Bioinformatics multivariate analysis determined a set of phase-specific biomarker candidates in a novel mouse model for viral myocarditis.
Bioinformatics multivariate analysis determined a set of phase-specific biomarker candidates in a novel mouse model for viral myocarditis.
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DOI：
10.1161/circgenetics.114.000505
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发表时间：
2014-08
期刊：
影响因子：
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通讯作者：
Tsunoda I
中科院分区：
文献类型：
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作者：
Omura S;Kawai E;Sato F;Martinez NE;Chaitanya GV;Rollyson PA;Cvek U;Trutschl M;Alexander JS;Tsunoda I
心肌炎是一种心肌炎性疾病，主要由病毒感染引起。病毒性心肌炎分为3个阶段：急性病毒期、亚急性免疫期和慢性心脏重塑期。尽管应根据阶段应用个体化治疗，但没有临床或实验研究发现区分3个阶段的生物标志物。泰勒氏鼠脑脊髓炎病毒属于病毒属，可引起易感小鼠品系的心肌炎。使用Theiler小鼠脑脊髓炎病毒诱导的病毒性心肌炎的新模型，我们进行了多变量分析，包括超声心动图，血清肌钙蛋白和病毒RNA滴定，以及微阵列，以确定可以区分3个阶段的生物标志物候选者。使用感染后4、7和60天感染Theiler小鼠脑脊髓炎病毒的C3 H小鼠，我们进行了生物信息学分析，包括微阵列数据的主成分分析和k均值聚类，因为我们传统的心脏和血清测定，包括微阵列数据的双向比较，没有导致识别单一生物标志物。主成分分析在感染后4、7和60天的组之间清楚地分离心脏样品。有助于分离的代表性基因如下：感染后4天和7天，先天免疫相关基因，如Irf 7和Cxcl 9;感染后7天和60天，获得性免疫相关基因，如Cd 3g和H2-Aa;以及心脏重塑相关基因，如Mmp 12和Gpnmb。发现通过无监督主成分分析鉴定的分子组而不是单个分子可用作阶段特异性生物标志物。
Myocarditis is an inflammatory disease of the cardiac muscle and is mainly caused by viral infections. Viral myocarditis has been proposed to be divided into 3 phases: the acute viral phase, the subacute immune phase, and the chronic cardiac remodeling phase. Although individualized therapy should be applied depending on the phase, no clinical or experimental studies have found biomarkers that distinguish between the 3 phases. Theiler’s murine encephalomyelitis virus belongs to the genus Cardiovirus and can cause myocarditis in susceptible mouse strains. Using this novel model for viral myocarditis induced with Theiler’s murine encephalomyelitis virus, we conducted multivariate analysis including echocardiography, serum troponin and viral RNA titration, and microarray to identify the biomarker candidates that can discriminate the 3 phases. Using C3H mice infected with Theiler’s murine encephalomyelitis virus on 4, 7, and 60 days post infection, we conducted bioinformatics analyses, including principal component analysis and k-means clustering of microarray data, because our traditional cardiac and serum assays, including 2-way comparison of microarray data, did not lead to the identification of a single biomarker. Principal component analysis separated heart samples clearly between the groups of 4, 7, and 60 days post infection. Representative genes contributing to the separation were as follows: 4 and 7 days post infection, innate immunity–related genes, such as Irf7 and Cxcl9; 7 and 60 days post infection, acquired immunity–related genes, such as Cd3g and H2-Aa; and cardiac remodeling–related genes, such as Mmp12 and Gpnmb. Sets of molecules, not single molecules, identified by unsupervised principal component analysis, were found to be useful as phase-specific biomarkers.