Meta-analysis of Transcriptomic Data Reveals Pathophysiological Modules Involved with Atrial Fibrillation

Abstract

Atrial fibrillation (AF) is a complex disease and affects millions of people around the world. The biological mechanisms that are involved with AF are complex and still need to be fully elucidated. Therefore, we performed a meta-analysis of transcriptome data related to AF to explore these mechanisms aiming at more sensitive and reliable results. Public transcriptomic datasets were downloaded, analyzed for quality control, and individually pre-processed. Differential expression analysis was carried out for each individual dataset, and the results were meta-analytically aggregated using the r-th ordered p-value method. We analyzed the final list of differentially expressed genes through network analysis, namely topological and modularity analysis, and functional enrichment analysis. The meta-analysis of transcriptomes resulted in 589 differentially expressed genes, whose protein-protein interaction network presented 11 hubs-bottlenecks and four main identified functional modules. These modules were enriched for, respectively, 23, 54, 33, and 53 biological pathways involved with the pathophysiology of AF, especially with the disease's structural and electrical remodeling processes. Stress of the endoplasmic reticulum, protein catabolism, oxidative stress, and inflammation are some of the enriched processes. Among hubs-bottlenecks genes, which are highly connected and probably have a key role in regulating these processes, we found HSPA5, ANK2, CTNNB1, and VWF. Further experimental investigation of our findings may shed light on the pathophysiology of the disease and contribute to the identification of new therapeutic targets and treatments.

Transcriptomic uniqueness and commonality of the ion channels and transporters in the four heart chambers

“…S4-S6 present the significant expression coordination of Ank2, Ctnnb1, Hspa5 and Mapk1 with Akt2 potential binding partners in the four heart chambers. All these four genes were identified in a recent paper 27 as key players in regulating the cardiac rhythm. While no statistically significant antagonism or independence was found in any of the four genes' networks, the percentages of significant synergisms within this selection of genes were substantially larger in ventricles than in atria.…”

“…A special attention was given to the expression coordination of Ank2 (encoding Ankyrin-B), a major player in cardiac physiology, with its potential binding partners 26 in each heart chamber. The coordination analysis with Ank2 partners was extended to Ctnnb1 (catenin (cadherin associated protein), beta 1), Hspa5 (heat shock protein 5) and Mapk1 (mitogen-activated protein kinase 1) which together with Ank2 were identified as hubbottleneck genes in atrial fibrillation 27 .…”