A mechanistic framework for cardiometabolic and coronary artery diseases.
A mechanistic framework for cardiometabolic and coronary artery diseases.
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DOI：
10.1038/s44161-021-00009-1
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发表时间：
2022-01
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通讯作者：
Bjorkegren, Johan L M
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作者：
Koplev, Simon;Seldin, Marcus;Sukhavasi, Katyayani;Ermel, Raili;Pang, Shichao;Zeng, Lingyao;Bankier, Sean;Di Narzo, Antonio;Cheng, Haoxiang;Meda, Vamsidhar;Ma, Angela;Talukdar, Husain;Cohain, Ariella;Amadori, Letizia;Argmann, Carmen;Houten, Sander M;Franzen, Oscar;Mocci, Giuseppe;Meelu, Omar A;Ishikawa, Kiyotake;Whatling, Carl;Jain, Anamika;Jain, Rajeev Kumar;Gan, Li-Ming;Giannarelli, Chiara;Roussos, Panos;Hao, Ke;Schunkert, Heribert;Michoel, Tom;Ruusalepp, Arno;Schadt, Eric E;Kovacic, Jason C;Lusis, Aldon J;Bjorkegren, Johan L M
冠状动脉粥样硬化是遗传和外源性危险因素相互作用的结果，主要发生在代谢器官和动脉壁。在这里，我们表明，通过整合来自患有（n = 600）和没有（n = 250）冠状动脉疾病（CAD）的患者的遗传和临床数据与来自斯德哥尔摩-塔尔图动脉粥样硬化反向网络工程任务（STARNET）研究中7种疾病相关组织的RNA-seq数据，确定了224个基因调控共表达网络（GRN），解释>54%的CAD遗传性。在与CAD临床严重程度相关的89个跨组织GRN中，374个内分泌因子促进器官间相互作用，主要是沿着从脂肪组织到肝脏的轴（n = 152）。该轴在遗传多样的小鼠品系中独立复制，并通过注射重组形式的脂肪内分泌因子（EPDR 1，FCN 2，FSTL 3和LBP）显着改变小鼠的血脂和葡萄糖水平。总之，STARNET数据库和相关的GRN浏览器（http：starnet.mssm.edu）为探索心脏代谢疾病和CAD之间的分子相互作用提供了多器官框架。
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.