Integrative Analysis of the Inflammatory Bowel Disease Serum Metabolome Improves Our Understanding of Genetic Etiology and Points to Novel Putative Therapeutic Targets.
Acyl-CoA Dehydrogenase
/ genetics
Adolescent
Adult
Aged
Aged, 80 and over
Biomarkers
/ blood
Butyrates
/ blood
Case-Control Studies
Child
Child, Preschool
Colitis, Ulcerative
/ blood
Crohn Disease
/ blood
Cross-Sectional Studies
Feces
/ chemistry
Female
Genome-Wide Association Study
Genotype
HEK293 Cells
Humans
Male
Mendelian Randomization Analysis
Metabolome
Middle Aged
Plasmalogens
/ blood
Quantitative Trait Loci
Severity of Illness Index
Young Adult
Differential Metabolite Abundance Analysis
Inflammatory Bowel Disease
Mendelian Randomization
Metabolome
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
received:
25
01
2021
revised:
01
11
2021
accepted:
07
11
2021
pubmed:
16
11
2021
medline:
9
3
2022
entrez:
15
11
2021
Statut:
ppublish
Résumé
Polygenic and environmental factors are underlying causes of inflammatory bowel disease (IBD). We hypothesized that integration of the genetic loci controlling a metabolite's abundance, with known IBD genetic susceptibility loci, may help resolve metabolic drivers of IBD. We measured the levels of 1300 metabolites in the serum of 484 patients with ulcerative colitis (UC) and 464 patients with Crohn's disease (CD) and 365 controls. Differential metabolite abundance was determined for disease status, subtype, clinical and endoscopic disease activity, as well as IBD phenotype including disease behavior, location, and extent. To inform on the genetic basis underlying metabolic diversity, we integrated metabolite and genomic data. Genetic colocalization and Mendelian randomization analyses were performed using known IBD risk loci to explore whether any metabolite was causally associated with IBD. We found 173 genetically controlled metabolites (metabolite quantitative trait loci, 9 novel) within 63 non-overlapping loci (7 novel). Furthermore, several metabolites significantly associated with IBD disease status and activity as defined using clinical and endoscopic indexes. This constitutes a resource for biomarker discovery and IBD biology insights. Using this resource, we show that a novel metabolite quantitative trait locus for serum butyrate levels containing ACADS was not supported as causal for IBD; replicate the association of serum omega-6 containing lipids with the fatty acid desaturase 1/2 locus and identify these metabolites as causal for CD through Mendelian randomization; and validate a novel association of serum plasmalogen and TMEM229B, which was predicted as causal for CD. An exploratory analysis combining genetics and unbiased serum metabolome surveys can reveal novel biomarkers of disease activity and potential mediators of pathology in IBD.
Sections du résumé
BACKGROUND & AIMS
Polygenic and environmental factors are underlying causes of inflammatory bowel disease (IBD). We hypothesized that integration of the genetic loci controlling a metabolite's abundance, with known IBD genetic susceptibility loci, may help resolve metabolic drivers of IBD.
METHODS
We measured the levels of 1300 metabolites in the serum of 484 patients with ulcerative colitis (UC) and 464 patients with Crohn's disease (CD) and 365 controls. Differential metabolite abundance was determined for disease status, subtype, clinical and endoscopic disease activity, as well as IBD phenotype including disease behavior, location, and extent. To inform on the genetic basis underlying metabolic diversity, we integrated metabolite and genomic data. Genetic colocalization and Mendelian randomization analyses were performed using known IBD risk loci to explore whether any metabolite was causally associated with IBD.
RESULTS
We found 173 genetically controlled metabolites (metabolite quantitative trait loci, 9 novel) within 63 non-overlapping loci (7 novel). Furthermore, several metabolites significantly associated with IBD disease status and activity as defined using clinical and endoscopic indexes. This constitutes a resource for biomarker discovery and IBD biology insights. Using this resource, we show that a novel metabolite quantitative trait locus for serum butyrate levels containing ACADS was not supported as causal for IBD; replicate the association of serum omega-6 containing lipids with the fatty acid desaturase 1/2 locus and identify these metabolites as causal for CD through Mendelian randomization; and validate a novel association of serum plasmalogen and TMEM229B, which was predicted as causal for CD.
CONCLUSIONS
An exploratory analysis combining genetics and unbiased serum metabolome surveys can reveal novel biomarkers of disease activity and potential mediators of pathology in IBD.
Identifiants
pubmed: 34780722
pii: S0016-5085(21)03738-0
doi: 10.1053/j.gastro.2021.11.015
pmc: PMC9214725
mid: NIHMS1807987
pii:
doi:
Substances chimiques
Biomarkers
0
Butyrates
0
Plasmalogens
0
Acyl-CoA Dehydrogenase
EC 1.3.8.7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
828-843.e11Subventions
Organisme : NIDDK NIH HHS
ID : K23 DK129762
Pays : United States
Organisme : NIDDK NIH HHS
ID : RC2 DK122532
Pays : United States
Organisme : NIH HHS
ID : S10 OD026880
Pays : United States
Organisme : NIH HHS
ID : S10 OD030463
Pays : United States
Informations de copyright
Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.
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