A mechanistic framework for cardiometabolic and coronary artery diseases

Koplev, Simon and Seldin, Marcus and Sukhavasi, Katyayani and Ermel, Raili and Pang, Shichao and Zeng, Lingyao and Bankier, Sean and Di Narzo, Antonio and Cheng, Haoxiang and Meda, Vamsidhar and Ma, Angela and Talukdar, Husain and Cohain, Ariella and Amadori, Letizia and Argmann, Carmen and Houten, Sander M. and Franzén, Oscar and Mocci, Giuseppe and Meelu, Omar A. and Ishikawa, Kiyotake and Whatling, Carl and Jain, Anamika and Jain, Rajeev Kumar and Gan, Li-Ming and Giannarelli, Chiara and Roussos, Panos and Hao, Ke and Schunkert, Heribert and Michoel, Tom and Ruusalepp, Arno and Schadt, Eric E. and Kovacic, Jason C. and Lusis, Aldon J. and Björkegren, Johan L. M. (2022) A mechanistic framework for cardiometabolic and coronary artery diseases. Nature Cardiovascular Research, 1 (1). pp.85-100. ISSN 2731-0590

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Link to published document: http://doi.org/10.1038/s44161-021-00009-1


Coronary atherosclerosis results from the delicate interplay of genetic and exogenous risk factors, principally taking place in metabolic organs and the arterial wall. Here we show that 224 gene-regulatory coexpression networks (GRNs) identified by integrating genetic and clinical data from patients with (n = 600) and without (n = 250) coronary artery disease (CAD) with RNA-seq data from seven disease-relevant tissues in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study largely capture this delicate interplay, explaining >54% of CAD heritability. Within 89 cross-tissue GRNs associated with clinical severity of CAD, 374 endocrine factors facilitated inter-organ interactions, primarily along an axis from adipose tissue to the liver (n = 152). This axis was independently replicated in genetically diverse mouse strains and by injection of recombinant forms of adipose endocrine factors (EPDR1, FCN2, FSTL3 and LBP) that markedly altered blood lipid and glucose levels in mice. Altogether, the STARNET database and the associated GRN browser (http://starnet.mssm.edu) provide a multiorgan framework for exploration of the molecular interplay between cardiometabolic disorders and CAD.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 03 Mar 2023 04:31
Last Modified: 03 Mar 2023 04:31
URI: http://eprints.victorchang.edu.au/id/eprint/1338

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