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  • 1
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    Online Resource
    Genetic loci associated with heart rate variability and their effects on cardiac disease risk
    Springer Science and Business Media LLC ; 2017
    In:  Nature Communications Vol. 8, No. 1 ( 2017-06-14)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2017-06-14)
    Abstract: Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755 ), expression quantitative trait loci (eQTLs) (influencing GNG11 , RGS6 and NEO1 ), or are located in genes preferentially expressed in the sinoatrial node ( GNG11 , RGS6 and HCN4) . Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (−0.74 〈 r g 〈 −0.55) and blood pressure (−0.35 〈 r g 〈 −0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants ( GNG11 , RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/ncomms15805
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2553671-0
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  • 2
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    Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk
    Springer Science and Business Media LLC ; 2017
    In:  Nature Communications Vol. 8, No. 1 ( 2017-08-02)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2017-08-02)
    Abstract: Nature Communications 8: Article number: 15805 (2017); Published: 14 June 2017; Updated: 2 August 2017 In Supplementary Fig. 10 of this Article, images for panels a and b were inadvertently omitted. The correct version of Supplementary Fig. 10 is provided as Supplementary Information associated withthis Erratum.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/ncomms16140
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
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  • 3
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    Abstract 472: Identifying and Characterizing Causal Genes in GWAS-identified Loci for Triglyceride Levels Using High-throughput, Image-based Screens in Zebrafish Larvae
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 38, No. Suppl_1 ( 2018-05)
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    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 38, No. Suppl_1 ( 2018-05)
    Abstract: Background: High triglyceride levels are an established risk factor for coronary artery disease (CAD). Unpublished results from our proof-of-principle studies show that triglyceride-levels are also associated with atherosclerosis in zebrafish larvae. Identifying and characterizing causal genes for triglyceride levels may yield novel drug targets. In 2013, a meta-analysis of genome-wide association studies identified 37 previously unanticipated loci that are associated with triglyceride levels. We aim to characterize positional candidate genes in these loci using a zebrafish model system. Methods: We prioritized 37 candidate genes for functional-follow up. These genes together have 41 zebrafish orthologues, which were targeted in five lines of ~8 genes each using a multiplex CRISPR-Cas9 approach. Founder mutants have been raised and 384 offspring for two of the five lines have so far been screened for body size as well as fluorescently labeled lipids, macrophages and neutrophils in the vessel wall, using a high-throughput imaging set-up. Image quantification was performed using automated, custom-written pipelines in CellProfiler and ImageJ. Additionally, whole body lipid fractions and glucose levels were measured in each larva using enzymatic assays. CRISPR-induced mutations were quantified using paired-end sequencing and data were analyzed using hierarchical mixed models and (zero-inflated) negative binomial regression. Results: Each additional disrupted allele in pepd resulted in higher triglyceride levels (beta±SE 0.21±0.09 SD). Mutants for met have less vascular infiltration by macrophages (-0.31±0.13), and less co-localization of macrophages with lipids (-0.56±0.21) and neutrophils (-0.49±0.18). Mutants for lpar2 have lower LDLc (-0.54±0.27) and HDLc levels (-0.57±0.27), while gmip mutants have less vascular lipid deposition (-1.05±0.43), and less co-localizing lipids and neutrophils (-1.26±0.56). Conclusion: By characterizing candidate genes for triglyceride levels using a high-throughput, largely image-based approach in zebrafish larvae, we identified previously unanticipated genes that influence a range of cardiometabolic risk factors. This approach is anticipated to identify novel drug targets.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.38.suppl_1.472
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1494427-3
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  • 4
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    Translating GWAS-identified loci for cardiac rhythm and rate using an in vivo image- and CRISPR/Cas9-based approach
    Springer Science and Business Media LLC ; 2020
    In:  Scientific Reports Vol. 10, No. 1 ( 2020-07-16)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2020-07-16)
    Abstract: A 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 30 s 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 25 µM ivabradine—an open channel blocker of HCNs—for 24 h 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 ).
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-020-68567-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2615211-3
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  • 5
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    Abstract 441: Zebrafish Larvae as a Model System for High-throughput, Image-based Genetic Screens in Dyslipidemia and Atherosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 38, No. Suppl_1 ( 2018-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 38, No. Suppl_1 ( 2018-05)
    Abstract: Background: Genome-wide association (GWAS) have identified hundreds of loci that are robustly associated with the risk of cardiometabolic risk factors and diseases. With few exceptions, the causal genes through which these loci influence disease risk remain uncharacterized. Since murine model systems are not suitable for systematic characterization of candidate genes in hundreds of loci, novel in vivo model systems are desirable. Methods: My group has developed and validated zebrafish model systems that make optimal use of: 1) the zebrafish’ well-annotated genome, with orthologues of at least 71.4% of human genes; 2) recent developments in multiplex CRISPR-Cas9-based mutagenesis; 3) advances in automated positioning of non-embedded zebrafish larvae; 4) fluorescent transgenes and dyes; and 5) custom-written image-quantification pipelines. Results: Five days of overfeeding, dietary cholesterol supplementation and/or exposure to glucose induce atherogenic and insulin resistant phenotypes (higher/more whole-body LDL cholesterol (LDLc) and triglyceride levels; vascular foam cell formation and inflammation; beta-cell number and volume; subcutaneous and hepatic accumulation of fat) that can largely be prevented by concomitant treatment with lipid-lowering or diabetes medication (N 〉 4000). In line with recent results in humans, treatment with atorvastatin and ezetimibe results in higher whole-body glucose levels (N~835). Each additional mutated allele in zebrafish orthologues of APOE results in higher LDLc levels, while mutations in LDLR affect vascular infiltration by lipids and macrophages (N~330). Ongoing characterization of 37 prioritized genes in GWAS-identified loci for triglyceride levels identified genes that influence triglycerides, LDLc, and/or vascular inflammatory and atherogenic traits, while characterizing prioritized genes in loci associated with heart rate variability yielded genes that influence cardiac rate and rhythm. Conclusions: Systematic characterization of candidate genes for cardiometabolic traits in zebrafish model systems will help increase our understanding of human disease and identify novel targets that can be translated into efficient therapeutics.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.38.suppl_1.441
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
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  • 6
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    Real-world analysis of ruxolitinib in myelofibrosis: interim results focusing on patients who were naïve to JAK inhibitor therapy treated within the JAKoMo non-interventional, phase IV trial
    Springer Science and Business Media LLC ; 2023
    In:  Annals of Hematology
    Details
    In: Annals of Hematology, Springer Science and Business Media LLC
    Abstract: Ruxolitinib (RUX) is a Janus kinase 1/2 inhibitor (JAKi) approved in the EU for treating disease‑related splenomegaly or symptoms in adults patients with myelofibrosis (MF). This is an interim analysis of JAKoMo, a prospective, non‑interventional, phase IV study in MF. Between 2012–2019 (cutoff March 2021), 928 patients (JAKi-naïve and -pretreated) enrolled from 122 German centers. This analysis focuses on JAKi-naïve patients. RUX was administered according to the Summary of Product Characteristics. Compared to the COMFORT-I, -II, and JUMP trials, patients in JAKoMo were older (median 73 years), had poorer Eastern Cooperative Oncology Group (ECOG) performance statuses (16.5% had ECOG ≥ 2), and were more transfusion dependent (48.5%). JAKoMo represents the more challenging patients with MF encountered outside of interventional studies. However, patients with low-risk International Prognostic Scoring System (IPSS) scores or without palpable splenomegaly were also included. Following RUX treatment, 82.5% of patients experienced rapid (≤ 1 month), significant decreases in palpable spleen size, which remained durable for 24 months (60% patients). Symptom assessment scores improved significantly in Month 1 (median –5.2) up to Month 12 (–6.2). Common adverse events (AEs) were anemia (31.2%) and thrombocytopenia (28.6%). At cutoff, 54.3% of patients had terminated the study due to, death, AEs, or deterioration of health. No new safety signals were observed. Interim analysis of the JAKoMo study confirms RUX safety and efficacy in a representative cohort of real-world, elderly, JAKi-naïve patients with MF. Risk scores were used in less than half of the patients to initiate RUX treatment. Trial registration: NCT05044026; September 14, 2021.
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    URL: Article
    DOI: 10.1007/s00277-023-05458-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1458429-3
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