Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation

Vad, Oliver Bundgaard; Paludan-Müller, Christian; Ahlberg, Gustav; Kalstø, Silje Madeleine; Ghouse, Jonas; Andreasen, Laura; Haunsø, Stig; Tveit, Arnljot; Sajadieh, Ahmad; Christophersen, Ingrid E.; Svendsen, Jesper Hastrup; Olesen, Morten S.

doi:10.3390/jcm9020372

Cited by 15 publications

(27 citation statements)

References 39 publications

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“…Recently, Vad et al identified six individuals with rare loss-of-function variants in three different DCM genes (DMD, PDLIM3, and FKTN), of which two variants were novel. These data suggest that rare loss-of-function variants in cytoskeletal genes previously associated with DCM may have a role in early-onset AF, perhaps through the development of an atrial cardiomyopathy [66].…”

Section: Cardiomyopathymentioning

confidence: 75%

Atrial fibrillation—a complex polygenetic disease

2020

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Atrial fibrillation (AF) is the most common type of arrhythmia. Epidemiological studies have documented a substantial genetic component. More than 160 genes have been associated with AF during the last decades. Some of these were discovered by classical linkage studies while the majority relies on functional studies or genome-wide association studies. In this review, we will evaluate the genetic basis of AF and the role of both common and rare genetic variants in AF. Rare variants in multiple ion-channel genes as well as gap junction and transcription factor genes have been associated with AF. More recently, a growing body of evidence has implicated structural genes with AF. An increased burden of atrial fibrosis in AF patients compared with non-AF patients has also been reported. These findings challenge our traditional understanding of AF being an electrical disease. We will focus on several quantitative landmark papers, which are transforming our understanding of AF by implicating atrial cardiomyopathies in the pathogenesis. This new AF research field may enable better diagnostics and treatment in the future.

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Section: Cardiomyopathymentioning

confidence: 75%

Atrial fibrillation—a complex polygenetic disease

2020

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“… Wang et al (2019) found that polymorphisms in PDLIM3 gene increased risk of idiopathic dilated cardiomyopathy. Other studies indicated PDLIM3 was also correlated to hypertrophic cardiomyopathy ( Lopes et al, 2015 ; Bagnall, Yeates & Semsarian, 2010 ), atrial fibrillation ( Vad et al, 2020 ), myofibrillar myopathy ( Williams et al, 2021 ), the prognosis of hepatocellular carcinoma ( Wu et al, 2021 ), early regional metastasis of tongue cancer ( Lee et al, 2021 ), muscle-invasive bladder urothelial carcinoma ( Feng et al, 2020 ) and medulloblastoma ( Shou et al, 2015 ). It is the first time that PDLIM3 has been linked to endometriosis.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatical analysis identifies PDLIM3 as a potential biomarker associated with immune infiltration in patients with endometriosis

Gan¹,

Sun²,

Sun³

2022

PeerJ

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Background Endometriosis is a chronic systemic disease, whose classic symptoms are pelvic pain and infertility. This disease seriously reduces the life quality of patients. The pathogenesis, recognition and treatment of endometriosis is still unclear, and cannot be over emphasized. The aim of our study was to investigate the potential biomarker of endometriosis for the mechanism and treatment. Methods Using GSE11691, GSE23339 and GSE5108 datasets, differentially expressed genes (DEGs) were identified between endometriosis and normal samples. The functions of DEGs were reflected by the analysis of gene ontology (GO), pathway enrichment and gene set enrichment analysis (GSEA). The LASSO regression model was performed to identify candidate biomarkers. The receiver operating characteristic curve (ROC) was used to evaluate discriminatory ability of candidate biomarkers. The predictive value of the markers in endometriosis were further validated in the GSE120103 dataset. Then, the expression level of biomarkers was detected by qRT-PCR and Western blot. Finally, the relationship between candidate biomarker expression and immune infiltration was estimated using CIBERSORT. Results A total of 42 genes were identified, which were mainly involved in cytokine–cytokine receptor interaction, systemic lupus erythematosus and chemokine signaling pathway. We confirmed PDLIM3 was a specific biomarker in endometriosis (AUC = 0.955) and validated in the GSE120103 dataset (AUC = 0.836). The mRNA and protein expression level of PDLIM3 in endometriosis tissue was significantly higher than normal. Immune cell infiltration analysis revealed that PDLIM3 was correlated with M2 macrophages, neutrophils, CD4+ memory resting T cells, gamma delta T cells, M1 Macrophages, resting mast cells, follicular helper T cells, activated NK cells, CD8+ T cells, regulatory T cells (Tregs), naive B cells, plasma cells and resting NK cells.

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“…This is also consistent with the results for expression of circulating microRNA profiles in post-stroke patients with early onset of PSD and for target genes of these miRNAs that were found to have been enriched with respect to MAPK-related signaling pathways (Zhang et al, 2016 ). Accumulating evidence has also indicated that genetic variation in 3′-UTR contributes to the etiology of human diseases (Latini et al, 2017 ; Wigner et al, 2019 ; Vad et al, 2020 ). In recent years, miRSNPs have been recognized as potential genetic risk factors that have been rapidly identified and investigated.…”

Section: Discussionmentioning

confidence: 99%

Network and Pathway-Based Integrated Analysis Identified a Novel “rs28457673–miR-15/16/195/424/497 Family–IGF1R–MAPK Signaling Pathway” Axis Associated With Post-stroke Depression

Wang

Zhu

et al. 2021

Front. Cell Dev. Biol.

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Single-nucleotide polymorphisms (SNPs) of microRNA (miRNA) (miRSNP) are SNPs located on miRNA genes or miRNA target sites, which have been supposed to be involved in the development of central nervous system diseases by interfering with miRNA-mediated regulatory functions. However, the association of miRSNP with post-stroke depression (PSD) has not been well-investigated. In this study, we collected 54 PSD risk genes via manual literature-mining and integrated PSD-related risk pathways based on multiple public databases. Furthermore, we systematically screened candidate functional miRSNPs for PSD and integrated a miRSNP-based PSD-associated pathway network, which included 99 miRNAs that target 12 PSD risk pathways. We also reviewed the association between three risk pathways and PSD pathogenetic mechanism thoroughly. Combining literature mining and network analysis, our results proposed an underlying mechanism of “miRSNP → miRNA → risk gene → pathway” axis effects on PSD pathogenesis, especially for rs28457673 (miR-15/16/195/424/497 family) → IGF1R → hsa04010 (MAPK signaling pathway). Our studies revealed a functional role in genetic modifier at the system level in the pathogenesis of PSD, which might provide further information for the miRSNP studies in PSD.

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Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation

Cited by 15 publications

References 39 publications

Atrial fibrillation—a complex polygenetic disease

Atrial fibrillation—a complex polygenetic disease

Bioinformatical analysis identifies PDLIM3 as a potential biomarker associated with immune infiltration in patients with endometriosis

Network and Pathway-Based Integrated Analysis Identified a Novel “rs28457673–miR-15/16/195/424/497 Family–IGF1R–MAPK Signaling Pathway” Axis Associated With Post-stroke Depression

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