Key result
Integrative multi-omics analysis identified novel lipid-associated gene subnetworks and key regulator genes, including F2 (thrombin) in adipose tissue, whose knockdown reduced intracellular lipid content.
Why the study?
GWAS loci for plasma lipid regulation explain only 17-27% of trait variance, and a comprehensive understanding of the underlying molecular mechanisms has not been achieved.
Integrative multi-omics analysis reveals novel gene networks and key drivers, such as F2 in adipose tissue, that regulate plasma lipid traits, offering potential new therapeutic targets.
No immediate clinical implications; leaves open F2 as a regulator of adipose lipid content for validation.
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.
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Blencowe et al. (2020) studied Plasma lipid traits (TC, HDL, LDL, TG) (n=100,184). Genetic variants associated with plasma lipid traits was evaluated on Gene networks and pathways associated with plasma lipid traits. Integrative multi-omics analysis identified novel lipid-associated gene subnetworks and key regulator genes, including F2 (thrombin) in adipose tissue, whose knockdown reduced intracellular lipid content.
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