TY - JOUR
T1 - Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis
AU - Wurfel, Mark M.
AU - Gordon, Anthony C.
AU - Holden, Tarah D.
AU - Radella, Frank
AU - Strout, Jeanna
AU - Kajikawa, Osamu
AU - Ruzinski, John T.
AU - Rona, Gail
AU - Black, R. Anthony
AU - Stratton, Seth
AU - Jarvik, Gail P.
AU - Hajjar, Adeline M.
AU - Nickerson, Deborah A.
AU - Rieder, Mark
AU - Sevransky, Jonathan
AU - Maloney, James P.
AU - Moss, Marc
AU - Martin, Greg
AU - Shanholtz, Carl
AU - Garcia, Joe G.N.
AU - Gao, Li
AU - Brower, Roy
AU - Barnes, Kathleen C.
AU - Walley, Keith R.
AU - Russell, James A.
AU - Martin, Thomas R.
PY - 2008/10/1
Y1 - 2008/10/1
N2 - 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). TLR-27202G 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 TLR-27202G predicted worse organ dysfunction and death (odds ratio, 1.82; 95% confidence interval, 1.07-3.09). In the case-control study TLR-27202G was associated with sepsis-related acute lung injury (odds ratio, 3.40; 95% confidence interval, 1.59-7.27). TLR-27202G 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.
AB - 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). TLR-27202G 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 TLR-27202G predicted worse organ dysfunction and death (odds ratio, 1.82; 95% confidence interval, 1.07-3.09). In the case-control study TLR-27202G was associated with sepsis-related acute lung injury (odds ratio, 3.40; 95% confidence interval, 1.59-7.27). TLR-27202G 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.
UR - http://www.scopus.com/inward/record.url?scp=52749085896&partnerID=8YFLogxK
U2 - 10.1164/rccm.200803-462OC
DO - 10.1164/rccm.200803-462OC
M3 - Article
C2 - 18635889
AN - SCOPUS:52749085896
SN - 1073-449X
VL - 178
SP - 710
EP - 720
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 7
ER -