期刊
GENOME BIOLOGY
卷 18, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s13059-017-1279-y
关键词
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资金
- National Health and Medical Research Council of Australia (NHMRC) [APP1062227]
- NHMRC
- Australian Heart Foundation Career Development Fellowship [1061435]
- NHMRC Early Career Fellowship [1090462]
- Australian Postgraduate Award
- Academy of Finland [312476, 312477, 141136, 269517, 283045, 294834, 297338, 285902, 286284, 134309, 126925, 121584, 124282, 129378, 117787, 41071, 139, 635]
- Finnish Foundation for Cardiovascular Research
- Strategic Research Funding from the University of Oulu, Finland
- Sigrid Juselius Foundation
- Yrjo Jahnsson Foundation
- Emil Aaltonen Foundation
- Novo Nordisk Foundation
- Finnish Diabetes Research Foundation
- Social Insurance Institution of Finland
- Competitive State Research Financing of the Expert Responsibility area of Tampere, Turku and Kuopio University Hospitals [X51001]
- Juho Vainio Foundation
- Paavo Nurmi Foundation
- Finnish Cultural Foundation
- Tampere Tuberculosis Foundation
- Signe and Ane Gyllenberg Foundation
- Diabetes Research Foundation of Finnish Diabetes Association
- Paulo Foundation
- Maud Kuistila Foundation
- Finnish Medical Foundation
- Academy of Finland
- TEKES-the Finnish Funding Agency for Technology and Innovation
- University of Oulu, Finland
- British Heart Foundation
- Wellcome Trust
- Medical Research Council, UK
- EU FP7 [313010, 305280, HZ2020 633589]
- University of Bristol
- UK Medical Research Council [MC_UU_1201/1]
- EU H2020 grants [692145]
- Estonian Research Council [IUT20-60]
- European Union through the European Regional Development Fund [2014-2020.4.01.15-0012 GENTRANSMED]
- National Health and Medical Research Council of Australia [1090462] Funding Source: NHMRC
- Novo Nordisk Fonden [NNF15OC0015998] Funding Source: researchfish
Background: Immunometabolism 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. Results: We 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. Conclusions: This 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.
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