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

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, Simon Koplev, Carl Whatling, Gillian M. Belbin, Jialiang Yang, Ke Hao, Eimear E. Kenny, Zhidong Tu, Jun Zhu, Li-Ming Gan, Ron Do, Chiara Giannarelli, Jason C. Kovacic, Arno Ruusalepp, Aldons J. Lusis, Johan L. M. Bjorkegren () and Eric E. Schadt ()
Additional contact information
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
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
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
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
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
Chiara Giannarelli: 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
Eric E. Schadt: Icahn School of Medicine at Mount Sinai

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20750-8

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DOI: 10.1038/s41467-020-20750-8

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