Genome Biology (Jul 2021)
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
Affiliations
- Xiaojing Chu
- Department of Genetics, University of Groningen, University Medical Center Groningen
- Martin Jaeger
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center
- Joep Beumer
- Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht
- Olivier B. Bakker
- Department of Genetics, University of Groningen, University Medical Center Groningen
- Raul Aguirre-Gamboa
- Department of Genetics, University of Groningen, University Medical Center Groningen
- Marije Oosting
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center
- Sanne P. Smeekens
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center
- Simone Moorlag
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center
- Vera P. Mourits
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center
- Valerie A. C. M. Koeken
- Department of Computational Biology for Individualised Medicine, Centre for Individualised Infection Medicine, CiiM, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research
- Charlotte de Bree
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center
- Trees Jansen
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center
- Ian T. Mathews
- Departments of Medicine and Pharmacology, University of California
- Khoi Dao
- Departments of Medicine and Pharmacology, University of California
- Mahan Najhawan
- Departments of Medicine and Pharmacology, University of California
- Jeramie D. Watrous
- Departments of Medicine and Pharmacology, University of California
- Irma Joosten
- Department of Laboratory Medicine, Laboratory for Medical Immunology, Radboud University Medical Center
- Sonia Sharma
- La Jolla Institute
- Hans J. P. M. Koenen
- Department of Laboratory Medicine, Laboratory for Medical Immunology, Radboud University Medical Center
- Sebo Withoff
- Department of Genetics, University of Groningen, University Medical Center Groningen
- Iris H. Jonkers
- Department of Genetics, University of Groningen, University Medical Center Groningen
- Romana T. Netea-Maier
- Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center
- Ramnik J. Xavier
- Broad Institute of MIT and Harvard University
- Lude Franke
- Department of Genetics, University of Groningen, University Medical Center Groningen
- Cheng-Jian Xu
- Department of Computational Biology for Individualised Medicine, Centre for Individualised Infection Medicine, CiiM, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research
- Leo A. B. Joosten
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center
- Serena Sanna
- Department of Genetics, University of Groningen, University Medical Center Groningen
- Mohit Jain
- Departments of Medicine and Pharmacology, University of California
- Vinod Kumar
- Department of Genetics, University of Groningen, University Medical Center Groningen
- Hans Clevers
- Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht
- Cisca Wijmenga
- Department of Genetics, University of Groningen, University Medical Center Groningen
- Mihai G. Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center
- Yang Li
- Department of Genetics, University of Groningen, University Medical Center Groningen
- DOI
- https://doi.org/10.1186/s13059-021-02413-z
- Journal volume & issue
-
Vol. 22,
no. 1
pp. 1 – 22
Abstract
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.
Keywords
