A single nucleotide polymorphism of Toll-like receptor 4 identifies the risk of developing graft failure after liver transplantation
A single nucleotide polymorphism of Toll-like receptor 4 identifies the risk of developing graft failure after liver transplantation
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DOI：
10.1016/j.jhep.2009.12.044
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发表时间：
2010-07-01
影响因子：
25.7
通讯作者：
Schroeppel, Bernd
中科院分区：
文献类型：
--
作者：
Dhillon, Navdeep;Walsh, Liron;Schroeppel, Bernd
背景和目标：虽然动物模型中的研究已经将Toll样受体（TLR）4信号传导与缺血/再灌注（IR）损伤和肝纤维化的病理生理学联系起来，但人肝移植后TLR 4活化的相关性尚不清楚。TLR 4单核苷酸多态性（SNP）D299 G位于细胞外结构域内，并减少受体结合到IR相关的分子patterns.Methods：我们研究了TLR 4 D299 G对IR损伤和移植物存活率的影响，在430个死亡供体LT受体。与表达野生型（WT）等位基因的肝脏相比，具有TLR 4功能丧失等位基因的肝脏显著更可能具有初始良好的移植物功能（IGGF）（OR 2.20，p = 0.01）。结果：根据丙型肝炎病毒（HCV）血清状态分析了TLR 4 D299 G基因型对移植物长期存活率的影响。在HCV感染的受体中，多变量考克斯回归分析证明受体而非供体TLR 4 D299 G的存在与长期移植失败之间存在显著关联（HR 2.48，CI 1.28-4.81 p = 0.007）。TLR 4突变体和野生型受体之间的非HCV感染recipients.Conclusions：总的来说，这些结果表明，供体和受体TLR 4信号在人类肝移植的差异影响移植物存活率没有差异。供体TLR 4导致冷保存后的无菌损伤，受体TLR 4基因型与HCV感染受者中移植物存活率低相关。(C)2010年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: While studies in animal models have linked Toll-like receptor (TLR) 4 signaling to the pathophysiology of ischemia/reperfusion (IR) injury and liver fibrosis, the relevance of TLR4 activation after human liver transplantation is unknown. The TLR4 single nucleotide polymorphism (SNP) D299G is situated within the extracellular domain and diminishes receptor binding to danger-associated molecular patterns.Methods: We studied the influence of TLR4 D299G on IR injury and graft survival in 430 deceased donor LT recipients. Compared with livers expressing wild-type (WT) alleles, livers with a TLR4 loss-of-function allele were significantly more likely to have initial good graft function (IGGF) (OR 2.20, p = 0.01). In contrast, there was no effect of recipient TLR4 genotype on the rate of IGGF.Results: The effect of TLR4 D299G on long-term graft survival was analyzed based on hepatitis C virus (HCV) serostatus. In HCV infected recipients, multivariate Cox regression analysis demonstrated a significant association between the presence of recipient, but not donor TLR4 D299G and long-term graft failure (HR 2.48, CI 1.28-4.81 p = 0.007). There was no difference in graft survival between TLR4 mutant and WT recipients among non-HCV infected recipients.Conclusions: Collectively, these results demonstrate the differential effects of donor and recipient TLR4 signaling in human liver transplantation. Donor TLR4 contributed to sterile injury following cold preservation and the recipient TLR4 genotype was linked with poor allograft survival among HCV infected recipients. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.