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Open Access 01-06-2010 | Research

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

Authors: 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 WM van der Meer, Peter M Schlag, Mihai G Netea, Kai Zacharowski, Ralf R Schumann

Published in: Critical Care | Issue 3/2010

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.

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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
Authors: 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 WM van der Meer
Peter M Schlag
Mihai G Netea
Kai Zacharowski
Ralf R Schumann
Publication date: 01-06-2010
Publisher: BioMed Central
Published in: Critical Care / Issue 3/2010
Electronic ISSN: 1364-8535
DOI: https://doi.org/10.1186/cc9047

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusions

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