Individualized interactomes for network-based precision medicine in hypertrophic cardiomyopathy with implications for other clinical pathophenotypes

Abstract

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.

Identification and Verification of Feature Immune-Related Genes in Patients With Hypertrophic Cardiomyopathy Based on Bioinformatics Analyses

“…There are five comparatively valuable datasets that contain more than 10 samples of HCM in GEO database, namely GSE160997 ( 6 ), GSE143786 ( 7 ), GSE148602 ( 8 ), GSE130036 ( 9 ), and GSE36961. Among these five datasets, GSE160997, GSE130036, and GSE36961 focus on transcriptome information and a previous study of our team had explored GSE130036 ( 10 ).…”

Urine peptidome analysis in cardiorenal syndrome reflects molecular processes

“…These included several collagen types, including COL4A2, COL4A4, COL6A5. Although few studies have aimed to investigate the role of collagen type IV and VI in cardio and renal failure, recently, it was suggested that COL4A2 is associated with cardiac fibrosis phenotype 42 , as well as with glomerular basement membrane alterations 43 , suggesting that COL4A2 may play an important role in CRS. In addition, COL4A4 and COL6A5 are associated with CKD 44 , 45 but no evidence was found to link COL4A4 and COL6A5 with HF.…”

Pathogenic Mechanisms of Hypertrophic Cardiomyopathy Beyond Sarcomere Dysfunction

“…Evidence for global TGF- activation is also found in plasma from HCM patients compared to controls [42]. Another recent study has implicated a JAK2-STAT3-COL4A2 pathway as a driver of the fibrotic phenotype that could distinguish individual HCM patients on the basis of fibrosis severity [78], and additional exploration of cardiac fibroblast function and activation in HCM in human tissue and experimental models are likely to yield additional candidate pathways.…”