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

Artika P Nath; Scott C Ritchie; Sean G Byars; Liam G Fearnley; Aki S Havulinna; Anni Joensuu; Antti J Kangas; Pasi Soininen; Annika Wennerström; Lili Milani; Andres Metspalu; Satu Männistö; Peter Würtz; Johannes Kettunen; Emma Raitoharju; Mika Kähönen; Markus Juonala; Aarno Palotie; Mika Ala-Korpela; Samuli Ripatti; Terho Lehtimäki; Gad Abraham; Olli Raitakari; Veikko Salomaa; Markus Perola; Michael Inouye

doi:10.1186/s13059-017-1279-y

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

Artika P Nath, Scott C Ritchie, Sean G Byars, Liam G Fearnley, Aki S Havulinna, Anni Joensuu, Antti J Kangas, Pasi Soininen, Annika Wennerström, Lili Milani, Andres Metspalu, Satu Männistö, Peter Würtz, Johannes Kettunen, Emma Raitoharju, Mika Kähönen, Markus Juonala, Aarno Palotie, Mika Ala-Korpela, Samuli RipattiTerho Lehtimäki, Gad Abraham, Olli Raitakari, Veikko Salomaa, Markus Perola, Michael Inouye

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Abstract

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.

Original language	English
Article number	146
Number of pages	15
Journal	Genome Biology
Volume	18
DOIs	https://doi.org/10.1186/s13059-017-1279-y
Publication status	Published - 1 Aug 2017

Keywords

Amino Acids/immunology
B-Lymphocytes/immunology
Basophils/immunology
Blood Platelets/immunology
C-Reactive Protein/genetics
Cardiovascular Diseases/genetics
Fatty Acids/immunology
Follow-Up Studies
Gene Expression Regulation/immunology
Gene Ontology
Gene Regulatory Networks/immunology
Genome, Human
Humans
Immunity, Innate
Lipoproteins/genetics
Metabolic Syndrome/genetics
Metabolome/genetics
Neutrophils/immunology
Polymorphism, Single Nucleotide
Quantitative Trait Loci/immunology
Rho Guanine Nucleotide Exchange Factors/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s13059-017-1279-y

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Nath, A. P., Ritchie, S. C., Byars, S. G., Fearnley, L. G., Havulinna, A. S., Joensuu, A., Kangas, A. J., Soininen, P., Wennerström, A., Milani, L., Metspalu, A., Männistö, S., Würtz, P., Kettunen, J., Raitoharju, E., Kähönen, M., Juonala, M., Palotie, A., Ala-Korpela, M., ... Inouye, M. (2017). An interaction map of circulating metabolites, immune gene networks, and their genetic regulation. Genome Biology, 18, Article 146. https://doi.org/10.1186/s13059-017-1279-y

@article{b2fdf2fc0dcd4cbdac2369e34da8fa8a,

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

abstract = "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.",

keywords = "Amino Acids/immunology, B-Lymphocytes/immunology, Basophils/immunology, Blood Platelets/immunology, C-Reactive Protein/genetics, Cardiovascular Diseases/genetics, Fatty Acids/immunology, Follow-Up Studies, Gene Expression Regulation/immunology, Gene Ontology, Gene Regulatory Networks/immunology, Genome, Human, Humans, Immunity, Innate, Lipoproteins/genetics, Metabolic Syndrome/genetics, Metabolome/genetics, Neutrophils/immunology, Polymorphism, Single Nucleotide, Quantitative Trait Loci/immunology, Rho Guanine Nucleotide Exchange Factors/genetics",

author = "Nath, {Artika P} and Ritchie, {Scott C} and Byars, {Sean G} and Fearnley, {Liam G} and Havulinna, {Aki S} and Anni Joensuu and Kangas, {Antti J} and Pasi Soininen and Annika Wennerstr{\"o}m and Lili Milani and Andres Metspalu and Satu M{\"a}nnist{\"o} and Peter W{\"u}rtz and Johannes Kettunen and Emma Raitoharju and Mika K{\"a}h{\"o}nen and Markus Juonala and Aarno Palotie and Mika Ala-Korpela and Samuli Ripatti and Terho Lehtim{\"a}ki and Gad Abraham and Olli Raitakari and Veikko Salomaa and Markus Perola and Michael Inouye",

year = "2017",

month = aug,

day = "1",

doi = "10.1186/s13059-017-1279-y",

language = "English",

volume = "18",

journal = "Genome Biology",

issn = "1474-7596",

publisher = "BioMed Central",

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Nath, AP, Ritchie, SC, Byars, SG, Fearnley, LG, Havulinna, AS, Joensuu, A, Kangas, AJ, Soininen, P, Wennerström, A, Milani, L, Metspalu, A, Männistö, S, Würtz, P, Kettunen, J, Raitoharju, E, Kähönen, M, Juonala, M, Palotie, A, Ala-Korpela, M, Ripatti, S, Lehtimäki, T, Abraham, G, Raitakari, O, Salomaa, V, Perola, M & Inouye, M 2017, 'An interaction map of circulating metabolites, immune gene networks, and their genetic regulation', Genome Biology, vol. 18, 146. https://doi.org/10.1186/s13059-017-1279-y

TY - JOUR

T1 - An interaction map of circulating metabolites, immune gene networks, and their genetic regulation

AU - Nath, Artika P

AU - Ritchie, Scott C

AU - Byars, Sean G

AU - Fearnley, Liam G

AU - Havulinna, Aki S

AU - Joensuu, Anni

AU - Kangas, Antti J

AU - Soininen, Pasi

AU - Wennerström, Annika

AU - Milani, Lili

AU - Metspalu, Andres

AU - Männistö, Satu

AU - Würtz, Peter

AU - Kettunen, Johannes

AU - Raitoharju, Emma

AU - Kähönen, Mika

AU - Juonala, Markus

AU - Palotie, Aarno

AU - Ala-Korpela, Mika

AU - Ripatti, Samuli

AU - Lehtimäki, Terho

AU - Abraham, Gad

AU - Raitakari, Olli

AU - Salomaa, Veikko

AU - Perola, Markus

AU - Inouye, Michael

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

KW - Amino Acids/immunology

KW - B-Lymphocytes/immunology

KW - Basophils/immunology

KW - Blood Platelets/immunology

KW - C-Reactive Protein/genetics

KW - Cardiovascular Diseases/genetics

KW - Fatty Acids/immunology

KW - Follow-Up Studies

KW - Gene Expression Regulation/immunology

KW - Gene Ontology

KW - Gene Regulatory Networks/immunology

KW - Genome, Human

KW - Humans

KW - Immunity, Innate

KW - Lipoproteins/genetics

KW - Metabolic Syndrome/genetics

KW - Metabolome/genetics

KW - Neutrophils/immunology

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci/immunology

KW - Rho Guanine Nucleotide Exchange Factors/genetics

U2 - 10.1186/s13059-017-1279-y

DO - 10.1186/s13059-017-1279-y

M3 - Article (Academic Journal)

C2 - 28764798

SN - 1474-7596

VL - 18

JO - Genome Biology

JF - Genome Biology

M1 - 146

ER -

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

Abstract

Keywords

UN SDGs

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