Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis.
Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis.
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DOI：
10.1038/gene.2013.60
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发表时间：
2014-03
影响因子：
5
通讯作者：
West, T. E.
中科院分区：
文献类型：
--
作者：
Chantratita, N.;Tandhavanant, S.;Myers, N. D.;Chierakul, W.;Robertson, J. D.;Mahavanakul, W.;Singhasivanon, P.;Emond, M. J.;Peacock, S. J.;West, T. E.
类鼻疽是一种严重的感染所造成的鞭毛细菌伯克霍尔德氏菌类鼻疽。无义多态性TLR 51174 C>T与泰国类鼻疽患者预后改善相关我们假设其他TLR 5变异体可能调节宿主反应并决定类鼻疽的结局。我们从HapMap数据库中重新选择了12个TLR 5变异体进行基因分型，并检查了每个变异体与健康泰国受试者全血鞭毛蛋白刺激诱导的细胞因子的相关性。我们发现，与非同义变体TLR 51846 T>C处于连锁不平衡的三个相关标记物的细胞因子应答减弱。TLR 51846 T>C的携带者具有由鞭毛蛋白诱导的广泛受损的细胞因子应答。TLR 51846 T>C与类鼻疽患者的死亡保护相关（OR 0.62，95%CI：0.42-0.93，p=0.021）。我们没有观察到TLR 51846 C依赖的NF-κB活化的损伤，但是，提示了该效应的另一种机制。我们发现TLR 51846 T>C与TLR 51174 C>T存在强连锁不平衡。在类鼻疽患者中观察到的许多钝化的细胞因子应答以及TLR 51846 T>C与存活的关联可能归因于TLR 51174 C>T，但是我们不能排除TLR 51846 T>C的独立作用。这些数据确定了TLR 51846 T>C的新关联，增强了我们对泰国人TLR 5遗传结构的理解，并提供了未来的研究方向。
Melioidosis is a severe infection caused by the flagellated bacterium Burkholderia pseudomallei. The nonsense polymorphism TLR51174C>T is associated with improved outcome in Thais with melioidosis. We hypothesized that other TLR5 variants may modulate the host response and determine outcome in melioidosis. We genotyped 12 TLR5 variants selected de novo from the HapMap database and examined the association of each with cytokines induced by flagellin stimulation of whole blood from healthy Thai subjects. We found a blunted cytokine response for three related markers that were in linkage disequilibrium with a non-synonymous variant, TLR51846T>C. Carriers of TLR51846T>C had broadly impaired cytokine responses induced by flagellin. TLR51846T>C was associated with protection against death in melioidosis patients (OR 0.62, 95% CI: 0.42-0.93, p=0.021). We observed no impairment in TLR51846C-dependent NF-κB activation, however, suggesting an alternative mechanism for the effect. We found that TLR51846T>C was in strong linkage disequilibrium with TLR51174C>T. Many of the blunted cytokine responses observed and the association of TLR51846T>C with survival in melioidosis patients may be attributable to TLR51174C>T, but we could not exclude an independent effect of TLR51846T>C. These data identify novel associations for TLR51846T>C, enhance our understanding of TLR5 genetic architecture in Thais, and provide future directions of study.
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一种常见的主导TLR5停止密码子多态性废除了鞭毛蛋白信号传导，并与对军团疾病的易感性有关。
影响因子：
15.3
作者：
Hawn, TR;Verbon, A;Lettinga, KD;Zhao, LP;Li, SS;Laws, RJ;Skerrett, SJ;Beutler, B;Schroeder, L;Nachman, A;Ozinsky, A;Smith, KD;Aderem, A
通讯作者：
Aderem, A
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
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DOI：
10.1073/pnas.0502040102
发表时间：
2005-06-28
影响因子：
11.1
作者：
Andersen-Nissen, E;Smith, KD;Aderem, A
通讯作者：
Aderem, A
影响因子：
56.9
作者：
Liu, Lin;Botos, Istvan;Davies, David R.
通讯作者：
Davies, David R.
影响因子：
64.8
作者：
Park, Beom Seok;Song, Dong Hyun;Lee, Jie-Oh
通讯作者：
Lee, Jie-Oh