Early onset lone atrial fibrillation case-control study
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ABSTRACT:
PROVIDER: EGAS00001003208 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Target sequencing W/ TruSight Cardio Sequencing Kit. 395 early onset lone AF cases and 375 controls. Sequencing was performed on Illumina NextSeq and HiSeq 2500 systems.
| EGAD00001004330 | EGA
Project description:Atrial fibrillation (AF) is a common arrhythmia with a complex genetic basis, yet the molecular mechanisms linking rare and common variants remain unclear. Using induced pluripotent stem cell-derived atrial cardiomyocytes, we uncover a novel mechanism by which a rare pathogenic LMNA variant encoding Lamin A/C disrupts chromatin accessibility and gene regulation at AF-associated loci. Specifically, reduced accessibility at an SCN5A enhancer harboring an AF-associated variant leads to reduced sodium current, conduction abnormalities, and re-entrant AF. These electrophysiological defects are rescued by CRISPR-mediated activation of the SCN5A promoter and enhancer providing the first molecular evidence of epistatic gene-gene interactions driving arrhythmia risk and mechanistically linking atrial myopathy and AF. At the population level, we demonstrate carriers of LMNA proteinaltering variants with a high polygenic risk score are at two-fold increased risk of earlyonset AF, highlighting the need to integrate rare and common variants for more accurate AF risk assessment.
2026-04-10 | GSE294948 | GEO
Project description:Atrial fibrillation (AF) is a common arrhythmia with a complex genetic basis, yet the molecular mechanisms linking rare and common variants remain unclear. Using induced pluripotent stem cell-derived atrial cardiomyocytes, we uncover a novel mechanism by which a rare pathogenic LMNA variant encoding Lamin A/C disrupts chromatin accessibility and gene regulation at AF-associated loci. Specifically, reduced accessibility at an SCN5A enhancer harboring an AF-associated variant leads to reduced sodium current, conduction abnormalities, and re-entrant AF. These electrophysiological defects are rescued by CRISPR-mediated activation of the SCN5A promoter and enhancer providing the first molecular evidence of epistatic gene-gene interactions driving arrhythmia risk and mechanistically linking atrial myopathy and AF. At the population level, we demonstrate carriers of LMNA proteinaltering variants with a high polygenic risk score are at two-fold increased risk of earlyonset AF, highlighting the need to integrate rare and common variants for more accurate AF risk assessment.
2026-04-10 | GSE295056 | GEO
Project description:Atrial fibrillation (AF) is a progressive arrhythmia for which current therapy is inadequate. During AF, rapid stimulation causes atrial remodeling that promotes further AF. The cellular signals that trigger this process remain poorly understood, however, and elucidation of these factors would likely identify new therapeutic targets. We have previously shown that immortalized mouse atrial (HL-1) myocytes subjected to 24 hr of rapid stimulation in culture undergo remodeling similar to that seen in animal models of atrial tachycardia (AT) and human AF. This preparation is devoid of confounding in vivo variables that can modulate gene expression (e.g., hemodynamics). Therefore, we investigated the transcriptional profile associated with early atrial cell remodeling. RNA was harvested from HL-1 cells cultured for 24 hr in the absence and presence of rapid stimulation and subjected to microarray analysis. Data were normalized using Robust Multichip Analysis (RMA), and genes exhibiting significant differential expression were identified using the Significance Analysis of Microarrays (SAM) method. Using this approach, 919 genes were identified that were significantly altered with rapid stimulation (763 up-regulated and 156 down-regulated). For many individual transcripts, changes typical of AF/AT were observed, with marked up-regulation of genes encoding BNP and ANP precursors, heat shock proteins, and MAP kinases, while novel signaling pathways and molecules were also identified. Both stress and survival response were evident, as well as up-regulation of multiple transcription factors. Genes were also functionally classified based on cellular component, biologic process, and molecular function using the Gene Ontology database to permit direct comparison of our data with other gene sets regulated in human AF and experimental AT. For broad categories of genes grouped by functional classification, there was striking conservation between rapidly stimulated HL-1 cells and AF/AT. Results were confirmed using real-time quantitative RT-PCR on 13 genes selected by physiological relevance in AF/AT and regulation in the microarray analysis (up, down, and nonregulated). Rapidly-stimulated atrial myocytes provide a complementary experimental paradigm to explore the initial cellular signals in AT remodeling to identify novel targets in the treatment of AF. Experiment Overall Design: HL-1 cell expression profile in vitro with and without rapid electric stimulation
2008-10-26 | E-GEOD-10598 | biostudies-arrayexpress
Project description:Atrial fibrillation (AF) is the most common sustained arrhythmia with increased risk of stroke and congestive heart failure. AF is a highly genetic heterogeneous disease, but a large proportion of AF cannot be explained by genetic variants only. Some risk factors of AF, tendentious heritable phenomenon, potentially reversible conditions and some subtypes without DNA sequence variation all indicate the participation of DNA methylation in the pathogenesis of AF. Bisulphite converted DNA from the 11 left atrium samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip GPL13534
2014-10-28 | E-GEOD-62727 | biostudies-arrayexpress
Project description:Atrial fibrillation (AF) is a progressive arrhythmia for which current therapy is inadequate. During AF, rapid stimulation causes atrial remodeling that promotes further AF. The cellular signals that trigger this process remain poorly understood, however, and elucidation of these factors would likely identify new therapeutic targets. We have previously shown that immortalized mouse atrial (HL-1) myocytes subjected to 24 hr of rapid stimulation in culture undergo remodeling similar to that seen in animal models of atrial tachycardia (AT) and human AF. This preparation is devoid of confounding in vivo variables that can modulate gene expression (e.g., hemodynamics). Therefore, we investigated the transcriptional profile associated with early atrial cell remodeling. RNA was harvested from HL-1 cells cultured for 24 hr in the absence and presence of rapid stimulation and subjected to microarray analysis. Data were normalized using Robust Multichip Analysis (RMA), and genes exhibiting significant differential expression were identified using the Significance Analysis of Microarrays (SAM) method. Using this approach, 919 genes were identified that were significantly altered with rapid stimulation (763 up-regulated and 156 down-regulated). For many individual transcripts, changes typical of AF/AT were observed, with marked up-regulation of genes encoding BNP and ANP precursors, heat shock proteins, and MAP kinases, while novel signaling pathways and molecules were also identified. Both stress and survival response were evident, as well as up-regulation of multiple transcription factors. Genes were also functionally classified based on cellular component, biologic process, and molecular function using the Gene Ontology database to permit direct comparison of our data with other gene sets regulated in human AF and experimental AT. For broad categories of genes grouped by functional classification, there was striking conservation between rapidly stimulated HL-1 cells and AF/AT. Results were confirmed using real-time quantitative RT-PCR on 13 genes selected by physiological relevance in AF/AT and regulation in the microarray analysis (up, down, and nonregulated). Rapidly-stimulated atrial myocytes provide a complementary experimental paradigm to explore the initial cellular signals in AT remodeling to identify novel targets in the treatment of AF. Keywords: stimulated atrial myocytes human atrial fibrillation
2008-10-01 | GSE10598 | GEO
Project description:Background: Horses and humans are among the few mammals prone to developing spontaneous atrial fibrillation (AF), both suffering from high recurrence rates after treatment. Treatment resistance is often attributed to functional, structural, and metabolic remodeling of the atria. The aim of this explorative study was to evaluate the molecular pathways associated with early stages of AF in horses and to compare the AF proteomes between horses and humans. Methods: We performed data-independent acquisition mass spectrometry on myocardial biopsies collected from the right atrium (RA), left atrium (LA), and left ventricular chamber (LV) in horses with early stages of naturally occurring persistent AF and controls (n=8 in each group). Results: We identified a total of 3400 quantifiable proteins, several of which were differentially regulated between AF horses and controls (268 in RA, 324 in LA, and 284 in LV, p<0.05). Pathway enrichment analyses identified changes in metabolic, contractile, and extracellular matrix (ECM) proteins. Atrial hypocontractility and ECM remodeling were confirmed by echocardiography and histology, respectively. Key proteomic changes in horses with AF overlapped with human AF public datasets, underscoring the translational relevance of the equine AF model. Particularly, contractile proteins, such as cardiac troponins (TNNT2), myosin (MYH6) and tropomyosin (TPM2), along with metabolic regulators as heat shock protein family A (HSPA4) and Proteasome 26S Subunit, Non-ATPase 13 (PSMD13) were shared between horses and humans with AF. Moreover, a significant increase in several ECM glycoproteins was detected in both species, highlighting the importance of early ECM remodeling that extends beyond the fibrotic changes often associated with AF. Conclusion: The horse and human cardiac proteome share similar AF-related changes. Metabolic, functional, and structural protein changes identified in early-stage AF may provide clues to pharmacological targets for preventing AF-associated atrial remodeling and improving treatment success across species.
2025-05-28 | PXD052818 | Pride
Project description:Background: Horses are one of the few animals that spontaneously develop atrial fibrillation (AF), making them a powerful model for studying AF mechanisms and treatment effects. Despite the initial effectiveness of treatment in both horses and humans, AF-induced atrial remodelling compromises long-term success. Observational studies have suggested that metformin reduces the risk of AF, but its effects on progressive AF-induced atrial remodelling have not yet been evaluated in a high-fidelity large animal model. Methods: Here, we employed a longitudinal horse model of tachypacing-induced self-sustained AF to characterize the electrical, molecular, and metabolic atrial changes over four months of disease, with and without metformin treatment. Electrophysiological and multi-omic approaches were combined with histology, echocardiography, biochemical and mitochondrial analyses to evaluate disease progression and treatment response. Results: The horse model replicated critical aspects of AF-induced atrial remodelling observed in humans, including electrical and structural changes. Despite upregulation of metabolic genes and proteins in AF, no significant ultrastructural mitochondrial changes were detected. Metformin-treated horses were less susceptible to AF and sustained a less complex AF substrate in the right atrium after four months of disease. These effects were associated with increased activity of the metabolic regulator, AMP-activated kinase (AMPK) , changes in metabolic pathways and modulation of ion-channel gene expression. Metformin did not appear to alter left atrial substrate remodelling. Conclusion: Metformin treatment conferred electrical protection in both the early and later stages of AF in a translationally relevant preclinical model. These findings support metformin as a lead molecul ar for AF-prevention, warranting further mechanistic and clinical studies.
2025-12-03 | PXD059963 | Pride
Project description:Atrial fibrillation (AF) is a cardiometabolic disease with obesity and diabetes as major risk factors. The cellular and molecular mechanisms by which obesity and metabolic stressors drive AF are poorly understood. Here we establish a new mouse model of spontaneous, obesity-induced AF. This two-hit model relies on genetic susceptibility coupled with an environmental factor of diet-induced obesity. Unbiased multi-omics analyses reveal cardiac conduction pathways, inflammation, and metabolic perturbations in AF. We demonstrate atrial NAD+ deficiency as a central pathological mediator in AF. Pharmacological replenishment of atrial NAD+ levels mitigates AF, protects against cardiac remodeling and fibrosis, reduces inflammation, and improves atrial metabolism. These results highlight the role of a metabolic pathway that could be therapeutically targeted for AF.
2026-06-24 | GSE334551 | GEO
Project description:Atrial fibrillation (AF) is the most frequent persistent arrhythmia, and many genes have been reported as a causal gene candidate for AF. However, most transcriptome analyses of AF have limited to the atrial samples and have not evaluated by multiple cardiac regions. In this study, we analyzed the expression levels of protein-coding and long noncoding RNAs (lncRNAs) in six different cardiac regions by RNA-seq. Surprisingly, the most changed region in gene expression by the presence of AF was the pulmonary vein (PV), not the atria. Upon analysis of these significant genes, the ion channel-related gene set was significantly enriched. In addition, cancer-related lncRNAs was up-regulated in PV in AF. A Co-expression network analysis could detect the functional gene clusters. In particular, the functional coupling between the lncRNA FOXCUT and transcription factor FOXC1 are known to be involved in process of the epithelial-mesenchymal transition in cancer tissues. Thus, they may also play an aggravating role in the pathogenesis of AF. In the least, this study suggests that (1) RNA alteration is most intense in PVs and (2) post-acquired gene regulation, such as the FOXCUT-FOXC1 axis, may contribute to the progression of AF.
2023-04-30 | GSE226282 | GEO