Key Genes and Pathways in Human Left Atrial Appendage Identified by Co-expression Analysis

Abstract Background and Objective Left atrial appendage (LAA) closure (LAAC) is a technique that has shown potential for the prevention of thrombo-embolic events in atrial fibrillation (AF) patients. The short and long-term effects of LAAC on neuro-hormonal changes have been highlighted in several recent studies. In addition, metabolic and hemodynamic profile changes were identified after LAAC, which may be attributed to the potential influence of specific LAA genetic profiling. However, only a few studies have deciphered the specific LAA genetic profiling. Therefore, we sought to conduct a weighted gene co-expression network analysis (WGCNA) to identify highly correlated gene modules in the LAA and to identify the hub genes with the highest degree of connectivity in selected modules. Functional enrichment analysis was performed to investigate the pivotal biological processes and pathways of defined gene modules in the LAA. Material and Methods Genes exhibiting the highest expression levels (top 25%) of variation in the microarray samples from the combined GSE41177 and GSE79768 dataset were identified. These datasets were obtained from the Gene Expression Omnibus (GEO) database. The combined dataset, which was used to conduct the WGCNA, included 38 paired samples that compared LAA (n = 19) with left atrium-pulmonary vein junction (LA-PV, n = 19) specimens. Gene ontology and functional enrichment analyses were performed to define genes belonging to the key modules of LAA. Hub genes were screened out from the key modules by algorithms and interactions analysis and which were visualized using Cytoscape software. Results Two modules with 397 (pink) and 419 (black) probes were identified to be specifically related to LAA (pink: r = 0.22, p = 9.7×10 − 6; black: r = 0.27, p = 2×10 − 8). In the functional analyses, the pink module showed an association with serine-type endopeptidase activity, cell-cell adhesion, synapse and axon guidance and protein processing. The black module was primarily associated with metabolic processes, such as the triglyceride metabolic process, triglyceride biosynthetic process, fatty acid oxidation, carbohydrate biosynthetic process, insulin signaling pathway, regulation of lipid storage, PPAR signaling pathway, regulation of lipolysis adipocytes, response to peptide hormone and amino acid biosynthesis. A total of five genes, including LRRN4 (leucine-rich repeat neuronal protein 4) and KLK11 (kallikrein related peptidase 11) in the pink module, as well as GYG2 (glycogenin 2), GPD1 (glycerol-3-phosphate dehydrogenase 1) and DGAT2 (diacylglycerol O-acyltransferase 2) from the black module, were identified as hub genes. Conclusions Using WGCNA bioinformatic approach, we defined key genes and pathways with specific biological characteristics in the human LAA, and our results thus are helpful to understand the underlying mechanisms responsible for the neuro-hormonal changes following LAA closure procedures.