scholarly journals In vivo identification and validation of novel potential predictors for human cardiovascular diseases

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261572
Author(s):  
Omar T. Hammouda ◽  
Meng Yue Wu ◽  
Verena Kaul ◽  
Jakob Gierten ◽  
Thomas Thumberger ◽  
...  
Keyword(s):  
Heart Rate ◽  
Cardiovascular Diseases ◽  
Heart Function ◽  
Association Studies ◽  
Blind Spot ◽  
Genome Wide Association Studies ◽  
Rate Analysis ◽  
Heart Rate Analysis ◽  
Functional Analyses

Genetics crucially contributes to cardiovascular diseases (CVDs), the global leading cause of death. Since the majority of CVDs can be prevented by early intervention there is a high demand for the identification of predictive causative genes. While genome wide association studies (GWAS) correlate genes and CVDs after diagnosis and provide a valuable resource for such causative candidate genes, often preferentially those with previously known or suspected function are addressed further. To tackle the unaddressed blind spot of understudied genes, we particularly focused on the validation of human heart phenotype-associated GWAS candidates with little or no apparent connection to cardiac function. Building on the conservation of basic heart function and underlying genetics from fish to human we combined CRISPR/Cas9 genome editing of the orthologs of human GWAS candidates in isogenic medaka with automated high-throughput heart rate analysis. Our functional analyses of understudied human candidates uncovered a prominent fraction of heart rate associated genes from adult human patients impacting on the heart rate in embryonic medaka already in the injected generation. Following this pipeline, we identified 16 GWAS candidates with potential diagnostic and predictive power for human CVDs.

scholarly journals In vivo identification and validation of novel potential predictors for human cardiovascular diseases

2021 ◽  
Author(s):  
Omar T. Hammouda ◽  
Meng Yue Wu ◽  
Verena Kaul ◽  
Thomas Thumberger ◽  
Joachim Wittbrodt
Keyword(s):  
Heart Rate ◽  
Cardiovascular Diseases ◽  
Heart Function ◽  
Association Studies ◽  
Blind Spot ◽  
Genome Wide Association Studies ◽  
Rate Analysis ◽  
High Conservation ◽  
Heart Rate Analysis

AbstractGenetics crucially contributes to cardiovascular diseases (CVDs), the global leading cause of death. Since the majority of CVDs can be prevented by early intervention there is a high demand for predictive markers. While genome wide association studies (GWAS) correlate genes and CVDs after diagnosis and provide a valuable resource for such markers, preferentially those with pre-assigned function are addressed further. To tackle the unaddressed blind spot of understudied genes, we particularly focused on the validation of heart GWAS candidates with little or no apparent connection to cardiac function. Building on the high conservation of basic heart function and underlying genetics from fish to human we combined CRISPR/Cas9 genome editing of the orthologs of human GWAS candidates in isogenic medaka with automated high-throughput heart rate analysis. Our functional analyses of understudied human candidates uncovered a prominent fraction of heart rate associated genes from adult human patients displaying a heart rate effect in embryonic medaka already in the injected generation. Following this pipeline, we identified 16 GWAS candidates with potential diagnostic and predictive power for human CVDs.

scholarly journals Translating GWAS-identified loci for cardiac rhythm and rate using an in vivo image- and CRISPR/Cas9-based approach

2018 ◽  
Author(s):  
Benedikt von der Heyde ◽  
Anastasia Emmanouilidou ◽  
Eugenia Mazzaferro ◽  
Silvia Vicenzi ◽  
Ida Höijer ◽  
...  
Keyword(s):  
Heart Rate ◽  
Candidate Genes ◽  
Association Studies ◽  
Meta Analysis ◽  
Automated Analysis ◽  
Zebrafish Embryos ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractA meta-analysis of genome-wide association studies (GWAS) identified eight loci that are associated with heart rate variability (HRV), but candidate genes in these loci remain uncharacterized. We developed an image- and CRISPR/Cas9-based pipeline to systematically characterize candidate genes for HRV in live zebrafish embryos. Nine zebrafish orthologues of six human candidate genes were targeted simultaneously in eggs from fish that transgenically express GFP on smooth muscle cells (Tg[acta2:GFP]), to visualize the beating heart. An automated analysis of repeated 30s recordings of beating atria in 381 live, intact zebrafish embryos at 2 and 5 days post-fertilization highlighted genes that influence HRV (hcn4 and si:dkey-65j6.2 [KIAA1755]); heart rate (rgs6 and hcn4); and the risk of sinoatrial pauses and arrests (hcn4). Exposure to 10 or 25µM ivabradine – an open channel blocker of HCNs – for 24h resulted in a dose-dependent higher HRV and lower heart rate at 5 days post-fertilization. Hence, our screen confirmed the role of established genes for heart rate and rhythm (RGS6 and HCN4); showed that ivabradine reduces heart rate and increases HRV in zebrafish embryos, as it does in humans; and highlighted a novel gene that plays a role in HRV (KIAA1755).

Genetic Interactions Effects of Cardiovascular Disorder Using Computational Models: A Review

2020 ◽  
Vol 9 (3) ◽  
pp. 177-191
Author(s):  
Sridharan Priya ◽  
Radha K. Manavalan
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Cardiovascular Diseases ◽  
Computational Models ◽  
Genetic Interaction ◽  
Association Studies ◽  
Genetic Interactions ◽  
Computational Techniques ◽  
Genome Wide Association Studies ◽  
Artery Disease

Background: The diseases in the heart and blood vessels such as heart attack, Coronary Artery Disease, Myocardial Infarction (MI), High Blood Pressure, and Obesity, are generally referred to as Cardiovascular Diseases (CVD). The risk factors of CVD include gender, age, cholesterol/ LDL, family history, hypertension, smoking, and genetic and environmental factors. Genome- Wide Association Studies (GWAS) focus on identifying the genetic interactions and genetic architectures of CVD. Objective: Genetic interactions or Epistasis infer the interactions between two or more genes where one gene masks the traits of another gene and increases the susceptibility of CVD. To identify the Epistasis relationship through biological or laboratory methods needs an enormous workforce and more cost. Hence, this paper presents the review of various statistical and Machine learning approaches so far proposed to detect genetic interaction effects for the identification of various Cardiovascular diseases such as Coronary Artery Disease (CAD), MI, Hypertension, HDL and Lipid phenotypes data, and Body Mass Index dataset. Conclusion: This study reveals that various computational models identified the candidate genes such as AGT, PAI-1, ACE, PTPN22, MTHR, FAM107B, ZNF107, PON1, PON2, GTF2E1, ADGRB3, and FTO, which play a major role in genetic interactions for the causes of CVDs. The benefits, limitations, and issues of the various computational techniques for the evolution of epistasis responsible for cardiovascular diseases are exhibited.

scholarly journals Fetal Heart Rate Analysis for Automatic Detection of Perinatal Hypoxia Using Normalized Compression Distance and Machine Learning

2017 ◽  
Vol 8 ◽  
Author(s):  
Óscar Barquero-Pérez ◽  
Ricardo Santiago-Mozos ◽  
José M. Lillo-Castellano ◽  
Beatriz García-Viruete ◽  
Rebeca Goya-Esteban ◽  
...  
Keyword(s):  
Machine Learning ◽  
Heart Rate ◽  
Fetal Heart Rate ◽  
Fetal Heart ◽  
Automatic Detection ◽  
Perinatal Hypoxia ◽  
Rate Analysis ◽  
Normalized Compression Distance ◽  
Heart Rate Analysis

A Variant Noncoding Region Regulates Prrx1 and Predisposes to Atrial Arrhythmias

2021 ◽  
Author(s):  
Fernanda M Bosada ◽  
Mathilde R Rivaud ◽  
Jae-Sun Uhm ◽  
Sander Verheule ◽  
Karel van Duijvenboden ◽  
...  
Keyword(s):  
Sodium Current ◽  
Association Studies ◽  
Noncoding Region ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Enhancer Activity ◽  
Atrial Cardiomyocytes ◽  
The Impact ◽  
Lineage Specific Gene

Rationale: Atrial Fibrillation (AF) is the most common cardiac arrhythmia diagnosed in clinical practice. Genome-wide association studies have identified AF-associated common variants across 100+ genomic loci, but the mechanism underlying the impact of these variant loci on AF susceptibility in vivo has remained largely undefined. One such variant region, highly associated with AF, is found at 1q24, close to PRRX1, encoding the Paired Related Homeobox 1 transcription factor. Objective: To identify the mechanistic link between the variant region at 1q24 and AF predisposition. Methods and Results: The mouse orthologue of the noncoding variant genomic region (R1A) at 1q24 was deleted using CRISPR genome editing. Among the genes sharing the topologically associated domain with the deleted R1A region (Kifap3, Prrx1, Fmo2, Prrc2c), only the broadly expressed gene Prrx1 was downregulated in mutants, and only in cardiomyocytes. Expression and epigenetic profiling revealed that a cardiomyocyte lineage-specific gene program (Mhrt, Myh6, Rbm20, Tnnt2, Ttn, Ckm) was upregulated in R1A-/- atrial cardiomyocytes, and that Mef2 binding motifs were significantly enriched at differentially accessible chromatin sites. Consistently, Prrx1 suppressed Mef2-activated enhancer activity in HL-1 cells. Mice heterozygous or homozygous for the R1A deletion were susceptible to atrial arrhythmia induction, had atrial conduction slowing and more irregular RR intervals. Isolated R1A-/- mouse left atrial cardiomyocytes showed lower action potential upstroke velocities and sodium current, as well as increased systolic and diastolic calcium concentrations compared to controls. Conclusions: The noncoding AF variant region at 1q24 modulates Prrx1 expression in cardiomyocytes. Cardiomyocyte-specific reduction of Prrx1 expression upon deletion of the noncoding region leads to a profound induction of a cardiac lineage-specific gene program and to propensity for AF. These data indicate that AF-associated variants in humans may exert AF predisposition through reduced PRRX1 expression in cardiomyocytes.

scholarly journals Movement-induced heart rate changes in epileptic and non-epileptic seizures

2009 ◽  
Vol 67 (3b) ◽  
pp. 789-791 ◽  
Author(s):  
Gisele R. de Oliveira ◽  
Francisco de A.A. Gondim ◽  
Edward R. Hogan ◽  
Francisco H. Rola
Keyword(s):  
Heart Rate ◽  
Motor Activity ◽  
Rate Increase ◽  
Epileptic Seizures ◽  
Baseline Heart Rate ◽  
Heart Rate Increase ◽  
Event Duration ◽  
Rate Analysis ◽  
Heart Rate Analysis ◽  
Video Eeg

Heart rate changes are common in epileptic and non-epileptic seizures. Previous studies have not adequately assessed the contribution of motor activity on these changes nor have evaluated them during prolonged monitoring. We retrospectively evaluated 143 seizures and auras from 76 patients admitted for video EEG monitoring. The events were classified according to the degree of ictal motor activity (severe, moderate and mild/absent) in: severe epileptic (SE, N=17), severe non-epileptic (SNE, N=6), moderate epileptic (ME, N=28), moderate non-epileptic (MNE, N=11), mild epileptic (mE, N=35), mild non-epileptic (mNE, N=33) and mild aura (aura, N=13). Heart rate increased in the ictal period in severe epileptic, severe non-epileptic, moderate epileptic and mild epileptic events (p<0.05). Heart rate returned to baseline levels during the post ictal phase in severe non-epileptic seizures but not in severe epileptic patients. Aura events had a higher baseline heart rate. A cut-off of 20% heart rate increase may distinguish moderate epileptic and mild epileptic events lasting more than 30 seconds. In epileptic seizures with mild/absent motor activity, the magnitude of heart rate increase is proportional to the event duration. Heart rate analysis in seizures with different degrees of movement during the ictal phase can help to distinguish epileptic from non-epileptic events.

scholarly journals Combined knockout of Lrrk2 and Rab29 does not result in behavioral abnormalities in vivo

2020 ◽  
Author(s):  
Melissa Conti Mazza ◽  
Victoria Nguyen ◽  
Alexandra Beilina ◽  
Jinhui Ding ◽  
Mark R. Cookson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Association Studies ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Genome Wide Association Studies ◽  
Double Knockout ◽  
Knockout Mouse Model

AbstractCoding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson’s disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, leading to the suggestion that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, here we generated a double knockout mouse model and determined whether there are any consequences on brain function with aging. From a battery of motor and non-motor behavioral tests, we noted only that 18-24 month Rab29-/- and double (Lrrk2-/-/Rab29-/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in number of substantia nigra pars compacta (SNc) dopamine neurons or in tyrosine hydroxylase levels in the SNc and striatum, which might reflect a PD-like pathology. These results suggest that depletion of both Lrrk2 and Rab29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans.Significance statementGenetic variation in LRRK2 that result in elevated kinase activity can cause Parkinson’s disease (PD), suggesting LRRK2 inhibition as a therapeutic strategy. RAB29, a substrate of LRRK2, has also been associated with increased PD risk. Evidence exists for an interactive relationship between LRRK2 and RAB29. Mouse models lacking either LRRK2 or RAB29 do not show brain pathologies. We hypothesized that the loss of both targets would result in additive effects across in vivo and post-mortem assessments in aging mice. We found that loss of both LRRK2 and RAB29 did not result in significant behavioral deficits or dopamine neuron loss. This evidence suggests that chronic inhibition of this pathway should be tolerated clinically.

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