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

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.

背景
肿瘤坏死因子（Tumor necrosis factor, TNF）及肿瘤坏死因子受体超家族（TNF receptor superfamily, TNFR）介导的免疫应答在重症脓毒症的发病机制中发挥关键作用。此前针对TNF及淋巴毒素-α（Lymphotoxin-α, LTA）单核苷酸多态性（single nucleotide polymorphism, SNP）与重症脓毒症关联的研究所得结果存在分歧。本研究旨在探讨中国汉族人群中TNF、LTA、TNFRSF1A及TNFRSF1B的基因变异是否与重症脓毒症的易感性或致死风险相关。

方法与主要结果
本研究对432例重症脓毒症患者、384例脓毒症患者及624例健康对照者的样本，完成了TNF、LTA、TNFRSF1A及TNFRSF1B基因上10个单核苷酸多态性位点的基因分型。结果显示，位于TNF启动子区域的rs1800629位点多态性与重症脓毒症的发病风险显著相关。该位点的次要等位基因频率在重症脓毒症患者中显著高于健康对照（校正后P值Padj=0.00046，校正后比值比ORadj=1.92）及普通脓毒症患者（Padj=0.002，ORadj=1.56）。本研究进一步分析了rs1800629基因型与健康志愿者外周血单个核细胞（peripheral blood mononuclear cells, PBMCs）体外经脂多糖（lipopolysaccharides, LPS）刺激后的TNF-α浓度之间的关联，同时探讨了该位点与重症脓毒症患者血清TNF-α水平的相关性。经脂多糖刺激后，携带AA+AG基因型的受试者外周血单个核细胞培养上清液中的TNF-α浓度显著高于GG基因型携带者（P=0.007）。此外，在重症脓毒症患者中，携带AA+AG基因型者的血清TNF-α浓度显著高于GG基因型携带者（Padj=0.02）。但上述四个候选基因的单核苷酸多态性与重症脓毒症患者的30天死亡率无显著关联。

结论与意义
本研究结果表明，功能性TNF基因单核苷酸多态性位点rs1800629与中国汉族人群重症脓毒症的易感性显著相关，但与该人群的重症脓毒症致死风险无关。