[Retracted] Multiomics Analysis of Genetics and Epigenetics Reveals Pathogenesis and Therapeutic Targets for Atrial Fibrillation

Abstract

Objective. This study is aimed at understanding the molecular mechanisms and exploring potential therapeutic targets for atrial fibrillation (AF) by multiomics analysis. Methods. Transcriptomics and methylation data of AF patients were retrieved from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) and differentially methylated sites between AF and normal samples were screened. Then, highly expressed and hypomethylated and lowly expressed and hypermethylated genes were identified for AF. Weighted gene coexpression network analysis (WGCNA) was presented to construct AF-related coexpression networks. 52 AF blood samples were used for whole exome sequence. The mutation was visualized by the maftools package in R. Key genes were validated in AF using independent datasets. Results. DEGs were identified between AF and controls, which were enriched in neutrophil activation and regulation of actin cytoskeleton. RHOA, CCR2, CASP8, and SYNPO2L exhibited abnormal expression and methylation, which have been confirmed to be related to AF. PCDHA family genes had high methylation and low expression in AF. We constructed two AF-related coexpression modules. Single-nucleotide polymorphism (SNP) was the most common mutation type in AF, especially T > C . MUC4 was the most frequent mutation gene, followed by PHLDA1, AHNAK2, and MAML3. There was no statistical difference in expression of AHNAK2 and MAML3, for AF. PHLDA1 and MUC4 were confirmed to be abnormally expressed in AF. Conclusion. Our findings identified DEGs related to DNA methylation and mutation for AF, which may offer possible therapeutic targets and a new insight into the pathogenesis of AF from a multiomics perspective.

CDK5R1, GSE1, HSPG2 and WDFY3 as indirect epigenetic‐sensitive genes in atrial fibrillation

“…[22][23][24][25][26]28,29 Specifically, AF multiomic analysis on atrial tissues has provided novel into the molecular pathways implicated in the pathology. 4,32,50,51 However, the need of cardiac biopsies, has limited enthusiasm of this technology to a small subpopulation of AF including those with valvular heart disease or CHD, for whom surgical intervention is already warranted. To overcome this, a surrogate tissue source is warranted to provide an indirect epigenetic and/or transcriptional phenotyping to mirror the failing myocardium.…”

“…2,3 Genome-wide association studies and network analyses have identified specific loci and genes associated to AF concerning ion channels, transcription factors, fibrosis, extracellular matrix remodelling and contractile/structural proteins. [2][3][4][5][6] Furthermore, a large proportion of AF-associated genetic variants resides within noncoding regions, thus inferring that the genetic risk of AF occurs via regulatory mechanisms that culminate in atrial electrical and structural remodelling. 7,8 A mounting body of scientific evidence also supports the link between innate and adaptive immune responses and AF [9][10][11][12][13][14] ; nevertheless, the exact mechanisms whereby immunologic changes confer disease pathogenesis is still unknown.…”

“…29 In addition, in the myocardial tissue AF patients was found both an aberrant global DNA methylation 8,30 and specific epigenetic dysregulations in genes involved in inflammation, sodium and potassium ion transport, fibrosis, transcription regulation as well as in noncoding regions. 4,7,[30][31][32][33][34] Although preliminary studies of DNA isolated from blood confer some predictive efficacy in post-operative AF, 35 no evidence currently links circulatory and/or immunologic changes in the epigenome to AF.…”

“…AF is theorized to occur as the result of a complex interplay between genetic and environmental factors 2,3 . Genome‐wide association studies and network analyses have identified specific loci and genes associated to AF concerning ion channels, transcription factors, fibrosis, extracellular matrix remodelling and contractile/structural proteins 2–6 . Furthermore, a large proportion of AF‐associated genetic variants resides within noncoding regions, thus inferring that the genetic risk of AF occurs via regulatory mechanisms that culminate in atrial electrical and structural remodelling 7,8 …”

Analysis of the Potential Role of Key Genes in Atrial Fibrillation Based on Bioinformatics Approach

“…In a mouse study, the expression of chemokines or cytokines in CCR2 + macrophages increased after myocardial injury, indicating that monocytes are recruited to the injured sit [38] . A recent study found that CCR2 is a key gene associated with AF progression [39] . The high number of CCR2-positive monocytes/macrophages in the LAA of patients with progressive atrial remodeling in AF may suggest enhanced monocyte/macrophage in ltration.…”