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Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
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(English)In: Article in journal (Refereed) Submitted
Abstract [en]

Background: Hundreds of loci have been robustly associated with circulating lipids, atherosclerosis and coronary artery disease; but for most loci the causal genes and mechanisms remain uncharacterized.

Methods: We developed a semi-automated experimental pipeline for systematic, quantitative, large-scale characterization of mechanisms, drugs and genes associated with dyslipidemia and atherosclerosis in a zebrafish model system. We validated our pipeline using a dietary (n>2000), drug treatment (n>1000), and genetic intervention (n=384).

Results: Our results show that five days of overfeeding and cholesterol supplementation had independent pro-atherogenic effects, which could be diminished by concomitant treatment with atorvastatin and ezetimibe. CRISPR-Cas9-induced mutations in orthologues of proof-of-concept genes resulted in higher LDL cholesterol levels (apoea), and more early stage atherosclerosis (apobb.1).

Conclusions: In summary, our pipeline facilitates systematic, in vivo characterization of drugs and candidate genes to increase our understanding of disease etiology, and can likely help identify novel targets for therapeutic intervention.

National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-378939OAI: oai:DiVA.org:uu-378939DiVA, id: diva2:1295141
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11
In thesis
1. Translating Cardiac and Cardiometabolic GWAS Using Zebrafish
Open this publication in new window or tab >>Translating Cardiac and Cardiometabolic GWAS Using Zebrafish
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Genome-wide association studies (GWAS) have identified thousands of loci associated with cardiac and cardiometabolic traits. However, the trait-associated variants usually do not clearly point to causal gene(s), mechanism(s) or tissue(s). Model systems that allow for a comprehensive and quick candidate gene screening are necessary, ideally in vivo. The overall objective of my thesis is to establish large-scale, imaged-based screens in zebrafish embryos and larvae to examine candidate genes for their effects on heart rate and rhythm, as well as on early-onset atherosclerosis and dyslipidemia.

In Study 1, I prioritized 18 candidate genes in eight loci identified in a meta-analysis of GWAS for heart rate variability. Some of these genes were already known to be involved in cardiac pacemaking, whereas others require functional characterization.

In Study 2, I established an experimental pipeline to examine genetic effects on cardiac rate and rhythm and used it to characterize orthologues of six human candidate genes for heart rate and rhythm. I confirmed known effects of rgs6 and hcn4, and established a role for KIAA1755 in HRV.

In Study 3, I contributed to large-scale experiments to establish the zebrafish as a model system for early-onset atherosclerosis and dyslipidemia. Overfeeding and cholesterol-supplementation of the diet were shown to propel independent pro-atherogenic effects. Atherosclerotic burden was alleviated using commonly prescribed drugs in humans. Lastly, the effects of proof-of-concept genes known to be involved in lipid metabolism were examined and showed higher LDLc (apoea) and early-onset atherosclerosis (apobb1).

In Study 4, I characterized genes in GWAS-identified loci for triglyceride levels for a role in lipid metabolism and early-stage atherosclerosis. I identified three previously unanticipated genes that influence triglyceride levels in zebrafish larvae. Several additional genes influence other cardiometabolic risk factors. Interestingly, two genes showed trends towards lower triglycerides levels (dock7 and lpar2a), with directionally opposite effects on vascular inflammation. This emphasizes that candidate genes need to be examined comprehensively to guide further mechanistic studies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 56
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1547
Keywords
GWAS, Zebrafish
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-378941 (URN)978-91-513-0590-5 (ISBN)
Public defence
2019-04-26, Humanistiska Teatern, Engelska Parken, Thunbergsv. 3H, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2019-04-02 Created: 2019-03-11 Last updated: 2019-05-07

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