Circadian rhythm of glucocorticoid administration entrains clock genes in immune cells: A DREAM trial ancillary study

Abstract

Context: Adrenal insufficiency (AI) requires life-long glucocorticoid replacement. Conventional therapies fail to mimic the endogenous cortisol circadian rhythm. Clock genes are essential components of the molecular machinery controlling an organ's circadian function and are influenced by glucocorticoids. However, clock gene expression has never been investigated in AI patients. Objective: To evaluate the effect of the timing of glucocorticoid administration on circadian gene expression in peripheral blood mononuclear cells (PBMCs) of AI patients from the DREAM trial. Design: Outcome assessors blinded, randomized, active comparator clinical trial. Participants and Intervention: Eighty-nine AI patients taking glucocorticoids were randomly assigned to continue their multiple daily doses, or switch to an equivalent dose of once-daily modified-release hydrocortisone, and compared to 25 healthy controls: 65 AI patients and 18 controls consented gene expression analysis by real-time qRT-PCR. Results: Compared to healthy controls, 19 of the 68 genes were found differentially expressed in AI patients at baseline, 18 of which were restored to control levels 12 week after switching therapy, comprising: ARNTL[BMAL] (P=0.024), CLOCK (P=0.016), PER3 (P<0.001), TIMELESS (<0.001), AANAT (p=0.021), CAMK2D (p<0.001), CREB1 (p=0.010), CREB3 (p=0.037), MAPK1 (p<0.001), MAT2A (p=0.013), PRKAR1A (p=0.006), PRKAR2A (p=0.006), PRKCB (p=0.006); SP1 (p<0.001), WEE1 (p<0.001), CSNK1A1 (p<0.001), ONP3 (p<0.001) and PRF1 (p<0.001). Changes in WEE1, PRF1 and PER3 expression correlated with glycated hemoglobin, inflammatory monocytes and CD16+ NK cells. Conclusions: AI patients on standard therapy exhibit a dysregulation of circadian genes in PBMCs. The once-daily administration reconditions peripheral tissue gene expression to levels close to healthy controls, paralleling the clinical outcomes of the DREAM trial [NCT02277587]. The Journal of Clinical Endocrinology & Metabolism;