Abstract
BackgroundImmunometabolism plays a central role in many cardiometabolic diseases. However, a robust map of immune-related gene networks in circulating human cells, their interactions with metabolites, and their genetic control is still lacking. Here, we integrate blood transcriptomic, metabolomic, and genomic profiles from two population-based cohorts (total N = 2168), including a subset of individuals with matched multi-omic data at 7-year follow-up.ResultsWe identify topologically replicable gene networks enriched for diverse immune functions including cytotoxicity, viral response, B cell, platelet, neutrophil, and mast cell/basophil activity. These immune gene modules show complex patterns of association with 158 circulating metabolites, including lipoprotein subclasses, lipids, fatty acids, amino acids, small molecules, and CRP. Genome-wide scans for module expression quantitative trait loci (mQTLs) reveal five modules with mQTLs that have both cis and trans effects. The strongest mQTL is in ARHGEF3 (rs1354034) and affects a module enriched for platelet function, independent of platelet counts. Modules of mast cell/basophil and neutrophil function show temporally stable metabolite associations over 7-year follow-up, providing evidence that these modules and their constituent gene products may play central roles in metabolic inflammation. Furthermore, the strongest mQTL in ARHGEF3 also displays clear temporal stability, supporting widespread trans effects at this locus.ConclusionsThis study provides a detailed map of natural variation at the blood immunometabolic interface and its genetic basis, and may facilitate subsequent studies to explain inter-individual variation in cardiometabolic disease.
Highlights
Immunometabolism plays a central role in many cardiometabolic diseases
While it is involved in diverse pathophysiologies, immunometabolism is relevant to diseases of immense global health burden, such as type 2 diabetes (T2D) and atherosclerosis
Studies have shown that macrophage infiltration and subsequent overexpression of proinflammatory cytokines, such as TNF-α, in adipose tissues is associated with insulin resistance [1, 2]
Summary
Immunometabolism plays a central role in many cardiometabolic diseases. a robust map of immune-related gene networks in circulating human cells, their interactions with metabolites, and their genetic control is still lacking. Over the past decade increasing evidence has implicated inflammation as a probable causal factor in metabolic and cardiovascular diseases. Research has begun to focus on the interplay between immunity and metabolism, or immunometabolism. While it is involved in diverse pathophysiologies, immunometabolism is relevant to diseases of immense global health burden, such as type 2 diabetes (T2D) and atherosclerosis. Evidence for metabolic inflammation has been shown in other tissues where, in blood, elevated glucose and free fatty acid levels potentiate IL1β-mediated destruction of pancreatic ß cells and subsequent T2D progression [3,4,5]. While circulating metabolites are known to be associated with cardiovascular disease [6], inflammation is an increasingly recognized factor in pathogenesis.
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