Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

Xiaojing Chu; Martin Jaeger; Joep Beumer; Olivier B. Bakker; Raul Aguirre-Gamboa; Marije Oosting; Sanne P. Smeekens; Simone Moorlag; Vera P. Mourits; Valerie A.C.M. Koeken; Charlotte de Bree; Trees Jansen; Ian T. Mathews; Khoi Dao; Mahan Najhawan; Jeramie D. Watrous; Irma Joosten; Sonia Sharma; Hans J.P.M. Koenen; Sebo Withoff; Iris H. Jonkers; Romana T. Netea-Maier; Ramnik J. Xavier; Lude Franke; Cheng Jian Xu; Leo A.B. Joosten; Serena Sanna; Mohit Jain; Vinod Kumar; Hans Clevers; Cisca Wijmenga; Mihai G. Netea; Yang Li

doi:10.1186/s13059-021-02413-z

Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

Xiaojing Chu, Martin Jaeger, Joep Beumer, Olivier B. Bakker, Raul Aguirre-Gamboa, Marije Oosting, Sanne P. Smeekens, Simone Moorlag, Vera P. Mourits, Valerie A.C.M. Koeken, Charlotte de Bree, Trees Jansen, Ian T. Mathews, Khoi Dao, Mahan Najhawan, Jeramie D. Watrous, Irma Joosten, Sonia Sharma, Hans J.P.M. Koenen, Sebo WithoffIris H. Jonkers, Romana T. Netea-Maier, Ramnik J. Xavier, Lude Franke, Cheng Jian Xu, Leo A.B. Joosten, Serena Sanna, Mohit Jain, Vinod Kumar, Hans Clevers, Cisca Wijmenga^*, Mihai G. Netea, Yang Li

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

2 Citations (Scopus)

Abstract

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.

Original language	English
Article number	198
Pages (from-to)	1-22
Journal	Genome Biology
Volume	22
Issue number	1
DOIs	https://doi.org/10.1186/s13059-021-02413-z
Publication status	Published - Dec 2021

Keywords

Genomics
Immune phenotypes
Integrative analysis
Metabolomics

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Chu, X., Jaeger, M., Beumer, J., Bakker, O. B., Aguirre-Gamboa, R., Oosting, M., Smeekens, S. P., Moorlag, S., Mourits, V. P., Koeken, V. A. C. M., de Bree, C., Jansen, T., Mathews, I. T., Dao, K., Najhawan, M., Watrous, J. D., Joosten, I., Sharma, S., Koenen, H. J. P. M., ... Li, Y. (2021). Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease. Genome Biology, 22(1), 1-22. Article 198. https://doi.org/10.1186/s13059-021-02413-z

@article{4c25c72fe2af40c198c2f1fe855d05ed,

title = "Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease",

abstract = "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{\textquoteright}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.",

keywords = "Genomics, Immune phenotypes, Integrative analysis, Metabolomics",

author = "Xiaojing Chu and Martin Jaeger and Joep Beumer and Bakker, {Olivier B.} and Raul Aguirre-Gamboa and Marije Oosting and Smeekens, {Sanne P.} and Simone Moorlag and Mourits, {Vera P.} and Koeken, {Valerie A.C.M.} and {de Bree}, Charlotte and Trees Jansen and Mathews, {Ian T.} and Khoi Dao and Mahan Najhawan and Watrous, {Jeramie D.} and Irma Joosten and Sonia Sharma and Koenen, {Hans J.P.M.} and Sebo Withoff and Jonkers, {Iris H.} and Netea-Maier, {Romana T.} and Xavier, {Ramnik J.} and Lude Franke and Xu, {Cheng Jian} and Joosten, {Leo A.B.} and Serena Sanna and Mohit Jain and Vinod Kumar and Hans Clevers and Cisca Wijmenga and Netea, {Mihai G.} and Yang Li",

note = "Funding Information: This work was supported in part by grants from the National Institutes of Health (NIH), including R01ES027595 and S10OD020025 (M.J.), R01CA199376 (S.S.), K01DK116917 (J.D.W.), and F31CA236405 (I.T.M.). X.C. was supported by the China Scholarship Council (201706040081). M.O. was supported by a Netherlands Organization for Scientific Research (NWO) VENI grant (016.176.006). R.J.X. was supported by NIH grants DK43351, AT009708, and AI137325. I.T.M. was additionally supported by NIH grant T32GM007752. M.G.N. was supported by an ERC Advanced Grant (833247), an IN-CONTROL CVON grant (CVON2012-03), and an NWO Spinoza prize (NWO SPI 94-212). This study was further supported by an ERC advanced grant (FP/2007-2013/ERC grant 2012-322698) and an NWO Spinoza prize (NWO SPI 92-266) to C.W.. Y.L. was supported by an ERC Starting Grant (948207) and the Radboud University Medical Centre Hypatia Grant (2018) for Scientific Research. Open Access funding enabled and organized by Projekt DEAL. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1186/s13059-021-02413-z",

language = "English",

volume = "22",

pages = "1--22",

journal = "Genome Biology",

issn = "1474-7596",

publisher = "BioMed Central",

number = "1",

}

Chu, X, Jaeger, M, Beumer, J, Bakker, OB, Aguirre-Gamboa, R, Oosting, M, Smeekens, SP, Moorlag, S, Mourits, VP, Koeken, VACM, de Bree, C, Jansen, T, Mathews, IT, Dao, K, Najhawan, M, Watrous, JD, Joosten, I, Sharma, S, Koenen, HJPM, Withoff, S, Jonkers, IH, Netea-Maier, RT, Xavier, RJ, Franke, L, Xu, CJ, Joosten, LAB, Sanna, S, Jain, M, Kumar, V, Clevers, H, Wijmenga, C, Netea, MG & Li, Y 2021, 'Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease', Genome Biology, vol. 22, no. 1, 198, pp. 1-22. https://doi.org/10.1186/s13059-021-02413-z

TY - JOUR

T1 - Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

AU - Chu, Xiaojing

AU - Jaeger, Martin

AU - Beumer, Joep

AU - Bakker, Olivier B.

AU - Aguirre-Gamboa, Raul

AU - Oosting, Marije

AU - Smeekens, Sanne P.

AU - Moorlag, Simone

AU - Mourits, Vera P.

AU - Koeken, Valerie A.C.M.

AU - de Bree, Charlotte

AU - Jansen, Trees

AU - Mathews, Ian T.

AU - Dao, Khoi

AU - Najhawan, Mahan

AU - Watrous, Jeramie D.

AU - Joosten, Irma

AU - Sharma, Sonia

AU - Koenen, Hans J.P.M.

AU - Withoff, Sebo

AU - Jonkers, Iris H.

AU - Netea-Maier, Romana T.

AU - Xavier, Ramnik J.

AU - Franke, Lude

AU - Xu, Cheng Jian

AU - Joosten, Leo A.B.

AU - Sanna, Serena

AU - Jain, Mohit

AU - Kumar, Vinod

AU - Clevers, Hans

AU - Wijmenga, Cisca

AU - Netea, Mihai G.

AU - Li, Yang

N1 - Funding Information: This work was supported in part by grants from the National Institutes of Health (NIH), including R01ES027595 and S10OD020025 (M.J.), R01CA199376 (S.S.), K01DK116917 (J.D.W.), and F31CA236405 (I.T.M.). X.C. was supported by the China Scholarship Council (201706040081). M.O. was supported by a Netherlands Organization for Scientific Research (NWO) VENI grant (016.176.006). R.J.X. was supported by NIH grants DK43351, AT009708, and AI137325. I.T.M. was additionally supported by NIH grant T32GM007752. M.G.N. was supported by an ERC Advanced Grant (833247), an IN-CONTROL CVON grant (CVON2012-03), and an NWO Spinoza prize (NWO SPI 94-212). This study was further supported by an ERC advanced grant (FP/2007-2013/ERC grant 2012-322698) and an NWO Spinoza prize (NWO SPI 92-266) to C.W.. Y.L. was supported by an ERC Starting Grant (948207) and the Radboud University Medical Centre Hypatia Grant (2018) for Scientific Research. Open Access funding enabled and organized by Projekt DEAL. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

KW - Genomics

KW - Immune phenotypes

KW - Integrative analysis

KW - Metabolomics

UR - http://www.scopus.com/inward/record.url?scp=85109259870&partnerID=8YFLogxK

U2 - 10.1186/s13059-021-02413-z

DO - 10.1186/s13059-021-02413-z

M3 - Article

C2 - 34229738

AN - SCOPUS:85109259870

SN - 1474-7596

VL - 22

SP - 1

EP - 22

JO - Genome Biology

JF - Genome Biology

IS - 1

M1 - 198

ER -

Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

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