An integrative multiomic network model links lipid metabolism to glucose regulation in coronary artery disease.
An integrative multiomic network model links lipid metabolism to glucose regulation in coronary artery disease.
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DOI：
10.1038/s41467-020-20750-8
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发表时间：
2021-01-22
影响因子：
16.6
通讯作者：
Schadt EE
中科院分区：
文献类型：
--
作者：
Cohain AT;Barrington WT;Jordan DM;Beckmann ND;Argmann CA;Houten SM;Charney AW;Ermel R;Sukhavasi K;Franzen O;Koplev S;Whatling C;Belbin GM;Yang J;Hao K;Kenny EE;Tu Z;Zhu J;Gan LM;Do R;Giannarelli C;Kovacic JC;Ruusalepp A;Lusis AJ;Bjorkegren JLM;Schadt EE
血浆胆固醇升高和2型糖尿病（T2D）与冠状动脉疾病（CAD）相关。接受降胆固醇他汀类药物治疗的个体T2D风险增加，而高胆固醇血症个体T2D风险降低。我们通过STARNET研究构建网络模型，利用冠状动脉旁路移植术期间从CAD患者获得的7个心脏代谢组织的测序数据，探索血脂和血糖控制之间的关系。通过整合基因表达，基因型，代谢组学和临床数据，我们确定了一个葡萄糖和脂质决定（GLD）的调控网络与脂质和葡萄糖性状呈反比关系。GLD网络的主调节因子也以相反的方向影响脂质和葡萄糖水平。在小鼠中对GLD网络主调节因子之一羊毛甾醇合酶（LSS）的实验抑制证实了我们的模型所预测的与葡萄糖和脂质水平的反比关系，并提供了机制见解。一些降胆固醇药物会增加2型糖尿病的风险，但其背后的机制尚未完全了解。在这里，作者表明，有一个单一的遗传调控模块，影响胆固醇水平和葡萄糖水平，提供了胆固醇水平和糖尿病之间的联系。
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. Some cholesterol-lowering drugs can increase the risk of type 2 diabetes, but the mechanism behind this is not fully understood. Here the authors show that there is a single genetic regulatory module that influences both cholesterol levels and glucose levels, providing a link between cholesterol levels and diabetes.
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影响因子：
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作者：
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DOI：
10.1126/science.aah6171
发表时间：
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期刊：
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作者：
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DOI：
10.1126/science.aad6970
发表时间：
2016-08-19
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
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影响因子：
3
作者：
Langfelder P;Horvath S
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英国生物库中的遗传分析将胰岛素抵抗和跨内皮迁移途径与冠状动脉疾病联系起来。
影响因子：
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Kathiresan S