Toll-like Receptor 1 Polymorphisms Affect Innate Immune Responses and Outcomes in Sepsis
Open accessAbstract
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 × 10−20). TLR1−7202G marked a coding SNP that causes higher TLR1-induced NF-κB 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. Conclusions: Hypermorphic genetic variation in TLR1 is associated with increased susceptibility to organ dysfunction, death, and gram-positive infection in sepsis.
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In a large population of septic patients, those with a single nucleotide polymorphism (SNP) marking a hyperfunctioning variant of TLR1 had increased organ dysfunction and morbidity from Gram-positive bacteremia.
“In a large population of septic patients, those with a single nucleotide polymorphism (SNP) marking a hyperfunctioning variant of TLR1 had increased organ dysfunction and morbidity from Gram-positive bacteremia (150).”
From Into the Eye of the Cytokine Storm (2012) · cites this paper as [150]
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References 50 · Cited by 244
Research works printed but not linked: 1
- [11]Wurfel MM, Gordon AC, Holden TD, Radella F, Stratton S, Rona G, Strout J, Black RA, Nickerson DA, Walley KR, *et al.* Variation in the *tlr1* gene affects TLR1 surface expression and is associated with increased mortality in septic shock [abstract]. Am J Respir Crit Care Med 2007;175:A898. [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Am%20J%20Respir%20Crit%20Care%20Med&volume=175&publication_year=2007&pages=A898&)]
- Authors
- Wurfel, M. M., Gordon, A. C., Holden, T. D., Radella, F., Strout, J., Kajikawa, O., Ruzinski, J. T., Rona, G., Black, A. R., Stratton, S., Jarvik, G. P., Hajjar, A. M., Nickerson, D. A., Rieder, M., Sevransky, J., Maloney, J. P., Moss, M., Martin, G., Shanholtz1, C., Garcia1, J. G. N., Gao1, L., Brower, R., Barnes, K. C., Walley, K. R., Russell, J. A., & Martin, T. R.
- Affiliations
- University of Washington (US)
- University of British Columbia (CA)
- Veterans Health Administration (US)
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, Washington
- Johns Hopkins University (US)
- University of Colorado Anschutz (US)
- Emory University (US)
- University of Maryland School of Medicine, Baltimore, Maryland
- Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois; and
- Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
- ORCID
- Venue
- American Journal of Respiratory and Critical Care Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-10-01
- Volume
- 178
- Issue
- 7
- Pages
- 710-720
- ISSN
- 1073-449X (ISSN-L)
- 1535-4970
- PMC
- PMC2556453
- OpenAlex
- W2000189931
- Cited by
- 244
- References
- 50
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 1 · 2023: 3 · 2022: 10 · 2021: 13 · 2020: 12 · 2019: 8 · 2018: 5 · 2017: 13 · 2016: 14 · 2015: 12 · 2014: 25 · 2013: 21 · 2012: 19
- FWCI
- 10.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Respiratory and Critical Care Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p50hl073994-05, UL1TR000454)
- National Heart, Lung, and Blood Institute (P50HL073996, HL-074366, HL-073996, HL73994, HL629063, R01HL074366)
- National Institute of Allergy and Infectious Diseases (U54AI057141, AI057141)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- TLR1, innate immunity, sepsis, organ dysfunction, mortality, NF-κB activation, cytokine production, Gram-positive bacterial infections, single nucleotide polymorphisms, genetic susceptibility
- MeSH terms
- Adult, Humans, Immunity, Innate, Prospective Studies, Respiratory Distress Syndrome, Case-Control Studies, Gram-Negative Bacterial Infections, Sepsis, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genomics, Toll-Like Receptor 1
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