Lipid-induced transcriptomic changes in blood link to lipid metabolism and allergic response

• Published in: Nature communications Vol. 14; no. 1; pp. 544 - 9
• Main Authors: Dekkers, Koen F., Slieker, Roderick C., Ioan-Facsinay, Andreea, van Iterson, Maarten, Ikram, M. Arfan, van Greevenbroek, Marleen M. J., Veldink, Jan H., Franke, Lude, Boomsma, Dorret I., Slagboom, P. Eline, Jukema, J. Wouter, Heijmans, Bastiaan T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 631/250/2502; 631/337/2019; 631/92/287; Allergic diseases; Arteriosclerosis; Arthritis; Association analysis; Atherosclerosis; Autoimmune diseases; Blood; Blood levels; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Gene expression; Genes; Genome-Wide Association Study; High density lipoprotein; Humanities and Social Sciences; Humans; Hypersensitivity; Immune system; Inflammatory diseases; Interleukin 4; Lipid metabolism; Lipid Metabolism - genetics; Lipids; Low density lipoprotein; Mendelian Randomization Analysis; Metabolism; multidisciplinary; Pleiotropy; Polymorphism, Single Nucleotide; Randomization; Rheumatoid arthritis; Risk Factors; Science; Science (multidisciplinary); Statistical analysis; Transcriptome; Transcriptomes; Transcriptomics; Triglycerides
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35663-x

Immune cell function can be altered by lipids in circulation, a process potentially relevant to lipid-associated inflammatory diseases including atherosclerosis and rheumatoid arthritis. To gain further insight in the molecular changes involved, we here perform a transcriptome-wide association analysis of blood triglycerides, HDL cholesterol, and LDL cholesterol in 3229 individuals, followed by a systematic bidirectional Mendelian randomization analysis to assess the direction of effects and control for pleiotropy. Triglycerides are found to induce transcriptional changes in 55 genes and HDL cholesterol in 5 genes. The function and cell-specific expression pattern of these genes implies that triglycerides downregulate both cellular lipid metabolism and, unexpectedly, allergic response. Indeed, a Mendelian randomization approach based on GWAS summary statistics indicates that several of these genes, including interleukin-4 ( IL4 ) and IgE receptors ( FCER1A , MS4A2 ), affect the incidence of allergic diseases. Our findings highlight the interplay between triglycerides and immune cells in allergic disease. Circulating lipids can influence immune cell function, which could have implications for inflammatory diseases such as rheumatoid arthritis. Here, the authors use Mendelian randomization to identify genes whose expression is influenced by triglyceride levels in blood, implicating genes involved in lipid metabolism and allergic response.