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Gene networks and pathways for plasma lipid traits via multitissue multiomics systems analysis.
Blencowe, Montgomery; Ahn, In Sook; Saleem, Zara; Luk, Helen; Cely, Ingrid; Mäkinen, Ville-Petteri; Zhao, Yuqi; Yang, Xia.
Afiliação
  • Blencowe M; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA; Molecular, Cellular, and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA.
  • Ahn IS; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Saleem Z; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Luk H; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Cely I; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Mäkinen VP; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA; South Australian Health and Medical Research Institute, Adelaide, Australia.
  • Zhao Y; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: zhaoyuqi616@gmail.com.
  • Yang X; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA; Molecular, Cellular, and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA; Interdepartmental Program of Bioinformatics, Universi
J Lipid Res ; 62: 100019, 2021.
Article em En | MEDLINE | ID: mdl-33561811
ABSTRACT
Genome-wide association studies (GWASs) 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, high and low density lipoprotein cholesterol (HDL and LDL), and triglycerides, from GWASs 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. In addition, we detected trait-specific subnetworks, including cadherin-associated subnetworks for LDL; glutathione metabolism for HDL; valine, leucine, and isoleucine biosynthesis for total cholesterol; and insulin signaling and complement pathways for triglyceride. Finally, by using 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 altered 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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Estudo de Associação Genômica Ampla Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Estudo de Associação Genômica Ampla Idioma: En Ano de publicação: 2021 Tipo de documento: Article