TY - JOUR
T1 - Identification of glucocorticoid-related molecular signature by whole blood methylome analysis
AU - Armignacco, Roberta
AU - Jouinot, Anne
AU - Bouys, Lucas
AU - Septier, Amandine
AU - Lartigue, Thomas
AU - Neou, Mario
AU - Gaspar, Cassandra
AU - Perlemoine, Karine
AU - Braun, Leah
AU - Riester, Anna
AU - Bonnet-Serrano, Fidéline
AU - Blanchard, Anne
AU - Amar, Laurence
AU - Scaroni, Carla
AU - Ceccato, Filippo
AU - Rossi, Gian Paolo
AU - Williams, Tracy Ann
AU - Larsen, Casper K.
AU - Allassonnière, Stéphanie
AU - Zennaro, Maria Christina
AU - Beuschlein, Felix
AU - Reincke, Martin
AU - Bertherat, Jérôme
AU - Assié, Guillaume
N1 - Publisher Copyright:
© 2022 The authors.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - 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 ins ufficiency. 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 (~850 000 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 sample s 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 speci fic 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 assessment of glucocorticoid action beyond hormone assays.
AB - 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 ins ufficiency. 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 (~850 000 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 sample s 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 speci fic 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 assessment of glucocorticoid action beyond hormone assays.
U2 - 10.1530/EJE-21-0907
DO - 10.1530/EJE-21-0907
M3 - Article
C2 - 34914631
AN - SCOPUS:85123651151
SN - 0804-4643
VL - 186
SP - 297
EP - 308
JO - European Journal of Endocrinology
JF - European Journal of Endocrinology
IS - 2
ER -
