Variants in the Toll-interacting protein gene are associated with susceptibility to sepsis in the Chinese Han population.
Variants in the Toll-interacting protein gene are associated with susceptibility to sepsis in the Chinese Han population.
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Toll相互作用蛋白基因的变异与中国汉族人群败血症的易感性相关
DOI：
10.1186/cc9413
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Tong C
中科院分区：
文献类型：
--
作者：
Song Z;Yin J;Yao C;Sun Z;Shao M;Zhang Y;Tao Z;Huang P;Tong C
宿主免疫反应失调或过度参与脓毒症的发病机制。toll样受体（TLR）信号通路及其负调节因子在宿主免疫反应的调节和败血症的发生中起关键作用。本研究的目的是探讨中国汉族人群中TLR信号通路基因及其负调节基因变异与脓毒症易感性的关系。方法选取严重脓毒症患者（378例）和健康对照组（390例）。采用标签单核苷酸多态性（SNP）策略研究了tlr2、TLR4、TLR9、myd88和tollip 5个基因与脓毒症易感性的关系。利用HapMap项目中北京地区汉族人群的数据，选择12个标签snp进行直接测序分型。采用实时定量聚合酶链式反应（PCR）检测tollipmrna表达水平，采用酶联免疫吸附法（ELISA）检测肿瘤坏死因子α (TNF-α)和白细胞介素6 （IL-6）浓度。结果经多因素logistic回归分析校正后，tollips中rs5743867小c等位基因与脓毒症风险降低显著相关（Padj= 0.00062，比值比（OR）adj= 0.71, 95%可信区间（CI） 0.59 ~ 0.86）。包含相关SNP rs5743867的3-SNP单倍型块也显示出与综合testp值0.00049的强关联。单倍型GTC对脓毒症具有保护作用（Padj= 0.0012），而单倍型GCT对脓毒症具有增加的风险（Padj= 0.00092）。暴露于脂多糖（LPS）后，rs5743867C等位基因纯合子外周血单核细胞（PBMCs）中TOLLIPmRNA的表达水平显著高于rs5743867T等位基因的杂合子和纯合子（P= 0.013和P= 0.01）。rs5743867CC基因型组培养上清中TNF-α和IL-6浓度显著低于CT和TT基因型组（TNF-α P= 0.016和P= 0.003, IL-6 P= 0.01和P= 0.002）。结论tollip基因变异与中国汉族人群脓毒症易感性显著相关。
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, namelyTLR2, TLR4, TLR9, MyD88andTOLLIP, 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 ofTOLLIPwere 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 inTOLLIPwas 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 testPvalue 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),TOLLIPmRNA 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 andP= 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 andP= 0.003 for TNF-α;P= 0.01 andP= 0.002 for IL-6, respectively).ConclusionsOur findings indicated that the variants inTOLLIPwere significantly associated with sepsis susceptibility in the Chinese Han population.
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DOI：
10.1152/ajpgi.00531.2006
发表时间：
2007-06-01
影响因子：
4.5
作者：
Shibolet, Oren;Podolsky, Daniel K.
通讯作者：
Podolsky, Daniel K.
影响因子：
8.8
作者：
Levy, MM;Fink, MP;Ramsay, G
通讯作者：
Ramsay, G
影响因子：
30.8
作者：
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影响因子：
56.9
作者：
Gabriel, SB;Schaffner, SF;Altshuler, D
通讯作者：
Altshuler, D
影响因子：
--
作者：
Schimming TT;Parwez Q;Petrasch-Parwez E;Nothnagel M;Epplen JT;Hoffjan S
通讯作者：
Hoffjan S