Genetic variation in the TNF receptor-associated factor 6 gene is associated with susceptibility to sepsis-induced acute lung injury.
Genetic variation in the TNF receptor-associated factor 6 gene is associated with susceptibility to sepsis-induced acute lung injury.
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TNF 受体相关因子 6 基因的遗传变异与脓毒症引起的急性肺损伤的易感性相关
DOI：
10.1186/1479-5876-10-166
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发表时间：
2012-08-17
影响因子：
7.4
通讯作者：
Bai C
中科院分区：
文献类型：
--
作者：
Song Z;Yao C;Yin J;Tong C;Zhu D;Sun Z;Jiang J;Shao M;Zhang Y;Deng Z;Tao Z;Sun S;Bai C
研究背景近年来的研究表明，由Toll样受体（TLR）相关通路介导的过度炎症反应在急性肺损伤（ALI）的发生发展中起重要作用。本研究旨在探讨TLR信号通路4个基因的共同遗传变异是否与中国汉族人群脓毒症诱导的ALI易感性和死亡风险相关。方法对272例脓毒症诱导的ALI患者和276例单纯脓毒症患者的MyD 88、IRAK 1、IRAK 4和TRAF 6的14个标签单核苷酸多态性（tagSNPs）进行基因分型。并在此病例对照组中进行关联性测试。然后，我们研究了相关SNP与相应基因的mRNA表达水平之间的相关性。同时，我们还研究了相关SNP与体外暴露于脂多糖（LPS）的外周血单个核细胞（PBMC）中肿瘤坏死因子α（TNF-α）和白细胞介素-6（IL-6）浓度的相关性。结果TRAF 6基因rs 4755453内含子SNP与脓毒症致ALI的易感性显著相关，而rs 4755453内含子SNP与脓毒症致ALI的易感性显著相关。单纯脓毒症组rs 4755453 C等位基因频率显著高于脓毒症致ALI组（P= 0.00026，OR = 0.52，95%可信区间（CI）0.37-0.74）。在基线时，来自rs 4755453 G等位基因纯合子的PBMC中TRAF 6 mRNA表达水平显著高于rs 4755453 C等位基因杂合子和纯合子（P= 0.012和P = 0.003）以及LPS刺激后（P= 0.009和P = 0.005）。rs 4755453 GG基因型受试者细胞培养上清中TNF-α和IL-6浓度也显著高于CG和CC基因型受试者。14个tagSNPs均未显示与ALI病例死亡风险和严重程度的相关性。结论TRAF 6基因的常见遗传变异与中国汉族人群脓毒症诱导的ALI易感性显著相关。这是第一个支持TRAF 6在ALI中作用的遗传学证据。
BackgroundRecent studies showed that overwhelming inflammatory response mediated by the toll-like receptor (TLR)-related pathway was important in the development of acute lung injury (ALI). The aim of this study was to determine whether common genetic variation in four genes of the TLR signaling pathway were associated with sepsis-induced ALI susceptibility and risk of death in Chinese Han population.MethodsFourteen tag single nucleotide polymorphisms (tagSNPs) inMyD88,IRAK1,IRAK4andTRAF6were genotyped in samples of sepsis-induced ALI (n = 272) and sepsis alone patients (n = 276), and tested for association in this case-control collection. Then, we investigated correlation between the associated SNP and the mRNA expression level of the corresponding gene. And we also investigated correlation between the associated SNP and tumor necrosis factor alpha (TNF-α) as well as interleukin-6 (IL-6) concentrations in peripheral blood mononuclear cells (PBMCs) exposed to lipopolysaccharides (LPS)ex vivo. The mRNA expression level was determined using real-time quantitative Polymerase Chain Reaction (PCR) assays, and concentrations of TNF-α and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA).ResultsThe association analysis revealed that rs4755453, an intronic SNP ofTRAF6, was significantly associated with susceptibility to sepsis-induced ALI. The C allele frequency of rs4755453 in the sepsis alone group was significantly higher than that in the sepsis-induced ALI group (P= 0.00026, odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.37–0.74). These associations remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons.TRAF6mRNA expression levels in PBMCs from homozygotes of the rs4755453G allele were significantly higher than that in heterozygotes and homozygotes of the rs4755453C allele at baseline (P= 0.012 andP= 0.003, respectively) as well as after LPS stimulation (P= 0.009 andP= 0.005). Moreover, the concentrations of TNF-α and IL-6 in cell culture supernatants were also significantly higher in the subjects with rs4755453GG genotype than in subjects with CG and CC genotype. None of the 14 tagSNPs showed associations with risk of death and severity among ALI cases.ConclusionsOur findings indicated that common genetic variants inTRAF6were significantly associated with susceptibility to sepsis-induced ALI in Chinese Han population. This was the first genetic evidence supporting a role forTRAF6in ALI.
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科学评论：寻找急性肺损伤中的基因候选者。
影响因子：
15.1
作者：
Grigoryev, DN;Finigan, JH;Hassoun, P;Garcia, JGN
通讯作者：
Garcia, JGN
影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
DOI：
10.1164/rccm.201005-0701oc
发表时间：
2011-05-15
影响因子：
24.7
作者：
Meyer, Nuala J.;Li, Mingyao;Christie, Jason D.
通讯作者：
Christie, Jason D.
DOI：
10.1165/rcmb.2005-0404oc
发表时间：
2006-04-01
影响因子：
6.4
作者：
Gao, L;Grant, A;Garcia, JGN
通讯作者：
Garcia, JGN
DOI：
10.1073/pnas.0811273106
发表时间：
2009-06-23
影响因子：
11.1
作者：
Ferwerda, Bart;Alonso, Santos;Netea, Mihai G.
通讯作者：
Netea, Mihai G.