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. 2010 Oct 29;5(10):e13759.
doi: 10.1371/journal.pone.0013759.

Common variants of TLR1 associate with organ dysfunction and sustained pro-inflammatory responses during sepsis

Maria Pino-Yanes  1 , Almudena Corrales, Milena Casula, Jesús Blanco, Arturo Muriel, Elena Espinosa, Miguel García-Bello, Antoni Torres, Miguel Ferrer, Elizabeth Zavala, Jesús Villar, Carlos Flores; GRECIA and GEN-SEP Groups
Affiliations

Common variants of TLR1 associate with organ dysfunction and sustained pro-inflammatory responses during sepsis

Maria Pino-Yanes et al. PLoS One. .

Abstract

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.

Methodology/principal findings: 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/significance: These results partially replicate and extend previous findings, supporting that variants of TLR1 gene are determinants of severe complications during sepsis.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. IL-6, IL-1β, IL-10, and CRP serum levels according to the TLR1 248Ser-602Ile haplotype status.
Values represent mean ± SEM biomarker levels at inclusion, at 48 hours, and at 7th day for patients showing homozygosity for the TLR1 248Ser-602Ile haplotype (n = 8) and for the rest of patients (n = 52). Note that values represented correspond to those from the 60 severe septic patients with serum measures available at the three time points. Significance of biomarker differences by the haplotype status was obtained using general linear models (GLM) for repeated measures in a longitudinal analysis assuming a recessive model (CRP, p = 0.024; IL-10, p = 0.015; for IL-1β and IL-6, p≥0.45).
Figure 2
Figure 2. Linkage disequilibrium (LD) plot of r 2 values between TLR1 SNPs.
The plot was created with the genotype data from the Spanish population-based controls. Each diamond of the LD plot represents a pair-wise SNP comparison with its r 2 value indicated and schematically symbolized by a color gradient ranging from black (r 2 = 100, corresponding to complete LD) to grey (100>r 2>0, moderate LD) to white (r 2 = 0, corresponding to absence of LD).
See this image and copyright information in PMC

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