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An integrative multiomic network model links lipid metabolism to glucose regulation in coronary artery disease

Author

Listed:
  • Ariella T. Cohain

    (Icahn School of Medicine at Mount Sinai)

  • William T. Barrington

    (University of California Los Angeles (UCLA))

  • Daniel M. Jordan

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Noam D. Beckmann

    (Icahn School of Medicine at Mount Sinai)

  • Carmen A. Argmann

    (Icahn School of Medicine at Mount Sinai)

  • Sander M. Houten

    (Icahn School of Medicine at Mount Sinai)

  • Alexander W. Charney

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Raili Ermel

    (Tartu University Hospital)

  • Katyayani Sukhavasi

    (Tartu University Hospital)

  • Oscar Franzen

    (Karolinska Institutet, Karolinska Universitetssjukhuset)

  • Simon Koplev

    (Icahn School of Medicine at Mount Sinai)

  • Carl Whatling

    (AstraZeneca)

  • Gillian M. Belbin

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Jialiang Yang

    (Icahn School of Medicine at Mount Sinai)

  • Ke Hao

    (Icahn School of Medicine at Mount Sinai)

  • Eimear E. Kenny

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Zhidong Tu

    (Icahn School of Medicine at Mount Sinai)

  • Jun Zhu

    (Icahn School of Medicine at Mount Sinai)

  • Li-Ming Gan

    (AstraZeneca)

  • Ron Do

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Chiara Giannarelli

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Jason C. Kovacic

    (Icahn School of Medicine at Mount Sinai)

  • Arno Ruusalepp

    (Tartu University Hospital)

  • Aldons J. Lusis

    (University of California Los Angeles (UCLA))

  • Johan L. M. Bjorkegren

    (Icahn School of Medicine at Mount Sinai
    Clinical Gene Networks AB)

  • Eric E. Schadt

    (Icahn School of Medicine at Mount Sinai
    Sema4)

Abstract

Elevated plasma cholesterol and type 2 diabetes (T2D) are associated with coronary artery disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while individuals with hypercholesterolemia have reduced T2D risk. We explore the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic, and clinical data, we identify a glucose and lipid determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impact lipid and glucose levels in inverse directions. Experimental inhibition of one of the GLD network master regulators, lanosterol synthase (LSS), in mice confirms the inverse relationships to glucose and lipid levels as predicted by our model and provides mechanistic insights.

Suggested Citation

  • Ariella T. Cohain & William T. Barrington & Daniel M. Jordan & Noam D. Beckmann & Carmen A. Argmann & Sander M. Houten & Alexander W. Charney & Raili Ermel & Katyayani Sukhavasi & Oscar Franzen & Simo, 2021. "An integrative multiomic network model links lipid metabolism to glucose regulation in coronary artery disease," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20750-8
    DOI: 10.1038/s41467-020-20750-8
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