Gene networks and pathways for plasma lipid traits via multitissue multiomics systems analysis
| Autor: | Zara Saleem, In Sook Ahn, Yuqi Zhao, Helen Luk, Montgomery Blencowe, Ingrid Cely, Ville-Petteri Mäkinen, Xia Yang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
FDR false discovery rate LD linkage disequilibrium GLGC Global Lipids Genetics Consortium Genome-wide association study pathway and network analysis T2D type 2 diabetes QD415-436 030204 cardiovascular system & hematology APOF CVD cardiovascular disease HAEC human aortic endothelial cell MAF minor allele frequency Biochemistry eQTL expression quantitative trait locus KEGG Kyoto Encyclopedia of Genes and Genomes MSEA Marker Set Enrichment Analysis KDA key driver analysis 03 medical and health sciences chemistry.chemical_compound integrative genomics eSNP expression SNP 0302 clinical medicine Endocrinology Adipocyte coagulation factor II lipid metabolism GWAS KEGG GWAS genome-wide association study Gene knockdown biology TG triglyceride Lipid metabolism Cell Biology Cell biology TC total cholesterol iGSEA improved gene-set-enrichment analysis 030104 developmental biology UC unesterified cholesterol chemistry ABCA1 Expression quantitative trait loci biology.protein lipids (amino acids peptides and proteins) Research Article Genome-Wide Association Study |
| Zdroj: | Journal of Lipid Research Journal of Lipid Research, Vol 62, Iss, Pp 100019-(2021) |
| ISSN: | 1539-7262 0022-2275 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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