Common variants of TLR1 associate with organ dysfunction and sustained pro-inflammatory responses during sepsis.
BACKGROUND
Toll-like receptors (TLRs) are critical components for host pathogen recognition and variants in genes participating in this response influence susceptibility to infections. Recently, TLR1 gene polymorphisms have been found correlated with whole blood hyper-inflammatory responses to pathogen-associated molecules and associated with sepsis-associated multiorgan dysfunction and acute lung injury (ALI). We examined the association of common variants of TLR1 gene with sepsis-derived complications in an independent study and with serum levels for four inflammatory biomarkers among septic patients.


RESULTS
Seven tagging single nucleotide polymorphisms of the TLR1 gene were genotyped in samples from a prospective multicenter case-only study of patients with severe sepsis admitted into a network of intensive care units followed for disease severity. Interleukin (IL)-1β, IL-6, IL-10, and C-reactive protein (CRP) serum levels were measured at study entry, at 48 h and at 7(th) day. Alleles -7202G and 248Ser, and the 248Ser-602Ile haplotype were associated with circulatory dysfunction among severe septic patients (0.001 ≤ p ≤ 0.022), and with reduced IL-10 (0.012 ≤ p ≤ 0.047) and elevated CRP (0.011 ≤ p ≤ 0.036) serum levels during the first week of sepsis development. Additionally, the -7202GG genotype was found to be associated with hospital mortality (p = 0.017) and ALI (p = 0.050) in a combined analysis with European Americans, suggesting common risk effects among studies.


CONCLUSIONS
These results partially replicate and extend previous findings, supporting that variants of TLR1 gene are determinants of severe complications during sepsis.
CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
Maria
M
Pino-Yanes
Almudena
A
Corrales
Milena
M
Casula
Jesús
J
Blanco
Arturo
A
Muriel
Elena
E
Espinosa
Miguel
M
García-Bello
Antoni
A
Torres
Miguel
M
Ferrer
Elizabeth
E
Zavala
Jesús
J
Villar
Carlos
C
Flores
D000368:Aged; D002097:C-Reactive Protein / Q000378:metabolism; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018805:Sepsis / Q000276:immunology / Q000503:physiopathology*; D051194:Toll-Like Receptor 1 / Q000235:genetics*
D016207:Cytokines; D051194:Toll-Like Receptor 1; D002097:C-Reactive Protein