Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation.
Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation.
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DOI：
10.1056/nejmoa0802629
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发表时间：
2008-10-23
期刊：
影响因子：
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通讯作者：
Boeckh M
中科院分区：
文献类型：
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作者：
Bochud PY;Chien JW;Marr KA;Leisenring WM;Upton A;Janer M;Rodrigues SD;Li S;Hansen JA;Zhao LP;Aderem A;Boeckh M
Toll样受体（TLR）是对真菌病原体的免疫应答的重要组成部分。我们研究了TLR多态性在异基因造血细胞移植受者中侵袭性曲霉菌病风险中的作用。我们分析了336例造血细胞移植受者及其无关供者中toll样受体2基因（TLR 2）、toll样受体3基因（TLR 3）、toll样受体4基因（TLR 4）和toll样受体9基因（TLR 9）的20个单核苷酸多态性（SNP）。侵袭性曲菌病的风险采用多变量考克斯回归分析进行评估。该分析在一项验证研究中得到了重复，该研究涉及103名病例患者和263名匹配的对照组，他们接受了来自相关和不相关捐赠者的造血细胞移植。在发现研究中，两种供体TLR 4单倍型（S3和S4）增加了侵袭性曲霉病的风险（S3的校正风险比，2.20; 95%置信区间[CI]，1.14至4.25; P = 0.02; S4的校正风险比，6.16; 95% CI，1.97至19.26; P = 0.002）。单倍型S4存在于影响TLR 4功能的两个SNP（1063 A/G [D299 G]和1363 C/T [T399 I]）的携带者中，具有强连锁不平衡。在验证研究中，供体单倍型S4也增加了侵袭性曲霉病的风险（校正比值比，2.49; 95%CI，1.15至5.41; P = 0.02）;该关联存在于无关的造血细胞移植受者中（比值比，5.00; 95% CI，1.04至24.01; P = 0.04），但在相关受者中没有（比值比，2.29; 95% CI，0.93至5.68; P = 0.07）。在发现研究中，与CMV和S4阴性结果相比，供体或受体巨细胞病毒（CMV）血清阳性、供体S4阳性或两者均阳性与3年侵袭性曲霉病（12% vs. 1%，P = 0.02）和与复发无关的死亡（35% vs. 22%，P = 0.02）概率增加相关。这项研究表明，供体TLR 4单倍型S4与无关供体造血细胞移植受者侵袭性曲霉菌病的风险之间存在关联。
Toll-like receptors (TLRs) are essential components of the immune response to fungal pathogens. We examined the role of TLR polymorphisms in conferring a risk of invasive aspergillosis among recipients of allogeneic hematopoietic-cell transplants. We analyzed 20 single-nucleotide polymorphisms (SNPs) in the toll-like receptor 2 gene (TLR2), the toll-like receptor 3 gene (TLR3), the toll-like receptor 4 gene (TLR4), and the toll-like receptor 9 gene (TLR9) in a cohort of 336 recipients of hematopoietic-cell transplants and their unrelated donors. The risk of invasive aspergillosis was assessed with the use of multivariate Cox regression analysis. The analysis was replicated in a validation study involving 103 case patients and 263 matched controls who received hematopoietic-cell transplants from related and unrelated donors. In the discovery study, two donor TLR4 haplotypes (S3 and S4) increased the risk of invasive aspergillosis (adjusted hazard ratio for S3, 2.20; 95% confidence interval [CI], 1.14 to 4.25; P = 0.02; adjusted hazard ratio for S4, 6.16; 95% CI, 1.97 to 19.26; P = 0.002). The haplotype S4 was present in carriers of two SNPs in strong linkage disequilibrium (1063 A/G [D299G] and 1363 C/T [T399I]) that influence TLR4 function. In the validation study, donor haplotype S4 also increased the risk of invasive aspergillosis (adjusted odds ratio, 2.49; 95% CI, 1.15 to 5.41; P = 0.02); the association was present in unrelated recipients of hematopoietic-cell transplants (odds ratio, 5.00; 95% CI, 1.04 to 24.01; P = 0.04) but not in related recipients (odds ratio, 2.29; 95% CI, 0.93 to 5.68; P = 0.07). In the discovery study, seropositivity for cytomegalovirus (CMV) in donors or recipients, donor positivity for S4, or both, as compared with negative results for CMV and S4, were associated with an increase in the 3-year probability of invasive aspergillosis (12% vs. 1%, P = 0.02) and death that was not related to relapse (35% vs. 22%, P = 0.02). This study suggests an association between the donor TLR4 haplotype S4 and the risk of invasive aspergillosis among recipients of hematopoietic-cell transplants from unrelated donors.