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Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosis

View ORCID ProfileManoj K Bandaru, Anastasia Emmanouilidou, Petter Ranefall, View ORCID ProfileBenedikt von der Heyde, Eugenia Mazzaferro, Tiffany Klingström, Mauro Masiero, Olga Dethlefsen, Johan Ledin, Anders Larsson, Hannah L Brooke, Carolina Wählby, Erik Ingelsson, View ORCID ProfileMarcel den Hoed
doi: https://doi.org/10.1101/502674
Manoj K Bandaru
1The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
2Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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  • ORCID record for Manoj K Bandaru
Anastasia Emmanouilidou
1The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
2Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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Petter Ranefall
3Science for Life Laboratory - BioImage Informatics Facility, Uppsala, Sweden
4Department of Information Technology, Division of Visual Information and Interaction, Uppsala University, Uppsala, Sweden
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Benedikt von der Heyde
1The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
2Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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Eugenia Mazzaferro
1The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
2Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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Tiffany Klingström
1The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
2Science for Life Laboratory, Uppsala University, Uppsala, Sweden
5Science for Life Laboratory - Genome Engineering Zebrafish National Facility, Uppsala University, Uppsala, Sweden
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Mauro Masiero
1The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
2Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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Olga Dethlefsen
6Science for Life Laboratory - National Bioinformatics Infrastructure Sweden, Stockholm University, Stockholm, Sweden
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Johan Ledin
5Science for Life Laboratory - Genome Engineering Zebrafish National Facility, Uppsala University, Uppsala, Sweden
7Department of Organismal Biology, Evolutionary and Developmental Biology, Uppsala University, Uppsala, Sweden
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Anders Larsson
8Department of Medical Sciences, Biochemical structure and function, Uppsala University, Uppsala, Sweden
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Hannah L Brooke
9Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
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Carolina Wählby
3Science for Life Laboratory - BioImage Informatics Facility, Uppsala, Sweden
4Department of Information Technology, Division of Visual Information and Interaction, Uppsala University, Uppsala, Sweden
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Erik Ingelsson
10Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
11Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, Sweden
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Marcel den Hoed
1The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
2Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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  • ORCID record for Marcel den Hoed
  • For correspondence: marcel.den_hoed@igp.uu.se
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Abstract

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), and used it to characterize three candidate genes in a GWAS-identified pleiotropic locus on chr 19p13.11 (n>500).

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). Finally, our pipeline helped identify putative causal genes for circulating lipids and early-stage atherosclerosis (LPAR2 and GATAD2A).

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.

Footnotes

  • Introduction updated; Discussion revised;

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 11, 2019.
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Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosis
Manoj K Bandaru, Anastasia Emmanouilidou, Petter Ranefall, Benedikt von der Heyde, Eugenia Mazzaferro, Tiffany Klingström, Mauro Masiero, Olga Dethlefsen, Johan Ledin, Anders Larsson, Hannah L Brooke, Carolina Wählby, Erik Ingelsson, Marcel den Hoed
bioRxiv 502674; doi: https://doi.org/10.1101/502674
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Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosis
Manoj K Bandaru, Anastasia Emmanouilidou, Petter Ranefall, Benedikt von der Heyde, Eugenia Mazzaferro, Tiffany Klingström, Mauro Masiero, Olga Dethlefsen, Johan Ledin, Anders Larsson, Hannah L Brooke, Carolina Wählby, Erik Ingelsson, Marcel den Hoed
bioRxiv 502674; doi: https://doi.org/10.1101/502674

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