Published ahead of print on July 17, 2008, doi:10.1164/rccm.200803-462OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200803-462OC
Toll-like Receptor 1 Polymorphisms Affect Innate Immune Responses and Outcomes in Sepsis1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, Washington; 2 James Hogg iCAPTURE Centre, St. Paul's Hospital and the University of British Columbia, Vancouver, Canada; 3 Medical Research Service of the Veterans Affairs Puget Sound Medical Center, Seattle, Washington; 4 Division of Medical Genetics, Department of Medicine; 5 Department of Immunology; and 6 Department of Genome Sciences, University of Washington, Seattle, Washington; 7 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland; 8 University of Colorado Health Sciences Center, Denver, Colorado; 9 Division of Pulmonary and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia; 10 University of Maryland School of Medicine, Baltimore, Maryland; 11 Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois; and 12 Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland Correspondence and requests for reprints should be addressed to Mark M. Wurfel, M.D., Ph.D., Section of Pulmonary and Critical Care Medicine, Harborview Medical Center, 300 Ninth Avenue, Seattle, WA 98104. 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. Objectives: To identify hypermorphic polymorphisms causing elevated TLR-mediated innate immune cytokine and chemokine responses and to 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 intensive care unit patients with sepsis, and a case–control study using patients with sepsis, patients with 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 < 2 x 10–20). TLR1–7202G marked a coding SNP that causes higher TLR1-induced NF- 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
Related articles in AJRCCM:
This article has been cited by other articles:
|
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
B activation and higher cell surface TLR1 expression. In the cohort of patients with sepsis TLR1–7202G predicted worse organ dysfunction and death (odds ratio, 1.82; 95% confidence interval, 1.07–3.09). In the case-control study TLR1–7202G was associated with sepsis-related acute lung injury (odds ratio, 3.40; 95% confidence interval, 1.59–7.27). TLR1–7202G also associated with a higher prevalence of gram-positive cultures in both clinical studies. 
