Abstract
Original language | English |
---|---|
Pages (from-to) | 828-843.e11 |
Number of pages | 16 |
Journal | Gastroenterology |
Volume | 162 |
Issue number | 3 |
DOIs | |
Publication status | Published - 1 Mar 2022 |
Keywords
- Differential Metabolite Abundance Analysis
- Inflammatory Bowel Disease
- Mendelian Randomization
- Metabolome
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In: Gastroenterology, Vol. 162, No. 3, 01.03.2022, p. 828-843.e11.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Integrative Analysis of the Inflammatory Bowel Disease Serum Metabolome Improves Our Understanding of Genetic Etiology and Points to Novel Putative Therapeutic Targets
AU - di'Narzo, Antonio F.
AU - Houten, Sander M.
AU - Kosoy, Roman
AU - Huang, Ruiqi
AU - Vaz, Frédéric M.
AU - Hou, Ruixue
AU - Wei, Gabrielle
AU - Wang, Wenhui
AU - Comella, Phillip H.
AU - Dodatko, Tetyana
AU - Rogatsky, Eduard
AU - Stojmirovic, Aleksandar
AU - Brodmerkel, Carrie
AU - Perrigoue, Jacqueline
AU - Hart, Amy
AU - Curran, Mark
AU - Friedman, Joshua R.
AU - Zhu, Jun
AU - Agrawal, Manasi
AU - Cho, Judy
AU - Ungaro, Ryan
AU - Dubinsky, Marla C.
AU - Sands, Bruce E.
AU - Suárez-Fariñas, Mayte
AU - Schadt, Eric E.
AU - Colombel, Jean-Frédéric
AU - Kasarskis, Andrew
AU - Hao, Ke
AU - Argmann, Carmen
N1 - Funding Information: Funding Mount Sinai co-authors (from Department of Genetics and Genomics Sciences, Icahn Institute for Data Science and Genomic Technology, Population Health Science and Policy, Division of Gastroenterology, Pediatric GI and Hepatology, Susan and Leonard Feinstein IBD Clinical Center at Icahn School of Medicine at Mount Sinai) were partially funded as part of the research alliance between Janssen Biotech and The Icahn School of Medicine at Mount Sinai. R.C.U. is supported by an National Institutes of Health K23 Career Development Award (K23KD111995-01A1). M.A. receives research support from the Dickler Family Fund, New York Community Trust, and the Leona M. and Harry B. Helmsley Charitable Trust Fund for Surveillance of Coronavirus Under Research Exclusion for IBD (SECURE-IBD). C.A. and E.S. receive research support from Leona M. and Harry B. Helmsley Charitable Trust and C.A. was a recipient of a Litwin IBD Pioneer’s Award from the Crohn’s and Colitis Foundation. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Funding Information: Carmen Argmann, PhD (Conceptualization: Lead; Formal analysis: Supporting; Investigation: Supporting; Validation: Supporting; Visualization: Equal; Writing – original draft: Lead; Writing – review & editing: Lead). Antonio F. Di'Narzo, PhD (Data curation: Equal; Formal analysis: Equal; Methodology: Equal; Writing – original draft: Supporting; Writing – review & editing: Supporting). Sander M. Houten, PhD (Conceptualization: Equal; Formal analysis: Supporting; Methodology: Supporting; Validation: Equal; Writing – original draft: Supporting; Writing – review & editing: Supporting). Roman Kosoy, PhD (Data curation: Supporting). Ruiqi Huang, MSc (Data curation: Supporting). Frédéric M. Vaz, PhD (Validation: Supporting). Ruixue Hou, PhD (Data curation: Supporting). Gabrielle Wei, BSc (Data curation: Supporting). Wenhui Wang, PhD (Formal analysis: Supporting). Phillip H. Comella, BSc (Data curation: Supporting). Tetyana Dodatko, PhD (Validation: Supporting). Eduard Rogatsky, PhD (Validation: Supporting). Aleksandar Stojmirovic, PhD (Conceptualization: Supporting; Resources: Supporting). Carrie Brodmerkel, PhD (Conceptualization: Supporting; Funding acquisition: Supporting). Jacqueline Perrigoue, PhD (Conceptualization: Supporting; Data curation: Supporting). Amy Hart, PhD (Data curation: Supporting; Formal analysis: Supporting). Mark Curran, PhD (Conceptualization: Supporting; Funding acquisition: Supporting). Joshua R. Friedman, MD (Conceptualization: Supporting; Funding acquisition: Supporting). Jun Zhu, PhD (Formal analysis: Supporting; Supervision: Supporting). Manasi Agrawal, MD (Writing – review & editing: Supporting). Judy Cho, MD (Writing – review & editing: Supporting). Ryan Ungaro, MD (Writing – review & editing: Supporting). Marla C. Dubinsky, MD (Conceptualization: Supporting; Funding acquisition: Supporting). Bruce E. Sands, MD (Conceptualization: Supporting; Funding acquisition: Supporting). Mayte Suárez-Fariñas, PhD (Data curation: Supporting). Eric E. Schadt, PhD (Conceptualization: Supporting; Funding acquisition: Supporting; Writing – review & editing: Supporting). Jean-Frédéric Colombel, MD (Writing – review & editing: Supporting). Andrew Kasarskis, PhD (Conceptualization: Supporting; Funding acquisition: Supporting). Ke Hao, PhD (Conceptualization: Supporting; Formal analysis: Equal; Methodology: Equal; Supervision: Equal; Writing – review & editing: Supporting). Conflicts of interest R.C.U. has served as an advisory board member or consultant for Eli Lilly, Janssen, Pfizer, and Takeda. M.C., A.S., A.H., J.P., and C.B. are employees at Janssen Research and Development. J.R.F. is a former employee at Janssen Research and Development and is currently employed at Alnylam Pharmaceuticals. M.D. is a consultant for Janssen. B.E.S. discloses consulting fees from 4D Pharma, Abbvie, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, BoehringerIngelheim, Boston Pharmaceuticals, Capella Biosciences, Celgene, Celltrion Healthcare, EnGene, Ferring, Genentech, Gilead, Hoffmann-La Roche, Immunic, Ironwood Pharmaceuticals, Janssen, Lilly, Lyndra, MedImmune, Morphic Therapeutic, Oppilan Pharma, OSE Immunotherapeutics, Otsuka, Palatin Technologies, Pfizer, Progenity, Prometheus Laboratories, Redhill Biopharma, Rheos Medicines, Seres Therapeutics, Shire, Synergy Pharmaceuticals, Takeda, Target PharmaSolutions, Theravance Biopharma R&D, TiGenix, and Vivelix Pharmaceuticals; honoraria for speaking in Continuing Medical Education programs from Takeda, Janssen, Lilly, Gilead, Pfizer, and Genetech; research funding from Celgene, Pfizer, Takeda, Theravance Biopharma R&D, and Janssen. M.C.D. discloses consulting fees from Abbvie, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, BoehringerIngelheim, Celgene, Ferring, Genentech, Gilead, Hoffmann-La Roche, Janssen, Pfizer, Prometheus Biosciences, Takeda, and Target PharmaSolutions and research funding from Abbvie, Janssen, Pfizer, and Prometheus Biosciences Takeda. J-F.C. received payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene Corporation, Celltrion, Eli Lilly, Enterome, Ferring Pharmaceuticals, Geneva, Genentech, Janssen Pharmaceuticals, Landos, Ipsen, Imedex, Medimmune, Merck, Novartis, O Mass, Otsuka, Pfizer, Shire, Takeda, Tigenix, and Viela bio; and holds stock options in Intestinal Biotech Development and Genfit. E.S., K.H., A.D., J.Z., and A.K. are associated with Sema4. Funding Mount Sinai co-authors (from Department of Genetics and Genomics Sciences, Icahn Institute for Data Science and Genomic Technology, Population Health Science and Policy, Division of Gastroenterology, Pediatric GI and Hepatology, Susan and Leonard Feinstein IBD Clinical Center at Icahn School of Medicine at Mount Sinai) were partially funded as part of the research alliance between Janssen Biotech and The Icahn School of Medicine at Mount Sinai. R.C.U. is supported by an National Institutes of Health K23 Career Development Award (K23KD111995-01A1). M.A. receives research support from the Dickler Family Fund, New York Community Trust, and the Leona M. and Harry B. Helmsley Charitable Trust Fund for Surveillance of Coronavirus Under Research Exclusion for IBD (SECURE-IBD). C.A. and E.S. receive research support from Leona M. and Harry B. Helmsley Charitable Trust and C.A. was a recipient of a Litwin IBD Pioneer's Award from the Crohn's and Colitis Foundation. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Publisher Copyright: © 2022 AGA Institute
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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.
AB - 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.
KW - Differential Metabolite Abundance Analysis
KW - Inflammatory Bowel Disease
KW - Mendelian Randomization
KW - Metabolome
UR - http://www.scopus.com/inward/record.url?scp=85125291422&partnerID=8YFLogxK
U2 - https://doi.org/10.1053/j.gastro.2021.11.015
DO - https://doi.org/10.1053/j.gastro.2021.11.015
M3 - Article
C2 - 34780722
SN - 0016-5085
VL - 162
SP - 828-843.e11
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -