Gene Networks and Pathways for Plasma Lipid Traits via Multi-tissue Multi-omics Systems Analysis
| Autor: | Blencowe, Montgomery, Ahn, In Sook, Saleem, Zara, Luk, Helen, Cely, Ingrid, Mäkinen, Ville-Petteri, Zhao, Yuqi, Yang, Xia |
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| Rok vydání: | 2020 |
| Předmět: |
Coagulation Factor II
Biochemistry & Molecular Biology HDL Human Genome pathway and network analysis Genomics Medical Biochemistry and Metabolomics Triacylglycerol LDL integrative genomics Cholesterol lipid metabolism Genetics GWAS 2.1 Biological and endogenous factors lipids (amino acids peptides and proteins) Gene expression Biochemistry and Cell Biology Aetiology Triglycerides Metabolic and endocrine Biotechnology Genome-Wide Association Study |
| Popis: | 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 oftheF2gene (Coagulation Factor II, Thrombin) in 3T3-L1 and C3H10T1/2 adipocytes reduced gene expression ofAbcb11,Apoa5,Apof,Fabp1, Lipc,andCd36,reduced intracellular adipocyte lipid content, and increased extracellular lipid content, supporting a link between adiposethrombin 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. |
| Databáze: | OpenAIRE |
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