Integration of Metabolomics, Genomics, and Immune Phenotypes Reveals the Causal Roles of Metabolites in Disease

Overview

Journal Genome Biol

Specialties Biology
Genetics

Date 2021 Jul 7

PMID 34229738

Citations 28

Authors

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

Soon will be listed here.

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.

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