Comprehensive Construction of a Circular RNA-Associated Competing Endogenous RNA Network Identified Novel Circular RNAs in Hypertrophic Cardiomyopathy by Integrated Analysis

Abstract

Hypertrophic cardiomyopathy (HCM), the most common heritable cardiomyopathy, is associated with a high risk of sudden cardiac death. The complexity and behavior of the circular RNA (circRNA)-associated competing endogenous RNA (ceRNA) network in HCM have not been thoroughly elucidated. Plasma circRNA and messenger RNA (mRNA) expression profiles were acquired by using a microarray. Weighted correlation network analysis (WGCNA) and linear models for microarray data (Limma) were used to analyze microarray data. The ceRNA network, including circRNA, microRNA (miRNA), and mRNA, was constructed based on the “ceRNA hypothesis” using an integrated systems biology method. By WGCNA, magenta and red modules were identified as being positively correlated with HCM. In the combined analysis of WGCNA and Limma, 36 hub circRNAs in the magenta module and 83 hub circRNAs in the red module were significantly upregulated compared to the controls. By coexpression analysis, 270 circRNA-mRNA pairs were identified with a coefficient ≥ 0.9 and p < 0.05. With Starbase and miRWalk tools, circRNA-miRNA pairs and miRNA-mRNA pairs were predicted. Once these pairs were combined, the ceRNA network with 6 circRNAs, 29 miRNAs, and 6 mRNAs was constructed. Functional analysis demonstrated that these circRNAs in the ceRNA network were associated with calcium-release channel activity and muscle filament sliding. Our study provided a global perspective and systematic analysis of the circRNA-associated ceRNA network in HCM. The identified circRNAs hsa_circ_0043762, hsa_circ_0036248, and hsa_circ_0071269 may be key regulators involved in HCM pathogenesis.