1. Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease.
- Author
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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, and Li Y
- Subjects
- Adolescent, Adult, Aged, Alanine blood, Alanine immunology, Arachidonic Acid blood, Arachidonic Acid immunology, Cohort Studies, Female, Genome-Wide Association Study, Genomics methods, Glutamic Acid blood, Glutamic Acid immunology, Healthy Volunteers, Humans, Male, Metabolic Networks and Pathways immunology, Metabolomics methods, Middle Aged, Immunity, Innate genetics, Metabolic Networks and Pathways genetics, Phenotype, Quantitative Trait Loci
- 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.
- Published
- 2021
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