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

Genome Biology

Ramnik J. Xavier¹  Valerie A. C. M. Koeken²  Cheng-Jian Xu²  Sebo Withoff³  Olivier B. Bakker³  Iris H. Jonkers³  Serena Sanna³  Vinod Kumar³  Raul Aguirre-Gamboa³  Lude Franke³  Xiaojing Chu⁴  Yang Li⁵  Cisca Wijmenga⁶  Vera P. Mourits⁷  Martin Jaeger⁷  Charlotte de Bree⁷  Simone Moorlag⁷  Trees Jansen⁷  Marije Oosting⁷  Sanne P. Smeekens⁷  Leo A. B. Joosten⁷  Mihai G. Netea⁸  Romana T. Netea-Maier⁹  Hans J. P. M. Koenen^1,10  Irma Joosten^1,10  Mahan Najhawan^1,11  Mohit Jain^1,11  Khoi Dao^1,11  Jeramie D. Watrous^1,11  Ian T. Mathews^1,12  Sonia Sharma^1,13  Joep Beumer^1,14  Hans Clevers^1,15 

[1] Broad Institute of MIT and Harvard University, 02142, Cambridge, MA, USA;Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard School of Medicine, 02114, Boston, MA, USA;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, Hannover, Germany;TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany;Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525, Nijmegen, HP, the Netherlands;Department of Genetics, University of Groningen, University Medical Center Groningen, 9700, Groningen, RB, the Netherlands;Department of Genetics, University of Groningen, University Medical Center Groningen, 9700, Groningen, RB, the Netherlands;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, Hannover, Germany;TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany;Department of Genetics, University of Groningen, University Medical Center Groningen, 9700, Groningen, RB, the Netherlands;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, Hannover, Germany;TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany;Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525, Nijmegen, HP, the Netherlands;Department of Genetics, University of Groningen, University Medical Center Groningen, 9700, Groningen, RB, the Netherlands;Department of Immunology, University of Oslo, Oslo University Hospital, Rikshospitalet, 0372, Oslo, Norway;Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525, Nijmegen, HP, the Netherlands;Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525, Nijmegen, HP, the Netherlands;Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115, Bonn, Germany;Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, 6525, Nijmegen, HP, the Netherlands;Department of Laboratory Medicine, Laboratory for Medical Immunology, Radboud University Medical Center, 6525, Nijmegen, GA, the Netherlands;Departments of Medicine and Pharmacology, University of California, San Diego, CA, USA;Departments of Medicine and Pharmacology, University of California, San Diego, CA, USA;La Jolla Institute, La Jolla, CA, USA;La Jolla Institute, La Jolla, CA, USA;Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, 3584, Utrecht, CT, the Netherlands;Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, 3584, Utrecht, CT, the Netherlands;Oncode Institute, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584, Utrecht, CS, the Netherlands;

关键词: Metabolomics;    Genomics;    Immune phenotypes;    Integrative analysis;   

DOI  :  10.1186/s13059-021-02413-z

来源: Springer

【 摘 要 】

BackgroundRecent 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.ResultWe 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.ConclusionThis 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.

【 授权许可】

CC BY