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Identification of glucocorticoid-related molecular signature by whole blood methylome analysis

Roberta Armignacco 1 Anne Jouinot 1 Lucas Bouys 1 Amandine Septier 1 Thomas Lartigue 2, 3 Mario Neou 1 Cassandra Gaspar 4 Karine Perlemoine 1 Leah Braun 5 Anna Riester 5 Fidéline Bonnet-Serrano 1, 6 Anne Blanchard 7 Laurence Amar 8, 9 Carla Scaroni 10 Filippo Ceccato 10 Gian Paolo Rossi 11 Tracy Ann Williams 12 Casper K. Larsen 8 Stéphanie Allassonnière 13, 14 Maria-Christina Zennaro 8, 15 Felix Beuschlein 5, 16 Martin Reincke 5 Jerome Bertherat 1, 17 Guillaume Assié 1, 17 
Abstract : Objective: Cushing’s syndrome represents a state of excessive glucocorticoids related to glucocorticoid treatments or to endogenous hypercortisolism. Cushing’s syndrome is associated with high morbidity, with significant inter-individual variability. Likewise, adrenal insufficiency is a life-threatening condition of cortisol deprivation. Currently, hormone assays contribute to identify Cushing’s syndrome or adrenal insufficiency. However, no biomarker directly quantifies the biological glucocorticoid action. The aim of this study was to identify such markers. Design: We evaluated whole blood DNA methylome in 94 samples obtained from patients with different glucocorticoid states (Cushing’s syndrome, eucortisolism, adrenal insufficiency). We used an independent cohort of 91 samples for validation. Methods: Leukocyte DNA was obtained from whole blood samples. Methylome was determined using the Illumina methylation chip array (~850000 CpG sites). Both unsupervised (Principal Component Analysis) and supervised (Limma) methods were used to explore methylome profiles. A Lasso-penalized regression was used to select optimal discriminating features. Results: Whole blood methylation profile was able to discriminate samples by their glucocorticoid status: glucocorticoid excess was associated with DNA hypomethylation, recovering within months after Cushing’s syndrome correction. In Cushing’s syndrome, an enrichment in hypomethylated CpG sites was observed in the region of FKBP5 gene locus. A methylation predictor of glucocorticoid excess was built on a training cohort and validated on two independent cohorts. Potential CpG sites associated with the risk for specific complications, such as glucocorticoid-related hypertension or osteoporosis, were identified, needing now to be confirmed on independent cohorts. Conclusions: Whole blood DNA methylome is dynamically impacted by glucocorticoids. This biomarker could contribute to better assess glucocorticoid action beyond hormone assays.
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Submitted on : Monday, December 20, 2021 - 3:53:59 PM
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[1479683X - European Journal o...
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Roberta Armignacco, Anne Jouinot, Lucas Bouys, Amandine Septier, Thomas Lartigue, et al.. Identification of glucocorticoid-related molecular signature by whole blood methylome analysis. European Journal of Endocrinology, 2021, pp.EJE-21-0907.R1. ⟨10.1530/EJE-21-0907⟩. ⟨hal-03497285⟩



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