Genetic Variation in the TNF Gene Is Associated with Susceptibility to Severe Sepsis, but Not with Mortality

Abstract

BackgroundTumor necrosis factor (TNF) and TNF receptor superfamily (TNFR)-mediated immune response play an essential role in the pathogenesis of severe sepsis. Studies examining associations of TNF and lymphotoxin-α (LTA) single nucleotide polymorphisms (SNPs) with severe sepsis have produced conflicting results. The objective of this study was to investigate whether genetic variation in TNF, LTA, TNFRSF1A and TNFRSF1B was associated with susceptibility to or death from severe sepsis in Chinese Han population.Methodology/Principal FindingsTen SNPs in TNF, LTA, TNFRSF1A and TNFRSF1B were genotyped in samples of patients with severe sepsis (n = 432), sepsis (n = 384) and healthy controls (n = 624). Our results showed that rs1800629, a SNP in the promoter region of TNF, was significantly associated with risk for severe sepsis. The minor allele frequency of rs1800629 was significantly higher in severe sepsis patients than that in both healthy controls (Padj = 0.00046, odds ratio (OR)adj = 1.92) and sepsis patients (Padj = 0.002, ORadj = 1.56). Further, we investigated the correlation between rs1800629 genotypes and TNF-α concentrations in peripheral blood mononuclear cells (PBMCs) of healthy volunteers exposed to lipopolysaccharides (LPS) ex vivo, and the association between rs1800629 and TNF-α serum levels in severe sepsis patients. After exposure to LPS, the TNF-α concentration in culture supernatants of PBMCs was significantly higher in the subjects with AA+AG genotypes than that with GG genotype (P = 0.007). Moreover, in patients with severe sepsis, individuals with AA+AG genotypes had significantly higher TNF-α serum concentrations than those with GG genotype (Padj = 0.02). However, there were no significant associations between SNPs in the four candidate genes and 30 day mortality for patients with severe sepsis.Conclusions/SignificanceOur findings suggested that the functional TNF gene SNP rs1800629 was strongly associated with susceptibility to severe sepsis, but not with lethality in Chinese Han population.

Association of tumor necrosis factor α −308G/A and interleukin-6 −174G/C gene polymorphism with pneumonia-induced sepsis

“…There was no significant association between mortality and these variants in patients with severe sepsis. These outcomes are similar to previous studies, which reported inconsistent associations between these SNPs and poor prognoses as well as no correlation between the mortality from sepsis and rs1800629 genotypes [9,12,13]. Together with our results, the current literature suggests a diverse role for rs1800629 and rs1800759 in contributing to the mortality rate in patients with sepsis shock.…”

“…The APACHE II and SOFA scores were calculated in the first 24 hours after the diagnosis of sepsis and severe sepsis [9]. Other indicators were monitored for clinical management, including a mean arterial pressure of 65 mm Hg or greater, a urine output of 0.5 mL/kg per hour or greater, and serum lactate levels of 4 mmol/L or greater.…”

“…The SNP rs1800629 (TNF − 308) has received much attention from researchers because there is evidence the SNP is closely related to sepsis risk and outcome [9]. This SNP was also reported to be associated with TNF expression levels in the circulatory system [10].…”

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

“…Study of sepsis and severe sepsis in the Chinese population obtained that allele A was higher but was not influence on mortality. TNF-α serum level was high in leptospirosis but did not correlated with TNF-α -308G/A 32 . A meta-analysis study showed that TNF-α -308G/A was associated with the incidence of sepsis not in death, and Asian had a strong contribution compared with other races 33 .…”

The role of genetics and antibodies in sepsis

“…In particular, rs1800750 leading to one G/A transition at the −376 position and rs361525 leading to one G/A transition at the −238 position. Carriage of A alleles of these SNPs is associated with increased susceptibility for severe sepsis but does not predict increased lethality among Chinese Han populations (29).…”