4.5 Article

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

Journal

GENOME BIOLOGY
Volume 22, Issue 1, Pages -

Publisher

BMC
DOI: 10.1186/s13059-021-02413-z

Keywords

Metabolomics; Genomics; Immune phenotypes; Integrative analysis

Funding

  1. National Institutes of Health (NIH) [R01ES027595, S10OD020025, R01CA199376, K01DK116917, F31CA236405]
  2. China Scholarship Council [201706040081]
  3. Netherlands Organization for Scientific Research (NWO) VENI grant [016.176.006]
  4. NIH [DK43351, AT009708, AI137325, T32GM007752]
  5. ERC Advanced Grant [833247, FP/2007-2013/ERC, 2012-322698]
  6. INCONTROL CVON grant [CVON2012-03]
  7. NWO Spinoza prize [NWO SPI 92-266]
  8. ERC Starting Grant [948207]
  9. Radboud University Medical Centre Hypatia Grant
  10. Projekt DEAL

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This study systematically investigated circulating metabolites in healthy subjects, revealing significant impact of major metabolic pathways on cytokine production. Through genome-wide association analysis, genetic regulation of metabolites associated with immune phenotypes was examined, leading to the identification of a locus causally associated with Crohn's disease.
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.

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