BXD mice; UK Biobank; computational biology; high-fat diet; human; inflammatory bowel disease (IBD); module quantitative trait locus (ModQTL) mapping; mouse; systems biology; systems genetics; Mice; Humans; Animals; Quantitative Trait Loci; Diet, High-Fat/adverse effects; Inflammation/genetics; Inflammation/complications; Genetic Predisposition to Disease; Inflammatory Bowel Diseases/genetics; Inflammatory Bowel Diseases/metabolism; Diet, High-Fat; Inflammation; Inflammatory Bowel Diseases; Neuroscience (all); Biochemistry, Genetics and Molecular Biology (all); Immunology and Microbiology (all); General Immunology and Microbiology; General Biochemistry, Genetics and Molecular Biology; General Medicine; General Neuroscience
Abstract :
[en] Inflammatory gut disorders, including inflammatory bowel disease (IBD), can be impacted by dietary, environmental, and genetic factors. While the incidence of IBD is increasing worldwide, we still lack a complete understanding of the gene-by-environment interactions underlying inflammation and IBD. Here, we profiled the colon transcriptome of 52 BXD mouse strains fed with a chow or high-fat diet (HFD) and identified a subset of BXD strains that exhibit an IBD-like transcriptome signature on HFD, indicating that an interplay of genetics and diet can significantly affect intestinal inflammation. Using gene co-expression analyses, we identified modules that are enriched for IBD-dysregulated genes and found that these IBD-related modules share cis-regulatory elements that are responsive to the STAT2, SMAD3, and REL transcription factors. We used module quantitative trait locus analyses to identify genetic loci associated with the expression of these modules. Through a prioritization scheme involving systems genetics in the mouse and integration with external human datasets, we identified Muc4 and Epha6 as the top candidates mediating differences in HFD-driven intestinal inflammation. This work provides insights into the contribution of genetics and diet to IBD risk and identifies two candidate genes, MUC4 and EPHA6, that may mediate IBD susceptibility in humans.
Disciplines :
Genetics & genetic processes
Author, co-author :
Li, Xiaoxu ; Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Morel, Jean-David; Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Benegiamo, Giorgia ; Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Poisson, Johanne ; Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Bachmann, Alexis; Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Rapin, Alexis; Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Sulc, Jonathan; Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
WILLIAMS, Evan ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Gene Expression and Metabolism
Perino, Alessia; Laboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Schoonjans, Kristina ; Laboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Bou Sleiman, Maroun; Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Auwerx, Johan ; Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
External co-authors :
yes
Language :
English
Title :
Genetic and dietary modulators of the inflammatory response in the gastrointestinal tract of the BXD mouse genetic reference population.
European Research Council National Research Foundation of Korea China Scholarship Council
Funding text :
We thank the Schoonjans’ and Auwerx’s lab members for technical assistance and discussions and Giacomo von Alvensleben for providing the GWAS analysis pipeline in human UKBB. The work in the JA laboratory was supported by grants from the Ecole Polytechnique Fédérale de Lausanne (EPFL), the European Research Council (ERC-AdG-787702), the Swiss National Science Foundation (SNSF 31003A_179435), and the Global Research Laboratory (GRL) National Research Foundation of Korea (NRF 2017K1A1A2013124). XL was supported by the China Scholarship Council (201906050019).
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