Glucocorticoid receptor haplotypes conferring increased sensitivity (BclI and N363S) are associated with faster progression of multiple sclerosis

• GR haplotypes conferring high GC sensitivity are associated with more aggressive MS.
• GR haplotype make-up does not affect cortisol secretion by the HPA-axis or shedding of CD163.
• Cortisol and soluble CD163 levels in the CSF of MS patients are positively correlated.

As high cortisol levels are implicated in suppressed disease activity of multiple sclerosis (MS), glucocorticoid receptor (GR) polymorphisms that affect glucocorticoid (GC) sensitivity may impact on this by changing local immunomodulation or regulation of the hypothalamus–pituitary–adrenal (HPA)-axis. In this post-mortem study, we investigated whether GR haplotypes affect MS disease course and production of cortisol and soluble CD163 (sCD163), a molecule induced by GC on microglia/macrophages. We found that GR haplotypes that confer high GC sensitivity are associated with more aggressive MS but do not affect levels of cortisol secreted by the HPA-axis or shedding of CD163.