Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis.

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-kappaB 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.

[1]  D. Golenbock,et al.  Lipoproteins are critical TLR2 activating toxins in group B streptococcal sepsis , 2009, The Journal of Immunology.

[2]  C. Chung,et al.  Regulatory T cell populations in sepsis and trauma , 2008, Journal of leukocyte biology.

[3]  A. Clark,et al.  Full-Exon Resequencing Reveals Toll-Like Receptor Variants Contribute to Human Susceptibility to Tuberculosis Disease , 2007, PloS one.

[4]  C. Seabury,et al.  Sequence variability and protein domain architectures for bovine Toll-like receptors 1, 5, and 10. , 2007, Genomics.

[5]  J. Farrar,et al.  A common human TLR1 polymorphism regulates the innate immune response to lipopeptides , 2007, European journal of immunology.

[6]  R. Tapping,et al.  Cutting Edge: A Common Polymorphism Impairs Cell Surface Trafficking and Functional Responses of TLR1 but Protects against Leprosy1 , 2007, The Journal of Immunology.

[7]  S. Bandinelli,et al.  Common genetic variation in the gene encoding interleukin-1-receptor antagonist (IL-1RA) is associated with altered circulating IL-1RA levels , 2007, Genes and Immunity.

[8]  Giorgio Sirugo,et al.  A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis , 2007, Nature Genetics.

[9]  Janet S. Lee,et al.  The Duffy Antigen Modifies Systemic and Local Tissue Chemokine Responses following Lipopolysaccharide Stimulation1 , 2006, The Journal of Immunology.

[10]  Deborah A. Nickerson,et al.  Efficient selection of tagging single-nucleotide polymorphisms in multiple populations , 2006, Human Genetics.

[11]  F. Liew,et al.  Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[12]  T. Beaty,et al.  Novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury. , 2006, American journal of respiratory cell and molecular biology.

[13]  Roger E Bumgarner,et al.  Identification of high and low responders to lipopolysaccharide in normal subjects: an unbiased approach to identify modulators of innate immunity , 2006, The Journal of Immunology.

[14]  L. Joosten,et al.  Toll-like receptor 2 controls expansion and function of regulatory T cells. , 2006, The Journal of clinical investigation.

[15]  Tomohiro Watanabe,et al.  Signalling pathways and molecular interactions of NOD1 and NOD2 , 2006, Nature Reviews Immunology.

[16]  J. Satagopan,et al.  TLR1 and TLR6 Polymorphisms Are Associated with Susceptibility to Invasive Aspergillosis after Allogeneic Stem Cell Transplantation , 2005, Annals of the New York Academy of Sciences.

[17]  H. S. Warren,et al.  Toll-like receptors. , 2005, Critical care medicine.

[18]  E. Abraham,et al.  GENETIC POLYMORPHISMS AND SEPSIS , 2005, Shock.

[19]  K. Walley,et al.  Interleukin-10 haplotype associated with increased mortality in critically ill patients with sepsis from pneumonia but not in patients with extrapulmonary sepsis. , 2005, Chest.

[20]  J. Dengjel,et al.  Staphylococcus aureus Deficient in Lipidation of Prelipoproteins Is Attenuated in Growth and Immune Activation , 2005, Infection and Immunity.

[21]  S. le Cessie,et al.  IL-10 and toll-like receptor-4 polymorphisms and the in vivo and ex vivo response to endotoxin. , 2005, Cytokine.

[22]  K. Walley,et al.  Polymorphisms in CD14, mannose-binding lectin, and Toll-like receptor-2 are associated with increased prevalence of infection in critically ill adults* , 2005, Critical care medicine.

[23]  J. P. McCoy,et al.  Multiplex bead array assays for detection of soluble cytokines: Comparisons of sensitivity and quantitative values among kits from multiple manufacturers , 2004, Cytometry. Part B, Clinical cytometry.

[24]  S. Way,et al.  Porphyromonas gingivalis Lipopolysaccharide Contains Multiple Lipid A Species That Functionally Interact with Both Toll-Like Receptors 2 and 4 , 2004, Infection and Immunity.

[25]  Monika Milewski,et al.  Decoding randomly ordered DNA arrays. , 2004, Genome research.

[26]  C. Carlson,et al.  Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. , 2004, American journal of human genetics.

[27]  Richard J. Laws,et al.  A Common Dominant TLR5 Stop Codon Polymorphism Abolishes Flagellin Signaling and Is Associated with Susceptibility to Legionnaires' Disease , 2003, The Journal of experimental medicine.

[28]  B. Beutler,et al.  How we detect microbes and respond to them: the Toll‐like receptors and their transducers , 2003, Journal of leukocyte biology.

[29]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  D. Mannino,et al.  The epidemiology of sepsis in the United States from 1979 through 2000. , 2003, The New England journal of medicine.

[31]  R. Hotchkiss,et al.  The pathophysiology and treatment of sepsis. , 2003, The New England journal of medicine.

[32]  P. Bork,et al.  Human non-synonymous SNPs: server and survey. , 2002, Nucleic acids research.

[33]  S. Akira,et al.  Cutting Edge: Role of Toll-Like Receptor 1 in Mediating Immune Response to Microbial Lipoproteins1 , 2002, The Journal of Immunology.

[34]  U. Prabhakar,et al.  Simultaneous quantification of proinflammatory cytokines in human plasma using the LabMAP assay. , 2002, Journal of immunological methods.

[35]  S. Akira,et al.  Toll-like receptors: critical proteins linking innate and acquired immunity , 2001, Nature Immunology.

[36]  L. Cardon,et al.  Association study designs for complex diseases , 2001, Nature Reviews Genetics.

[37]  A. Aderem,et al.  Cutting Edge: Functional Interactions Between Toll-Like Receptor (TLR) 2 and TLR1 or TLR6 in Response to Phenol-Soluble Modulin1 , 2001, The Journal of Immunology.

[38]  S. L. Murphy.  Deaths: final data for 1998. , 2000, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

[39]  D. Schwartz,et al.  TLR4 mutations are associated with endotoxin hyporesponsiveness in humans , 2000, Nature Genetics.

[40]  K. Livak,et al.  Allelic discrimination using fluorogenic probes and the 5' nuclease assay. , 1999, Genetic analysis : biomolecular engineering.

[41]  R. Westendorp,et al.  Interleukin 10 secretion in relation to human IL-10 locus haplotypes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[42]  G. Bernard,et al.  A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group. , 1997, Chest.

[43]  M. Lamy,et al.  The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. , 1994, American journal of respiratory and critical care medicine.

[44]  R. A. Castillo-Lara,et al.  Definitions for sepsis and organ failure. , 1993, JAMA.

[45]  R. Danner,et al.  Brief report: shock and multiple-organ dysfunction after self-administration of Salmonella endotoxin. , 1993, The New England journal of medicine.

[46]  J. E. Carceller.  American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis , 1992, Critical care medicine.

[47]  E. Thompson,et al.  Performing the exact test of Hardy-Weinberg proportion for multiple alleles. , 1992, Biometrics.

[48]  W. Knaus,et al.  Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. , 1992, Chest.