Genome-wide association studies (GWAS) have implicated ~380 genetic loci for plasma lipid regulation. However, these loci only explain 17-27% of the trait variance and a comprehensive understanding of the molecular mechanisms has not been achieved. In this study, we utilized an integrative genomics approach leveraging diverse genomic data from human populations to investigate whether genetic variants associated with various plasma lipid traits, namely total cholesterol (TC), high and low density lipoprotein cholesterol (HDL and LDL), and triglycerides (TG), from GWAS were concentrated on specific parts of tissue-specific gene regulatory networks. In addition to the expected lipid metabolism pathways, gene subnetworks involved in 'interferon signaling', 'autoimmune/immune activation', 'visual transduction', and 'protein catabolism' were significantly associated with all lipid traits. Additionally, we detected trait-specific subnetworks, including cadherin-associated subnetworks for LDL, glutathione metabolism for HDL, valine, leucine and isoleucine biosynthesis for TC, and insulin signaling and complement pathways for TG. Finally, utilizing gene-gene relations revealed by tissue-specific gene regulatory networks, we detected both known (e.g. APOH, APOA4, and ABCA1) and novel (e.g. F2 in adipose tissue) key regulator genes in these lipid-associated subnetworks. Knockdown of the F2 gene (Coagulation Factor II, Thrombin) in 3T3-L1 and C3H10T1/2 adipocytes reduced gene expression of Abcb11, Apoa5, Apof, Fabp1, Lipc, and Cd36, reduced intracellular adipocyte lipid content, and increased extracellular lipid content, supporting a link between adipose thrombin and lipid regulation. Our results shed light on the complex mechanisms underlying lipid metabolism and highlight potential novel targets for lipid regulation and lipid-associated diseases.

中文翻译：

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通过多组织多组学系统分析血浆脂质特征的基因网络和途径。

全基因组关联研究 (GWAS) 表明约 380 个基因位点与血脂调节有关。然而，这些位点只能解释 17-27% 的性状变异，尚未实现对分子机制的全面理解。在这项研究中，我们利用综合基因组学方法，利用来自人群的不同基因组数据来研究遗传变异是否与各种血浆脂质特征相关，即总胆固醇（TC）、高密度脂蛋白胆固醇和低密度脂蛋白胆固醇（HDL和LDL）以及甘油三酯（TG），来自 GWAS 的研究集中于组织特异性基因调控网络的特定部分。除了预期的脂质代谢途径外，参与“干扰素信号传导”、“自身免疫/免疫激活”、“视觉转导”和“蛋白质分解代谢”的基因子网络与所有脂质特征显着相关。此外，我们还检测了性状特异性子网，包括 LDL 的钙粘蛋白相关子网、HDL 的谷胱甘肽代谢、TC 的缬氨酸、亮氨酸和异亮氨酸生物合成，以及 TG 的胰岛素信号和补体途径。最后，利用组织特异性基因调控网络揭示的基因-基因关系，我们在这些脂质相关子网络中检测到已知的（例如APOH、APOA4和ABCA1）和新的（例如脂肪组织中的F2）关键调控基因。敲除 3T3-L1 和 C3H10T1/2 脂肪细胞中的 F2 基因（凝血因子 II、凝血酶）会降低 Abcb11、Apoa5、Apof、Fabp1、Lipc 和 Cd36 的基因表达，降低细胞内脂肪细胞脂质含量，并增加细胞外脂质含量，支持脂肪凝血酶和脂质调节之间的联系。我们的研究结果揭示了脂质代谢背后的复杂机制，并强调了脂质调节和脂质相关疾病的潜在新靶点。