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An interaction map of circulating metabolites, immune gene networks, and their genetic regulation

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,...

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Autores principales: Nath, Artika P., Ritchie, Scott C., Byars, Sean G., Fearnley, Liam G., Havulinna, Aki S., Joensuu, Anni, Kangas, Antti J., Soininen, Pasi, Wennerström, Annika, Milani, Lili, Metspalu, Andres, Männistö, Satu, Würtz, Peter, Kettunen, Johannes, Raitoharju, Emma, Kähönen, Mika, Juonala, Markus, Palotie, Aarno, Ala-Korpela, Mika, Ripatti, Samuli, Lehtimäki, Terho, Abraham, Gad, Raitakari, Olli, Salomaa, Veikko, Perola, Markus, Inouye, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540552/
https://www.ncbi.nlm.nih.gov/pubmed/28764798
http://dx.doi.org/10.1186/s13059-017-1279-y
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author Nath, Artika P.
Ritchie, Scott C.
Byars, Sean G.
Fearnley, Liam G.
Havulinna, Aki S.
Joensuu, Anni
Kangas, Antti J.
Soininen, Pasi
Wennerström, Annika
Milani, Lili
Metspalu, Andres
Männistö, Satu
Würtz, Peter
Kettunen, Johannes
Raitoharju, Emma
Kähönen, Mika
Juonala, Markus
Palotie, Aarno
Ala-Korpela, Mika
Ripatti, Samuli
Lehtimäki, Terho
Abraham, Gad
Raitakari, Olli
Salomaa, Veikko
Perola, Markus
Inouye, Michael
author_facet Nath, Artika P.
Ritchie, Scott C.
Byars, Sean G.
Fearnley, Liam G.
Havulinna, Aki S.
Joensuu, Anni
Kangas, Antti J.
Soininen, Pasi
Wennerström, Annika
Milani, Lili
Metspalu, Andres
Männistö, Satu
Würtz, Peter
Kettunen, Johannes
Raitoharju, Emma
Kähönen, Mika
Juonala, Markus
Palotie, Aarno
Ala-Korpela, Mika
Ripatti, Samuli
Lehtimäki, Terho
Abraham, Gad
Raitakari, Olli
Salomaa, Veikko
Perola, Markus
Inouye, Michael
author_sort Nath, Artika P.
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-017-1279-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-55405522017-08-07 An interaction map of circulating metabolites, immune gene networks, and their genetic regulation Nath, Artika P. Ritchie, Scott C. Byars, Sean G. Fearnley, Liam G. Havulinna, Aki S. Joensuu, Anni Kangas, Antti J. Soininen, Pasi Wennerström, Annika Milani, Lili Metspalu, Andres Männistö, Satu Würtz, Peter Kettunen, Johannes Raitoharju, Emma Kähönen, Mika Juonala, Markus Palotie, Aarno Ala-Korpela, Mika Ripatti, Samuli Lehtimäki, Terho Abraham, Gad Raitakari, Olli Salomaa, Veikko Perola, Markus Inouye, Michael Genome Biol Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-017-1279-y) contains supplementary material, which is available to authorized users. BioMed Central 2017-08-01 /pmc/articles/PMC5540552/ /pubmed/28764798 http://dx.doi.org/10.1186/s13059-017-1279-y Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Nath, Artika P.
Ritchie, Scott C.
Byars, Sean G.
Fearnley, Liam G.
Havulinna, Aki S.
Joensuu, Anni
Kangas, Antti J.
Soininen, Pasi
Wennerström, Annika
Milani, Lili
Metspalu, Andres
Männistö, Satu
Würtz, Peter
Kettunen, Johannes
Raitoharju, Emma
Kähönen, Mika
Juonala, Markus
Palotie, Aarno
Ala-Korpela, Mika
Ripatti, Samuli
Lehtimäki, Terho
Abraham, Gad
Raitakari, Olli
Salomaa, Veikko
Perola, Markus
Inouye, Michael
An interaction map of circulating metabolites, immune gene networks, and their genetic regulation
title An interaction map of circulating metabolites, immune gene networks, and their genetic regulation
title_full An interaction map of circulating metabolites, immune gene networks, and their genetic regulation
title_fullStr An interaction map of circulating metabolites, immune gene networks, and their genetic regulation
title_full_unstemmed An interaction map of circulating metabolites, immune gene networks, and their genetic regulation
title_short An interaction map of circulating metabolites, immune gene networks, and their genetic regulation
title_sort interaction map of circulating metabolites, immune gene networks, and their genetic regulation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540552/
https://www.ncbi.nlm.nih.gov/pubmed/28764798
http://dx.doi.org/10.1186/s13059-017-1279-y
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