Variants in the Toll-interacting protein gene are associated with susceptibility to sepsis in the Chinese Han population

Abstract

IntroductionDeregulated or excessive host immune responses contribute to the pathogenesis of sepsis. Toll-like receptor (TLR) signaling pathways and their negative regulators play a pivotal role in the modulation of host immune responses and the development of sepsis. The objective of this study was to investigate the association of variants in the TLR signaling pathway genes and their negative regulator genes with susceptibility to sepsis in the Chinese Han population.MethodsPatients with severe sepsis (n = 378) and healthy control subjects (n = 390) were enrolled. Five genes, namely TLR2, TLR4, TLR9, MyD88 and TOLLIP, were investigated for their association with sepsis susceptibility by a tag single nucleotide polymorphism (SNP) strategy. Twelve tag SNPs were selected based on the data of Chinese Han in Beijing from the HapMap project and genotyped by direct sequencing. The mRNA expression levels of TOLLIP were determined using real-time quantitative Polymerase Chain Reaction (PCR) assays, and concentrations of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA).ResultsOur results showed that the minor C-allele of rs5743867 in TOLLIP was significantly associated with the decreased risk of sepsis (Padj = 0.00062, odds ratio (OR)adj = 0.71, 95% confidence interval (CI) 0.59 to 0.86) after adjustment for covariates in multiple logistic regression analysis. A 3-SNP haplotype block harboring the associated SNP rs5743867 also displayed strong association with omnibus test P value of 0.00049. Haplotype GTC showed a protective role against sepsis (Padj = 0.0012), while haplotype GCT showed an increased risk for sepsis (Padj = 0.00092). After exposure to lipopolysaccharide (LPS), TOLLIP mRNA expression levels in peripheral blood mononuclear cells (PBMCs) from homozygotes for the rs5743867C allele were significantly higher than in heterozygotes and homozygotes for the rs5743867T allele (P = 0.013 and P = 0.01, respectively). Moreover, the concentrations of TNF-α and IL-6 in culture supernatants were significantly lower in the subjects of rs5743867CC genotype than in CT and TT genotype subjects (P = 0.016 and P = 0.003 for TNF-α; P = 0.01 and P = 0.002 for IL-6, respectively).ConclusionsOur findings indicated that the variants in TOLLIP were significantly associated with sepsis susceptibility in the Chinese Han population.

Alteration of Lysosome Fusion and Low-grade Inflammation Mediated by Super-low-dose Endotoxin

“…For example, humans with a rare Tollip haplotype have reduced Tollip levels and elevated risks for infection and tuberculosis (41). Other studies suggest that Tollip variants may be associated with elevated risks of sepsis, dermatitis, and pulmonary fibrosis (43)(44)(45). Our wound-healing model clearly demonstrates a key role for Tollip in the resolution of inflammation during tissue repair.…”

MyD 88 Polymorphisms in Children Diagnosed with Sepsis

“…MyD 88 SNP allele and genotypes were found statistically insignificant between two groups. As a result, Song et al (10) showed that MyD 88 SNP was not a risk factor for sepsis in China population. Von Bernuth et al (8) discovered 3 different mutations in MyD 88 deficient children who are susceptible to pyogenic bacterial infections.…”

“…Literature on MyD 88 SNP and sepsis relationship in human is limited. Song et al (10) showed that gene variations of TLR signaling pathways and negative regulators of these pathways increase susceptibility to sepsis. That study was conducted between February 2006 and November 2009, in China.…”

Polymorphisms of TLR4 Asp299Gly and TNF-α -308G/A in Leptospirosis

“…Other studies showed similar result that there were no significant differences of TLR4 Asp299Gly between DHF/DSS and control group, or severity of meningococcal infection and outcome of gram negative sepsis [20][21][22][23] . Metaanalysis studies in Caucasian and in China found that there were not strong correlation between sepsis and TLR4 Asp299Gly polymorphism [24][25][26][27] . Race, ethnic and geography seem to affect the frequency of TLR4 Asp299Gly polymorphism.…”