Circulating plasma circular RNAs as novel diagnostic biomarkers for congenital heart disease in children

Abstract

ObjectiveThe diagnostic value of circulating circular RNAs (circRNAs) has received more and more attention. However, little has been reported about their potential in the diagnosis of congenital heart diseases (CHD). In this study, we explored differential expression of circRNAs from children with CHD to evaluate their potential as clinical biomarkers.MethodsWe established a discovery cohort (four CHD cases; four matched healthy controls) and a validation cohort (40 CHD cases; 40 matched healthy controls). Microarray expression analysis was performed on the discovery set to identify candidate circRNAs. Candidates were further validated in the validation set. The diagnostic accuracy of circRNAs was determined by receiver operating characteristic (ROC) analysis. Gene ontology (GO), pathway, and network analysis were performed to predict a network of circRNA/miRNA and target mRNAs related to CHD.ResultsThe top seven significantly differentially expressed CHD‐associated circRNAs were validated by RT‐PCR as follows: hsa_circRNA_004183, hsa_circRNA_079265, hsa_circRNA_105039, hsa_circRNA_404686, hsa_circRNA_101050, hsa_circRNA_100787, and hsa_circRNA_101328. Three significantly down‐regulated circRNAs (hsa_circRNA_004183, hsa_circRNA_079265, and hsa_circRNA_105039) were identified with area under curve (AUC) values of 0.758, 0.809, and 0.907, respectively; the combination had an AUC of 0.965. An interaction network was constructed by 43 circRNAs, 9 miRNAs, and 29 mRNAs, which involved in heart development.ConclusionsWe identified three circRNAs under‐expressed in plasma from children with CHD. These circRNAs may be crucial in the development of CHD and may serve as novel non‐invasive biomarkers for the diagnosis of CHD in children.

Non-Coding RNAs as Blood-Based Biomarkers in Cardiovascular Disease

“…A study including 40 children with CHD (namely VSD and ASD) and 40 healthy children identified 10 upregulated and 157 downregulated circRNAs in the plasma of the CHD group. Validation by qPCR demonstrated three circRNAs, hsa_circRNA_004183, hsa_circRNA_079265, and hsa_circRNA_105039, to be significantly decreased in the affected group [90]. Hsa_circRNA_105039 presented the best diagnostic value with a sensitivity of 80%, a specificity of 100%, and AUC of 0.907, but altogether, the three circRNAs had an AUC of 0.965, suggesting a combinatorial approach to be effective in the diagnosis of CHD [90].…”

Circular RNAs: Functions and Clinical Significance in Cardiovascular Disease

“…With the use of advanced technologies in sequencing and data analysis, a lot of circRNAs have been detected in human hearts and been reported to be associated with CVD ( Jakobi et al, 2016 ; Werfel et al, 2016 ; Fan et al, 2017 ; Tan et al, 2017 ) ( Table 2 and Figure 2 ). Moreover, circRNAs have been observed to have great potential as biomarkers for the diagnosis and prognosis of CVD ( Vausort et al, 2016 ; Sonnenschein et al, 2019 ; Wu et al, 2019 ; Vilades et al, 2020 ) ( Table 3 and Figure 2 ).…”

“…Moreover, circTMEM56 and circDNAJC6 could be indicators of disease severity in patients with HCM ( Sonnenschein et al, 2019 ). Wu et al (2019) reported three notably downregulated circRNAs (hsa_circRNA_004183, hsa_circRNA_079265 and hsa_circRNA_105039) in the plasma of children with congenital heart diseases (CHD) and employed ROC analyses to determine their potential to be biomarkers. They found the great potential of three circRNAs as novel non-invasive diagnostic biomarkers for CHD ( Wu et al, 2019 ).…”

“… Wu et al (2019) reported three notably downregulated circRNAs (hsa_circRNA_004183, hsa_circRNA_079265 and hsa_circRNA_105039) in the plasma of children with congenital heart diseases (CHD) and employed ROC analyses to determine their potential to be biomarkers. They found the great potential of three circRNAs as novel non-invasive diagnostic biomarkers for CHD ( Wu et al, 2019 ). Hsa_circ_0001445 was shown to have lower plasma levels in CAD patients than in the control group ( Vilades et al, 2020 ).…”

Circular RNAs in Cardiac Regeneration: Cardiac Cell Proliferation, Differentiation, Survival, and Reprogramming

“…A study from 2019 established a circRNA-miRNA-mRNA network and identified circYOD-1 as a circulating biomarker for coronary artery disease ( Miao et al, 2019 ). A study by Wu et al (2019) identified three differentialy regulated circRNAs in pediatric patients with congenital heart disease: hsa_circRNA_004183, hsa_circRNA_079265 and hsa_circRNA_105039. Another study reported several circRNAs linked to hypertrophic cardiomyopathy (HCM) in humans.…”