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

• Published in: eLife Vol. 10
• Main Authors: Chantzichristos, Dimitrios, Svensson, Per-Arne, Garner, Terence, Glad, Camilla Am, Walker, Brian R, Bergthorsdottir, Ragnhildur, Ragnarsson, Oskar, Trimpou, Penelope, Stimson, Roland H, Borresen, Stina W, Feldt-Rasmussen, Ulla, Jansson, Per-Anders, Skrtic, Stanko, Stevens, Adam, Johannsson, Gudmundur
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 06.04.2021; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Adipose tissue; Adipose Tissue - metabolism; Adipose tissues; Adult; Adverse events; Analysis; Bioinformatics (Computational Biology); Bioinformatik (beräkningsbiologi); Biomarkers; Biomarkers - blood; Biomarkers - metabolism; Blindness; Blood pressure; Body fat; Cardiovascular diseases; Case-Control Studies; Computational and Systems Biology; Computer and Information Science; Corticosteroids; Cross-Over Studies; Cross-Sectional Studies; Data- och informationsvetenskap; Denmark; Disease; Drug addiction; Drug dosages; Drug withdrawal; Drugs; Endocrine disorders; Endocrinology; Endocrinology and Diabetes; Endokrinologi och diabetes; Etiology; Female; Gene expression; Glucocorticoids; Glucocorticoids - pharmacology; Hormones; Humans; Intervention; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Male; Medical research; Medicine; Medicine, Experimental; Metabolism; Metabolites; Metabolomics; microRNA; MicroRNAs; MicroRNAs - metabolism; Middle Aged; miRNA; multi-omics; Peripheral blood mononuclear cells; Physiological aspects; Physiology; Plasma - metabolism; Potassium; Prescribing; Random Allocation; Scotland; Serum - metabolism; Single-Blind Method; Skin; Sweden; Transcriptome; Transcriptomes; Transcriptomics; Young Adult; Denmark; Scotland; Sweden; United Kingdom; computational biology; systems biology; biomarkers; multi-omics; microRNA; medicine; glucocorticoids; human; metabolites; gene expression
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.62236

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. 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. 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). 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. 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. NCT02152553.