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Cited by 36Adrenal Hormones and DisordersStress Responses and CortisolEstrogen and related hormone effects

Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial

Open access
Chantzichristos, Dimitrios, Svensson, Per-Arne, Garner, Terence, Glad, Camilla AM, Walker, Brian R, Bergthorsdottir, Ragnhildur, Ragnarsson, Oskar, Trimpou, Penelope +7 more·2021·eLife
DOI 10.7554/elife.62236PMC PMC8024021
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Abstract

Background: Glucocorticoids are among the most commonly prescribed drugs, but there is no biomarker that can quantify their action. The aim of the study was to identify and validate circulating biomarkers of glucocorticoid action. Methods: In a randomized, crossover, single-blind, discovery study, 10 subjects with primary adrenal insufficiency (and no other endocrinopathies) were admitted at the in-patient clinic and studied during physiological glucocorticoid exposure and withdrawal. A randomization plan before the first intervention was used. Besides mild physical and/or mental fatigue and salt craving, no serious adverse events were observed. The transcriptome in peripheral blood mononuclear cells and adipose tissue, plasma miRNAomic, and serum metabolomics were compared between the interventions using integrated multi-omic analysis. Results: We identified a transcriptomic profile derived from two tissues and a multi-omic cluster, both predictive of glucocorticoid exposure. A microRNA (miR-122-5p) that was correlated with genes and metabolites regulated by glucocorticoid exposure was identified (p=0.009) and replicated in independent studies with varying glucocorticoid exposure (0.01 ≤ p≤0.05). Conclusions: We have generated results that construct the basis for successful discovery of biomarker(s) to measure effects of glucocorticoids, allowing strategies to individualize and optimize glucocorticoid therapy, and shedding light on disease etiology related to unphysiological glucocorticoid exposure, such as in cardiovascular disease and obesity. Funding: The Swedish Research Council (Grant 2015-02561 and 2019-01112); The Swedish federal government under the LUA/ALF agreement (Grant ALFGBG-719531); The Swedish Endocrinology Association; The Gothenburg Medical Society; Wellcome Trust; The Medical Research Council, UK; The Chief Scientist Office, UK; The Eva Madura’s Foundation; The Research Foundation of Copenhagen University Hospital; and The Danish Rheumatism Association. Clinical trial number: NCT02152553 .

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Authors
Chantzichristos, D., Svensson, P.-A., Garner, T., Glad, C. A., Walker, B. R., Bergthorsdottir, R., Ragnarsson, O., Trimpou, P., Stimson, R. H., Borresen, S. W., Feldt-Rasmussen, U., Jansson, P.-A., Skrtic, S., Stevens, A., & Johannsson, G.
Affiliations
  • Sahlgrenska University Hospital (SE)
  • University of Gothenburg (SE)
  • University of Manchester (GB)
  • Newcastle University (GB)
  • Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  • University of Edinburgh (GB)
  • University of Copenhagen (DK)
  • Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital, Copenhagen, Denmark
Corresponding author
Chantzichristos, Dimitrios
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2021-04-06
Volume
10
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.62236
PMC
PMC8024021
OpenAlex
W3145234731
Cited by
36
References
97
Citations by year
2026: 5 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 10 · 2021: 4 · 2020: 1
FWCI
4.67
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • Research Explorer (The University of Manchester) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • Newcastle University ePrints (Newcastle Univesity) (cc-by)
Funders
  • Vetenskapsrådet (Project 2015-02561 and 2019-01112)
  • The Swedish federal government under the LUA/ALF agreement (Project ALFGBG-719531)
  • The Swedish Endocrinology Association
  • Gothenburg Medical Society
  • Wellcome Trust (Investigator Award)
  • Medical Research Council (MR/K010271/1)
  • Chief Scientist Office (SCAF/17/02)
  • The Eva Madura's Foundation
  • Rigshospitalet
  • Danish Rheumatism Association
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
glucocorticoids, Addison's disease, glucocorticoid withdrawal, miR-122-5p, microRNA, peripheral blood mononuclear cells, adipose tissue transcriptome, plasma microRNA, serum metabolomics, multi-omics integration
MeSH terms
Adipose Tissue, Adult, Cross-Sectional Studies, Denmark, Female, Glucocorticoids, Humans, Leukocytes, Mononuclear, Male, Middle Aged, Plasma, Random Allocation, Scotland, Sweden, Biomarkers, Case-Control Studies, Single-Blind Method, Cross-Over Studies, MicroRNAs, Serum, Young Adult, Transcriptome

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