Background: Glucocorticoids exert profound immune-modulating effects and regulate the expression of genes involved in cell cycle progression and apoptosis. Synthetic glucocorticoids are the most potent agents used in the treatment of inflammatory, autoimmune and lymphoproliferative disorders. Considerable variation in response to therapeutic doses of glucocorticoids exists among individuals, as evidenced by differences both in disease response and in the incidence of glucocorticoid side-effects.
Objective and hypotheses: To identify novel glucocorticoid (GC) sensitivity-determining genes using genome-wide expression profiling in healthy volunteers.
Methods and Results: One hundred healthy adults were given 0.25 mg of Dexamethasone at midnight, and serum cortisol concentrations were determined at 08:00 h the following morning. Accordingly, subjects were polarized into the 10% most GC sensitive (n=10) and 10% most GC-resistant (n=10). Sequencing of the human glucocorticoid receptor (NR3C1) gene in the 20 subjects revealed no mutations or polymorphisms. RNA sequencing identified 133 upregulated and 49 downregulated genes involved in immune response and NF-κB cascade in the GC-resistant versus the GC-sensitive group. Several Systemic Lupus Erythematosus-associated genes were more active in the GC-sensitive group, while multiple targets of NR3C1 gene were positively regulated in the GC-resistant group. Cluster analysis in the expression profile of the 20 subjects revealed clear differences between the two groups with 3 GC-sensitive and 3 GC-resistant individuals. Differential expression analysis revealed upregulation of 900 and downregulation of 1100 additional genes. Alzheimer disease-amyloid secretase pathway, dopamine receptor-mediated signaling pathway and telomere maintenance were novel signaling pathways more active in the GC-sensitive subjects. Key molecules associated with neurological diseases, such as Synuclein A in Parkinsons disease, were upregulated in the GC-sensitive group. Finally, the NR3C2 gene was more active in the GC-resistant group.
Conclusion: Differences in tissue sensitivity to glucocorticoids among healthy adults are associated with differential expression of genes related to autoimmune and neurological disorders.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology