Individualized interactomes for network-based precision medicine in hypertrophic cardiomyopathy with implications for other clinical pathophenotypes.
Individualized interactomes for network-based precision medicine in hypertrophic cardiomyopathy with implications for other clinical pathophenotypes.
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DOI：
10.1038/s41467-021-21146-y
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发表时间：
2021-02-08
影响因子：
16.6
通讯作者：
Loscalzo J
中科院分区：
文献类型：
--
作者：
Maron BA;Wang RS;Shevtsov S;Drakos SG;Arons E;Wever-Pinzon O;Huggins GS;Samokhin AO;Oldham WM;Aguib Y;Yacoub MH;Rowin EJ;Maron BJ;Maron MS;Loscalzo J
精确医学的进展受到定义患者之间病理生物学差异的相关组织中转录组学或蛋白质组学特征的知识不足的限制。在这里，来自梗阻性肥厚型心肌病和心力衰竭患者的肌切除组织使用RNA-Seq进行分析，结果用于开发个性化的蛋白质-蛋白质相互作用网络。从这种方法中，肥厚型心肌病区别于扩张型心肌病的基础上蛋白质-蛋白质相互作用网络模式。在肥厚型心肌病队列中，患者特异性网络的复杂性是可变的，并富集了30种内表型。由网络提供的心脏Janus激酶2-信号转导和转录激活因子3-胶原4A 2（JAK 2-STAT 3-COL 4A 2）表达谱能够区分两名具有极端纤维化表型的肥厚型心肌病患者。患者特异性网络特征也与其他重要的肥厚型心肌病临床表型相关。这些概念验证的发现引入了个性化的蛋白质-蛋白质相互作用网络（reticulotypes），用于表征患者特异性病理生物学，从而为推进精准医学提供了直接的策略。了解患者特异性病理生物学途径是推进精准医学的关键一步。在这里，作者表明，个性化的蛋白质-蛋白质相互作用网络提供了对复杂疾病中患者水平病理生物学和临床相关病理表型特征的关键见解。
Progress in precision medicine is limited by insufficient knowledge of transcriptomic or proteomic features in involved tissues that define pathobiological differences between patients. Here, myectomy tissue from patients with obstructive hypertrophic cardiomyopathy and heart failure is analyzed using RNA-Seq, and the results are used to develop individualized protein-protein interaction networks. From this approach, hypertrophic cardiomyopathy is distinguished from dilated cardiomyopathy based on the protein-protein interaction network pattern. Within the hypertrophic cardiomyopathy cohort, the patient-specific networks are variable in complexity, and enriched for 30 endophenotypes. The cardiac Janus kinase 2-Signal Transducer and Activator of Transcription 3-collagen 4A2 (JAK2-STAT3-COL4A2) expression profile informed by the networks was able to discriminate two hypertrophic cardiomyopathy patients with extreme fibrosis phenotypes. Patient-specific network features also associate with other important hypertrophic cardiomyopathy clinical phenotypes. These proof-of-concept findings introduce personalized protein-protein interaction networks (reticulotypes) for characterizing patient-specific pathobiology, thereby offering a direct strategy for advancing precision medicine. Understanding patient-specific pathobiological pathways is a critical step for advancing precision medicine. Here the authors show that individualized protein-protein interaction networks provide key insight on patient-level pathobiology and clinically relevant pathophenotypic characteristics in a complex disease.
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