RNA-seq-driven expression analysis to investigate cardiovascular disease genes with associated phenotypes among atrial fibrillation patients.
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ABSTRACT:
SUBMITTER: Berber A
PROVIDER: S-EPMC9309637 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
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RNA-seq-driven expression analysis to investigate cardiovascular disease genes with associated phenotypes among atrial fibrillation patients.
Berber Asude A Abdelhalim Habiba H Zeeshan Saman S Vadapalli Sreya S von Oehsen Barr B Yanamala Naveena N Sengupta Partho P Ahmed Zeeshan Z
Clinical and translational medicine 20220701 7
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Project description:BackgroundHeart failure (HF) is one of the most common complications of cardiovascular diseases (CVDs) and among the leading causes of death in the US. Many other CVDs can lead to increased mortality as well. Investigating the genetic epidemiology and susceptibility to CVDs is a central focus of cardiology and biomedical life sciences. Several studies have explored expression of key CVD genes specially in HF, yet new targets and biomarkers for early diagnosis are still missing to support personalized treatment. Lack of gender-specific cardiac biomarker thresholds in men and women may be the reason for CVD underdiagnosis in women, and potentially increased morbidity and mortality as a result, or conversely, an overdiagnosis in men. In this context, it is important to analyze the expression and enrichment of genes with associated phenotypes and disease-causing variants among high-risk CVD populations.MethodsWe performed RNA sequencing focusing on key CVD genes with a great number of genetic associations to HF. Peripheral blood samples were collected from a broad age range of adult male and female CVD patients. These patients were clinically diagnosed with CVDs and CMS/HCC HF, as well as including cardiomyopathy, hypertension, obesity, diabetes, asthma, high cholesterol, hernia, chronic kidney, joint pain, dizziness and giddiness, osteopenia of multiple sites, chest pain, osteoarthritis, and other diseases.ResultsWe report RNA-seq driven case-control study to analyze patterns of expression in genes and differentiating the pathways, which differ between healthy and diseased patients. Our in-depth gene expression and enrichment analysis of RNA-seq data from patients with mostly HF and other CVDs on differentially expressed genes and CVD annotated genes revealed 4,885 differentially expressed genes (DEGs) and regulation of 41 genes known for HF and 23 genes related to other CVDs, with 15 DEGs as significantly expressed including four genes already known (FLNA, CST3, LGALS3, and HBA1) for HF and CVDs with the enrichment of many pathways. Furthermore, gender and ethnic group specific analysis showed shared and unique genes between the genders, and among different races. Broadening the scope of the results in clinical settings, we have linked the CVD genes with ICD codes.ConclusionsMany pathways were found to be enriched, and gender-specific analysis showed shared and unique genes between the genders. Additional testing of these genes may lead to the development of new clinical tools to improve diagnosis and prognosis of CVD patients.
| S-EPMC8590246 | biostudies-literature
Project description:Long non-coding RNAs (lncRNAs) are an emerging class of RNA species that may play a critical regulatory role in gene expression. However, the association between lncRNAs and atrial fibrillation (AF) is still not fully understood. In this study, we used RNA sequencing data to identify and quantify the both protein coding genes (PCGs) and lncRNAs. The high enrichment of these up-regulated genes in biological functions concerning response to virus and inflammatory response suggested that chronic viral infection may lead to activated inflammatory pathways, thereby alter the electrophysiology, structure, and autonomic remodeling of the atria. In contrast, the downregulated GO terms were related to the response to saccharides. To identify key lncRNAs involved in AF, we predicted lncRNAs regulating expression of the adjacent PCGs, and characterized biological function of the dysregulated lncRNAs. We found that two lncRNAs, ETF1P2, and AP001053.11, could interact with protein-coding genes (PCGs), which were implicated in AF. In conclusion, we identified key PCGs and lncRNAs, which may be implicated in AF, which not only improves our understanding of the roles of lncRNAs in AF, but also provides potentially functional lncRNAs for AF researchers.
| S-EPMC6783610 | biostudies-literature
Project description:Atrial fibrillation (AF) and heart failure (HF) contribute to about 45% of all cardiovascular disease (CVD) deaths in the USA and around the globe. Due to the complex nature, progression, inherent genetic makeup, and heterogeneity of CVDs, personalized treatments are believed to be critical. To improve the deciphering of CVD mechanisms, we need to deeply investigate well-known and identify novel genes that are responsible for CVD development. With the advancements in sequencing technologies, genomic data have been generated at an unprecedented pace to foster translational research. Correct application of bioinformatics using genomic data holds the potential to reveal the genetic underpinnings of various health conditions. It can help in the identification of causal variants for AF, HF, and other CVDs by moving beyond the one-gene one-disease model through the integration of common and rare variant association, the expressed genome, and characterization of comorbidities and phenotypic traits derived from the clinical information. In this study, we examined and discussed variable genomic approaches investigating genes associated with AF, HF, and other CVDs. We collected, reviewed, and compared high-quality scientific literature published between 2009 and 2022 and accessible through PubMed/NCBI. While selecting relevant literature, we mainly focused on identifying genomic approaches involving the integration of genomic data; analysis of common and rare genetic variants; metadata and phenotypic details; and multi-ethnic studies including individuals from ethnic minorities, and European, Asian, and American ancestries. We found 190 genes associated with AF and 26 genes linked to HF. Seven genes had implications in both AF and HF, which are SYNPO2L, TTN, MTSS1, SCN5A, PITX2, KLHL3, and AGAP5. We listed our conclusion, which include detailed information about genes and SNPs associated with AF and HF.
| S-EPMC10239148 | biostudies-literature
Project description:BackgroundPrevious studies have suggested PITX2, KCNN3 and ZFHX3 as atrial fibrillation (AF) susceptibility genes. Single common genetic polymorphisms of those genes have been linked with AF phenotypes and rhythm outcome of AF catheter ablation although their mechanisms remain elusive. New gene-based association tests may help clarifying genotype-phenotype correlations. Therefore, we hypothesized that PITX2, KCNN3 and ZFHX3 associate with left atrial enlargement and persistent AF and subsequently with ablation outcome.Methods and resultsSamples from 660 patients with paroxysmal (n = 370) or persistent AF (n = 290) undergoing AF catheter ablation were genotyped for ~1,000,000 SNPs. Gene-based association was investigated using two different gene-based association tests (VEGAS, minSNP). Among the three candidate genes, only ZFHX3 associated with left atrial dilatation and AF recurrence after catheter ablation.ConclusionThis study suggests a contribution of ZFHX3 to AF remodeling and response to therapy. Future and larger studies are necessary to replicate and apply these findings with an emphasis on designing AF pathophysiology-based multi-locus risk scores.
| S-EPMC5381139 | biostudies-literature
Project description:To investigate the expression profiles of long non-coding RNAs (lncRNAs) in atrial fibrillation (AF), atrial tissues from 3 AF patients and 3 non-AF patients that were collected for lncRNA expression microarray analyses to explore the role of lncRNA in the pathogenesis of AF. Gene Ontology (GO) categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to identify the main functions of the differentially expressed genes and AF-related pathways. A total of 219 lncRNAs was found to be differentially expressed between AFs and controls. Among them, 156 were upregulated and 63 were downregulated. Eight out of 10 dysregulated lncRNAs such as uc001eqh.1 were validated by quantitative real-time PCR. GO categories, pathway analyses, and interaction network showed a consistent result that differentially expressed genes contribute to the pathogenesis of AF. In conclusion, the findings of our study provide a perspective on lncRNA in AF and the foundation for further study of the biological functions of lncRNAs in AF.
| S-EPMC4555738 | biostudies-literature
Project description:BackgroundMyocardial fibrosis is a key pathological feature of many cardiovascular diseases, leading to cardiac dysfunction. Transforming growth factor β1 (TGF-β1) induces the proliferation and activation of cardiac fibroblasts (CFs), key contributors to myocardial fibrosis. To explore the mechanism underlying myocardial fibrosis, we aimed to determine whether serine/threonine kinase 38 like (STK38L) contributes to the development of myocardial fibrosis by regulating the proliferation and activation of CFs triggered by TGF-β1.MethodsIn this study, atrial tissue samples from atrial fibrillation (AF) patients with features of myocardial fibrosis (a category of atrial cardiomyopathy) and sinus rhythm (SR) patients without myocardial fibrosis were collected for RNA sequencing (RNA-seq). The specific molecule STK38L was identified. Primary mouse CFs were activated with TGF-β1 and subsequently transfected with STK38L-small interfering RNA (siRNA). The effect of STK38L-siRNA on fibroblast activation and proliferation was assessed using scratch and Cell Counting Kit-8 (CCK-8) assays. Furthermore, a mouse model of myocardial fibrosis induced by continuous subcutaneous injection of isoprenaline (ISO) was established to assess STK38L expression levels. Molecular experiments confirmed the expression of STK38L in fibrotic atrial tissues, ventricular tissues of ISO mouse, and primary CFs of neonatal mice.ResultsWe identified 1,870 genes exhibiting differential expression in the RNA-seq data between the AF and SR groups. Masson's trichrome staining revealed increased fibrosis in the heart tissues of the AF group. Elevated levels of STK38L were observed in the atrial tissues of the AF group and in the TGF-β1-stimulated primary mouse CFs. In vitro, STK38L knockdown suppressed mouse CFs activation and proliferation. Additionally, in vivo experiments showed that elevated mRNA levels of STK38L, periostin (POSTN), and collagen type I alpha 1 chain (COL1A1) in ISO-treated mouse hearts correlated with greater myocardial fibrosis, suggesting that STK38L plays an important role in the development of fibrosis.ConclusionsThis study revealed a significant correlation between increased STK38L expression and AF characterized by atrial fibrosis as well as between STK38L expression and the TGF-β1-related induction of myocardial fibrosis. Additionally, STK38L knockdown was shown to suppress CFs activation and proliferation under TGF-β1 stimulation. These findings suggest an important role of STK38L in the development of fibrosis, and help screen for new strategies to treat this complex disease.
| S-EPMC11538834 | biostudies-literature
Project description:Arginine, homoarginine (hArg), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) affect nitric oxide metabolism and altered concentrations are associated with cardiovascular morbidity and mortality. We analyzed these metabolites using liquid chromatography-tandem mass spectrometry in patients with atrial fibrillation (AF) (n = 241) with a focus on heart rhythm at blood withdrawal, AF progression phenotypes, and successful sinus rhythm (SR) restoration (n = 22). AF progression phenotypes were defined as paroxysmal AF with/without low voltage areas (LVA) and persistent AF with/without LVA. While arginine, ADMA, and hArg were within reference limits for healthy controls, SDMA was higher in the AF cohort (0.57 ± 0.12 vs. 0.53 μmol/L (97.5th percentile in reference cohort)). SR restoration in AF patients resulted in normalization of SDMA concentrations (0.465 ± 0.082 vs. 0.570 ± 0.134 μmol/L at baseline, p < 0.001). Patients with AF at the time of blood sampling had significantly lower hArg (1.65 ± 0.51 vs. 1.85 ± 0.60 μmol/L, p = 0.006) and higher ADMA concentrations (0.526 ± 0.08 vs. 0.477 ± 0.08 μmol/L, p < 0.001) compared with AF patients in SR. hArg concentrations were lower in patients with advanced AF progression phenotypes (persistent AF with LVA (p = 0.046)) independent of heart rhythm at blood sampling. Summarizing, arginine metabolism imbalance is associated with AF in general and AF progression and may contribute to associated risk. KEY MESSAGES: • Heart rhythm at blood withdrawal affects ADMA and hArg level in AF patients. • SDMA is higher in AF patients. • SDMA levels normalize after sinus rhythm restoration. • hArg levels decrease in advanced AF progression phenotypes.
| S-EPMC8556202 | biostudies-literature
Project description:Background: ZFHX3, a gene that encodes a large transcription factor, is the second-most significantly associated locus with AF, but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the ZFHX3 locus and examine the impact of Zfhx3 loss on cardiac function in mice. Methods: CRISPR-Cas9 genome editing, chromatin immunoprecipitation, and luciferase assays in pluripotent stem cell-derived cardiomyocytes were used to identify causative genetic variation related to AF at the ZFHX3 locus. Cardiac function was assessed by echocardiography, MRI, electrophysiology studies, calcium imaging, and RNA sequencing in mice with heterozygous and homozygous cardiomyocyte-restricted Zfhx3 deletion (Zfhx3 Het and KO, respectively). Human cardiac single-nucleus ATAC-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by ZFHX3. Results: We found SNP rs12931021 modulates an enhancer regulating ZFHX3 expression, and the AF risk allele is associated with decreased ZFHX3 transcription. We observed a gene-dose response in AF susceptibility withZfhx3KO mice having higher incidence, frequency, and burden of AF thanZfhx3Het and WT mice, with alterations in conduction velocity, atrial action potential duration, calcium handling and the development of atrial enlargement and thrombus, and dilated cardiomyopathy. Zfhx3 loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF. Conclusions: Our findings implicate ZFHX3 as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac Zfhx3 are due to atrial-specific dysregulation of pathways involved in AF-susceptibility. Together, these data reveal a novel and important role for Zfhx3 in the control of cardiac genes and signaling pathways essential for normal atrial function.
2023-06-30 | GSE229525 | GEO
Project description:Understanding the interconnectedness of structural remodelling processes atrial fibrillation (AF) in patients could identify targets for future therapies. These data include transcriptome sequencing of atrial tissues of patients without AF, with paroxysmal AF and persistent AF (total n=64). In AF patients, epicardial cell gene expression decreased, contrasting with an upregulation of epithelial to mesenchymal transition (EMT) and mesenchymal cell gene expression. Immunohistochemistry demonstrated thickening of the epicardium and an increased proportion of (myo)fibroblast-like cells in the myocardium, supporting enhanced EMT in AF. We furthermore report an upregulation of endothelial cell proliferation, angiogenesis and endothelial signalling. EMT and endothelial cell proliferation concurred with increased interstitial (myo)fibroblast-like cells and extracellular matrix gene expression including enhanced tenascin-c, thrombospondins, biglycan and versican. Morphological analysis discovered increased and redistributed glycosaminoglycans and collagens in the atria of AF patients. Signalling pathways, including cell-matrix interactions, PI3K-AKT and Notch signalling, that could regulate mesenchymal cell activation, were upregulated. These dynamic processes may provide targets to prevent or reverse structural remodelling.
| EGAS00001005295 | EGA
Project description:BackgroundThis study assessed the associations of metabolic obesity phenotypes with the risk of atrial fibrillation (Afib).MethodsThis prospective cohort study categorized Taiwanese adults according to their body mass index (BMI) and metabolic health status at baseline. We assigned the participants to the underweight (BMI < 18.5 kg/m2), normal weight (BMI = 18.5-23.9 kg/m2), and overweight/obesity groups (BMI ≥ 24 kg/m2). Metabolically healthy was defined as absence of hypertension, diabetes, and hyperlipidemia and the presence of healthy metabolic profiles.ResultsIn total, 5,742 adults were included. During a median follow-up of 13.7 years, 148 patients developed Afib. Compared to the metabolically healthy normal weight group, the risk of Afib was significantly higher than those in the metabolically unhealthy overweight/obesity (hazard ratio = 2.20, 95% confidence interval [1.12-4.33]) and metabolically unhealthy normal weight groups (HR = 2.64, 95% CI [1.34-5.17]). Additionally, the point estimate suggested a 1.97-fold greater risk among the metabolically healthy overweight/obesity group, although this difference was not significant given the wide confidence interval (HR = 1.97, 95% CI [0.80-4.86]).ConclusionOur results demonstrated the relationships of metabolic health and weight regarding the risk of Afib in Taiwanese adults. The Afib risk among metabolic and obesity phenotypes is associated with a metabolically unhealthy status. A trend toward a higher Afib risk with obesity among metabolically healthy subjects was observed. However, the result was not robust and it still suggested further study.
| S-EPMC8557684 | biostudies-literature