Published ahead of print on July 17, 2008, doi:10.1164/rccm.200803-462OC Am. J. Respir. Crit. Care Med., Volume 178, Number 7, October 2008, 710-720 A more recent version of this article appeared on October 1, 2008
Submitted on March 25, 2008 Toll-like Receptor 1 Polymorphisms Affect Innate Immune Responses and Outcomes in SepsisMark M Wurfel1*,1 Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA, 2 The James Hogg iCAPTURE Center, St. Paul's Hospital and the University of British Columbia, Vancouver, BC, USA, 3 Medical Research Service of the VA Puget Sound Medical Center, Seattle, WA, USA, 4 Department of Medical Genetics, University of Washington, Seattle, WA, USA, 5 Department of Immunology, University of Washington, Seattle, WA, USA, 6 Department of Genome Sciences, University of Washington, Seattle, WA, Canada, 7 Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA, 8 University of Colorado Health Sciences Center, Denver, CO, USA, 9 Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA; Department of Allergy and Clinical Immunology, The Johns Hopkins University, Baltimore, MD, USA, 10 Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA; Medical Research Service of the VA Puget Sound Medical Center, Seattle, WA, USA * To whom correspondence should be addressed. E-mail: mwurfel{at}u.washington.edu.
Rationale: Polymorphisms affecting toll-like receptor (TLR)-mediated responses could predispose to excessive inflammation during an infection and contribute to an increased risk for poor outcomes in patients with sepsis. Objective: Identify hypermorphic polymorphisms causing elevated TLR-mediated innate immune cytokine and chemokine responses and test whether these polymorphisms are associated with increased susceptibility to death, organ dysfunction, and infections in patients with sepsis. Methods: We screened single nucleotide polymorphisms (SNPs) in 43 TLR-related genes to identify variants affecting TLR-mediated inflammatory responses in blood from healthy volunteers ex vivo. The SNP associated most strongly with hypermorphic responses was tested for associations with death, organ dysfunction, and type of infection in two studies; a nested case-control study in a cohort of ICU patients with sepsis, and a case-control study using patients with sepsis, sepsis-related acute lung injury, and healthy control subjects. Measurements and Main Results: The SNP demonstrating the most hypermorphic effect was the G allele of TLR1-7202A/G (rs5743551)which associated with elevated TLR1-mediated cytokine production (P < 2x10-20). TLR1-7202G marked a coding SNP that causes higher TLR1-induced NF-kB activation and higher cell surface TLR1 expression. In the cohort of patients with sepsis TLR1-7202G predicted worse organ dysfunction and death (OR 1.82, 95% CI 1.07-3.09). In the case-control study TLR1-7202G was associated with sepsis-related ALI (OR 3.40, 95% CI 1.59-7.27). TLR1-7202G also associated with a higher prevalence of gram-positive cultures in both clinical studies. Conclusions: Hypermorphic genetic variation in TLR1 is associated with increased susceptibility to organ dysfunction, death, and gram-positive infection in sepsis. Key words: innate immunity, genetic variation, genetic predisposition
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