Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease.
Adolescent
Adult
Aged
Alanine
/ blood
Arachidonic Acid
/ blood
Cohort Studies
Female
Genome-Wide Association Study
Genomics
/ methods
Glutamic Acid
/ blood
Healthy Volunteers
Humans
Immunity, Innate
/ genetics
Male
Metabolic Networks and Pathways
/ genetics
Metabolomics
/ methods
Middle Aged
Phenotype
Quantitative Trait Loci
Genomics
Immune phenotypes
Integrative analysis
Metabolomics
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
06 07 2021
06 07 2021
Historique:
received:
15
01
2021
accepted:
21
06
2021
entrez:
7
7
2021
pubmed:
8
7
2021
medline:
22
1
2022
Statut:
epublish
Résumé
Recent studies highlight the role of metabolites in immune diseases, but it remains unknown how much of this effect is driven by genetic and non-genetic host factors. We systematically investigate circulating metabolites in a cohort of 500 healthy subjects (500FG) in whom immune function and activity are deeply measured and whose genetics are profiled. Our data reveal that several major metabolic pathways, including the alanine/glutamate pathway and the arachidonic acid pathway, have a strong impact on cytokine production in response to ex vivo stimulation. We also examine the genetic regulation of metabolites associated with immune phenotypes through genome-wide association analysis and identify 29 significant loci, including eight novel independent loci. Of these, one locus (rs174584-FADS2) associated with arachidonic acid metabolism is causally associated with Crohn's disease, suggesting it is a potential therapeutic target. This study provides a comprehensive map of the integration between the blood metabolome and immune phenotypes, reveals novel genetic factors that regulate blood metabolite concentrations, and proposes an integrative approach for identifying new disease treatment targets.
Sections du résumé
BACKGROUND
Recent studies highlight the role of metabolites in immune diseases, but it remains unknown how much of this effect is driven by genetic and non-genetic host factors.
RESULT
We systematically investigate circulating metabolites in a cohort of 500 healthy subjects (500FG) in whom immune function and activity are deeply measured and whose genetics are profiled. Our data reveal that several major metabolic pathways, including the alanine/glutamate pathway and the arachidonic acid pathway, have a strong impact on cytokine production in response to ex vivo stimulation. We also examine the genetic regulation of metabolites associated with immune phenotypes through genome-wide association analysis and identify 29 significant loci, including eight novel independent loci. Of these, one locus (rs174584-FADS2) associated with arachidonic acid metabolism is causally associated with Crohn's disease, suggesting it is a potential therapeutic target.
CONCLUSION
This study provides a comprehensive map of the integration between the blood metabolome and immune phenotypes, reveals novel genetic factors that regulate blood metabolite concentrations, and proposes an integrative approach for identifying new disease treatment targets.
Identifiants
pubmed: 34229738
doi: 10.1186/s13059-021-02413-z
pii: 10.1186/s13059-021-02413-z
pmc: PMC8259168
doi:
Substances chimiques
Arachidonic Acid
27YG812J1I
Glutamic Acid
3KX376GY7L
Alanine
OF5P57N2ZX
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
198Subventions
Organisme : NCCIH NIH HHS
ID : R01 AT009708
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES027595
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK043351
Pays : United States
Organisme : NIH HHS
ID : S10 OD020025
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA236405
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA199376
Pays : United States
Organisme : European Research Council
ID : 833247
Pays : International
Organisme : NIDDK NIH HHS
ID : K01 DK116917
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007752
Pays : United States
Références
Genet Epidemiol. 2016 May;40(4):304-14
pubmed: 27061298
Inflamm Bowel Dis. 2018 Mar 19;24(4):892-896
pubmed: 29522107
Biopreserv Biobank. 2015 Oct;13(5):307-8
pubmed: 26484569
J Allergy Clin Immunol. 2015 Oct;136(4):923-31.e3
pubmed: 25910714
Cell. 2016 Nov 3;167(4):894-896
pubmed: 27814519
Circ Cardiovasc Genet. 2014 Jun;7(3):321-331
pubmed: 24823311
Nat Genet. 2017 Feb;49(2):256-261
pubmed: 28067908
Hum Mol Genet. 2015 Oct 15;24(R1):R93-R101
pubmed: 26160913
PLoS Genet. 2015 Sep 24;11(9):e1005510
pubmed: 26401656
PLoS Genet. 2015 Jun 18;11(6):e1005274
pubmed: 26086077
Nat Protoc. 2016 Jan;11(1):1-9
pubmed: 26633127
Cell Mol Life Sci. 2018 Sep;75(18):3353-3369
pubmed: 29974127
Nat Genet. 2017 Apr;49(4):568-578
pubmed: 28263315
Nat Genet. 2014 Jun;46(6):543-550
pubmed: 24816252
Cell. 2018 Dec 13;175(7):1780-1795.e19
pubmed: 30392958
Expert Rev Clin Pharmacol. 2017 Mar;10(3):315-326
pubmed: 27977304
Nat Protoc. 2015 Oct;10(10):1474-85
pubmed: 26334867
Int J Epidemiol. 2003 Feb;32(1):1-22
pubmed: 12689998
Sci Transl Med. 2017 Mar 29;9(383):
pubmed: 28356508
Gastroenterology. 2011 Nov;141(5):1762-72
pubmed: 21889923
Curr Opin Lipidol. 2010 Feb;21(1):64-9
pubmed: 19809313
Int J Epidemiol. 2017 Dec 1;46(6):1985-1998
pubmed: 29040600
PLoS One. 2017 Jun 28;12(6):e0179574
pubmed: 28658259
Elife. 2018 May 30;7:
pubmed: 29846171
Nat Genet. 2015 Apr;47(4):381-6
pubmed: 25751624
Eur J Epidemiol. 2015 Jul;30(7):543-52
pubmed: 25773750
Nucleic Acids Res. 2017 Jul 3;45(W1):W130-W137
pubmed: 28472511
Brain Behav Immun. 2018 Jan;67:59-64
pubmed: 28867283
PLoS Genet. 2014 May 15;10(5):e1004383
pubmed: 24830394
Innate Immun. 2017 Jan;23(1):3-10
pubmed: 27697850
Bioinformatics. 2012 Jun 15;28(12):1598-603
pubmed: 22500001
Cell Immunol. 2013 Nov-Dec;286(1-2):45-52
pubmed: 24321565
Nutrients. 2018 Sep 06;10(9):
pubmed: 30200659
Immunol Lett. 2017 Jan;181:51-57
pubmed: 27838468
Arch Med Res. 2017 Jul;48(5):432-440
pubmed: 29133194
Hum Mutat. 2013 Mar;34(3):515-24
pubmed: 23281178
Am J Clin Nutr. 2016 Sep;104(3):776-89
pubmed: 27510537
Genome Biol. 2021 Jul 6;22(1):198
pubmed: 34229738
Cytokine. 2013 Apr;62(1):52-7
pubmed: 23498057
Nat Immunol. 2018 Jul;19(7):776-786
pubmed: 29784908
Cell. 2016 Nov 17;167(5):1415-1429.e19
pubmed: 27863252
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Nat Genet. 2011 Nov 06;43(12):1193-201
pubmed: 22057235
Cell. 2016 Nov 3;167(4):1111-1124.e13
pubmed: 27814508
Endocrinol Metab Clin North Am. 2017 Dec;46(4):1061-1094
pubmed: 29080635
Int J Mol Sci. 2018 Sep 23;19(10):
pubmed: 30249062
Methods Mol Biol. 2019;1862:17-35
pubmed: 30315457
Br J Clin Pharmacol. 2013 Mar;75(3):645-62
pubmed: 22765297
Gastroenterology. 2014 Apr;146(4):929-31
pubmed: 24406470
Nat Commun. 2017 Nov 28;8(1):1826
pubmed: 29184056
Clin Nutr. 2004 Aug;23(4):647-55
pubmed: 15297102
PLoS Genet. 2014 Feb 20;10(2):e1004132
pubmed: 24586186
Biochem Biophys Res Commun. 2012 Jan 13;417(2):653-8
pubmed: 22155241
Cell Chem Biol. 2019 Mar 21;26(3):433-442.e4
pubmed: 30661990
Nucleic Acids Res. 2017 Jan 4;45(D1):D896-D901
pubmed: 27899670
Cell. 2016 Dec 15;167(7):1897
pubmed: 27984736
Nucleic Acids Res. 2018 Jul 2;46(W1):W486-W494
pubmed: 29762782
Eur J Clin Invest. 2018 Nov;48 Suppl 2:e12983
pubmed: 29931668
Metabolism. 2010 Jul;59(7):993-9
pubmed: 20045144
Cell Rep. 2016 Nov 22;17(9):2474-2487
pubmed: 27818087
Biochem Biophys Res Commun. 2017 Aug 5;489(4):466-471
pubmed: 28576495
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
Cell. 2016 Nov 3;167(4):1099-1110.e14
pubmed: 27814507
PLoS Genet. 2015 Jan 08;11(1):e1004835
pubmed: 25569235
Bioinformatics. 2010 Sep 15;26(18):2336-7
pubmed: 20634204
Inflamm Bowel Dis. 2007 Jul;13(7):807-21
pubmed: 17262812
World Rev Nutr Diet. 2015;112:17-30
pubmed: 25471799
J Immunol. 2012 Jan 1;188(1):21-8
pubmed: 22187483
Nat Protoc. 2013 Nov;8(11):2281-2308
pubmed: 24157548
Nat Commun. 2016 Mar 23;7:11122
pubmed: 27005778
Genome Biol. 2017 Aug 1;18(1):146
pubmed: 28764798
Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082
pubmed: 29126136
J Immunol. 2015 Oct 15;195(8):3605-16
pubmed: 26363050
Gut. 1992 Oct;33(10):1365-9
pubmed: 1446861