| Introduction: Tetralogy of Fallot (TOF) is the most common cyanotic form of
congenital heart defects. However, there is no effective therapeutic approach and
current therapies have limited curative efficacy. Moreover, the exact etiology of TOF
has remained largely unknown. Improved understanding of molecular mechanisms
can give an insight into TOF pathogenesis and development of therapeutic
approaches.
Methods: Here, we conducted a systematic study on the right ventricular
myocardium of 24 infants (16 ToF/8 control) using weighted gene co-expression
network analysis (WGCNA) to identify meaningful modules or candidate biomarkers.
Results: Co-expression network analysis by WGCNA suggested that a highly
preserved turquoise module with 2,493 genes and a P-value of 3×10-11 was
significantly correlated to TOF. The top 5 hub genes of this module were PSMA2,
MYL12A, C11ORF71, COMMD6, and CREG1. The result of turquoise module
enrichment showed that the most correlation topic in biological processes and KEGG
pathways were positive regulation of cardiac neural crest migration involved in outflow
tract morphogenesis and positive regulation of neural crest cell differentiation. Also,
we recognized 4 FDA-approved drug candidates for other indications could potentially
use for the treatment of TOF patients through regulation of two hub genes of the coexpression network (PSMA2 and NDUFA4). Our findings also showed that the 13
experimentally validated microRNAs regulated the co-expression network through 5
hub genes.
Conclusion: We systematically recognized co-expressed gene modules and hub
genes associated with TOF progression, which offered insights into the mechanisms
underlying TOF progression and some potential drugs for the treatment of TOF. |