lutz Hamann; Maria Mouktaroudi; Djin Ye Oh; Eicke Latz; Eva Lorenz; David A. Schwartz; Bart Ferwerda; Christina Routsi; Chryssanthi Skalioti; Bart Jan Kullberg; Jos W.M. van der Meer; Peter M. Schlag; Mihai G. Netea; Kai Zacharowski; Ralf R. Schumann

doi:https://doi.org/10.1186/cc9047

Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: An observational study in three cohorts

Oliver Kumpf, Evangelos J. Giamarellos-Bourboulis, Alexander Koch, Lutz Hamann, Maria Mouktaroudi, Djin Ye Oh, Eicke Latz, Eva Lorenz, David A. Schwartz, Bart Ferwerda, Christina Routsi, Chryssanthi Skalioti, Bart Jan Kullberg, Jos W.M. van der Meer, Peter M. Schlag, Mihai G. Netea, Kai Zacharowski, Ralf R. Schumann

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Abstract

Introduction: It has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms (SNPs) within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer (TIRAP/Mal) on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations.Methods: Three intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia (VAP) were included. TLR4 and TIRAP/Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course.Results: Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (odds ratio (OR) 5.5; confidence interval (CI): 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively). Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP/Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes.Conclusions: Carriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery.

Original language	English
Article number	R103
Journal	Critical Care
Volume	14
Issue number	3
DOIs	https://doi.org/10.1186/cc9047
Publication status	Published - 3 Jun 2010

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Kumpf, O., Giamarellos-Bourboulis, E. J., Koch, A., Hamann, L., Mouktaroudi, M., Oh, D. Y., Latz, E., Lorenz, E., Schwartz, D. A., Ferwerda, B., Routsi, C., Skalioti, C., Kullberg, B. J., van der Meer, J. W. M., Schlag, P. M., Netea, M. G., Zacharowski, K., & Schumann, R. R. (2010). Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: An observational study in three cohorts. Critical Care, 14(3), Article R103. https://doi.org/10.1186/cc9047

@article{9b3436ec029c40d792ea0a991206d180,

title = "Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: An observational study in three cohorts",

abstract = "Introduction: It has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms (SNPs) within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer (TIRAP/Mal) on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations.Methods: Three intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia (VAP) were included. TLR4 and TIRAP/Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course.Results: Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (odds ratio (OR) 5.5; confidence interval (CI): 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively). Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP/Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes.Conclusions: Carriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery.",

author = "Oliver Kumpf and Giamarellos-Bourboulis, {Evangelos J.} and Alexander Koch and Lutz Hamann and Maria Mouktaroudi and Oh, {Djin Ye} and Eicke Latz and Eva Lorenz and Schwartz, {David A.} and Bart Ferwerda and Christina Routsi and Chryssanthi Skalioti and Kullberg, {Bart Jan} and {van der Meer}, {Jos W.M.} and Schlag, {Peter M.} and Netea, {Mihai G.} and Kai Zacharowski and Schumann, {Ralf R.}",

note = "Funding Information: We acknowledge the excellent technical help of Ina Wendler, Fr{\"a}nzi Creutz-burg and Diana Woellner, Berlin, Germany and the support in data acquisition by Nina Klinger MD. D.-Y. Oh is a recipient of a Rahel-Hirsch-Grant of the Charit{\'e} University Medical Center. K.Z. was supported by grants of the Deutsche Forsc- hungsgemeinschaft (DFG) (Za243/8-1, 8-2 and 9-1). M.G.N. was supported by a Vidi Grant of the Netherlands Organization for Scientific Research. R.R.S. was supported by grants of the DFG and the Charit{\'e} University Medical Center. A.K. was supported by a grant of the Forschungskommission, University D{\"u}sseldorf, Germany.",

year = "2010",

month = jun,

day = "3",

doi = "https://doi.org/10.1186/cc9047",

language = "English",

volume = "14",

journal = "Critical Care",

issn = "1364-8535",

publisher = "Springer Science + Business Media",

number = "3",

}

Kumpf, O, Giamarellos-Bourboulis, EJ, Koch, A, Hamann, L, Mouktaroudi, M, Oh, DY, Latz, E, Lorenz, E, Schwartz, DA, Ferwerda, B, Routsi, C, Skalioti, C, Kullberg, BJ, van der Meer, JWM, Schlag, PM, Netea, MG, Zacharowski, K & Schumann, RR 2010, 'Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: An observational study in three cohorts', Critical Care, vol. 14, no. 3, R103. https://doi.org/10.1186/cc9047

TY - JOUR

T1 - Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release

T2 - An observational study in three cohorts

AU - Kumpf, Oliver

AU - Giamarellos-Bourboulis, Evangelos J.

AU - Koch, Alexander

AU - Hamann, Lutz

AU - Mouktaroudi, Maria

AU - Oh, Djin Ye

AU - Latz, Eicke

AU - Lorenz, Eva

AU - Schwartz, David A.

AU - Ferwerda, Bart

AU - Routsi, Christina

AU - Skalioti, Chryssanthi

AU - Kullberg, Bart Jan

AU - van der Meer, Jos W.M.

AU - Schlag, Peter M.

AU - Netea, Mihai G.

AU - Zacharowski, Kai

AU - Schumann, Ralf R.

N1 - Funding Information: We acknowledge the excellent technical help of Ina Wendler, Fränzi Creutz-burg and Diana Woellner, Berlin, Germany and the support in data acquisition by Nina Klinger MD. D.-Y. Oh is a recipient of a Rahel-Hirsch-Grant of the Charité University Medical Center. K.Z. was supported by grants of the Deutsche Forsc- hungsgemeinschaft (DFG) (Za243/8-1, 8-2 and 9-1). M.G.N. was supported by a Vidi Grant of the Netherlands Organization for Scientific Research. R.R.S. was supported by grants of the DFG and the Charité University Medical Center. A.K. was supported by a grant of the Forschungskommission, University Düsseldorf, Germany.

PY - 2010/6/3

Y1 - 2010/6/3

N2 - Introduction: It has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms (SNPs) within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer (TIRAP/Mal) on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations.Methods: Three intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia (VAP) were included. TLR4 and TIRAP/Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course.Results: Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (odds ratio (OR) 5.5; confidence interval (CI): 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively). Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP/Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes.Conclusions: Carriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery.

AB - Introduction: It has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms (SNPs) within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer (TIRAP/Mal) on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations.Methods: Three intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia (VAP) were included. TLR4 and TIRAP/Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course.Results: Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (odds ratio (OR) 5.5; confidence interval (CI): 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively). Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP/Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes.Conclusions: Carriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery.

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U2 - https://doi.org/10.1186/cc9047

DO - https://doi.org/10.1186/cc9047

M3 - Article

C2 - 20525286

SN - 1364-8535

VL - 14

JO - Critical Care

JF - Critical Care

IS - 3

M1 - R103

ER -

Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: An observational study in three cohorts

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