Toll-like Receptor 1 Polymorphisms Increase Susceptibility to Candidemia
Toll-like Receptor 1 Polymorphisms Increase Susceptibility to Candidemia
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DOI：
10.1093/infdis/jir867
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发表时间：
2012-03-15
影响因子：
6.4
通讯作者：
Netea, Mihai G.
中科院分区：
文献类型：
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作者：
Plantinga, Theo S.;Johnson, Melissa D.;Netea, Mihai G.
背景真菌血症是一种严重的侵袭性真菌感染，死亡率高。念珠菌属物种的识别通过模式识别受体如Toll样受体（TLR）介导。本研究评估TLR信号转导的遗传变异是否影响念珠菌病的易感性。在338名念珠菌血症患者（237名白色，93名非洲裔美国人，8名其他种族）和351名非感染对照（263名白色，88名非洲裔美国人）中，对编码TLR和信号衔接子MyD 88和Mal/TIRAP的基因的13个主要非同义单核苷酸多态性（SNP）进行基因分型。单变量分析中显著的SNPs进一步用多变量逻辑回归分析以确定与临床结果的关联。通过体外刺激试验评估这些多态性的功能后果。TLR 1 SNPs分析显示，3个TLR 1 SNPs（R80 T、S248 N、I602 S）与白人念珠菌血症易感性显著相关。在非裔美国人中未发现这种关联，可能是由于在这个较小的研究人群中的功率较低。此外，这些TLR 1多态性显示原代单核细胞的细胞因子释放受损。TLR 2、TLR 4、TLR 6、TLR 9、MyD 88或TIRAP中的SNPs与念珠菌血症的易感性无关。TLR 1中的非同义SNPs与白人TLR 1功能受损、细胞因子反应降低和念珠菌血症易感性相关。
Background. Candidemia is a severe invasive fungal infection with high mortality. Recognition of Candida species is mediated through pattern recognition receptors such as Toll-like receptors (TLRs). This study assessed whether genetic variation in TLR signaling influences susceptibility to candidemia.Methods. Thirteen mostly nonsynonymous single nucleotide polymorphisms (SNPs) in genes encoding TLRs and signaling adaptors MyD88 and Mal/TIRAP were genotyped in 338 patients (237 white, 93 African American, 8 other race) with candidemia and 351 noninfected controls (263 white, 88 African American). The SNPs significant in univariate analysis were further analyzed with multivariable logistic regression to determine association with clinical outcomes. Functional consequences of these polymorphisms were assessed via in vitro stimulation assays.Results. Analyses of TLR SNPs revealed that 3 TLR1 SNPs (R80T, S248N, I602S) were significantly associated with candidemia susceptibility in whites. This association was not found in African Americans, likely due to lower power in this smaller study population. Furthermore, these TLR1 polymorphisms displayed impaired cytokine release by primary monocytes. No associations with susceptibility to candidemia were observed for SNPs in TLR2, TLR4, TLR6, TLR9, MyD88, or TIRAP.Conclusions. Nonsynonymous SNPs in TLR1 are associated with impaired TLR1 function, decreased cytokine responses, and predisposition to candidemia in whites.