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Abstract:
BACKGROUND: Impaired stress resilience and a dysfunctional
hypothalamic-pituitary-adrenal (HPA) axis are suggested to play key
roles in the pathophysiology of illness progression in bipolar disorder
(BD), but the mechanisms leading to this dysfunction have never been
elucidated. This study aimed to examine HPA axis activity and underlying
molecular mechanisms in patients with BD and unaffected siblings of BD
patients.
METHODS: Twenty-four euthymic patients with BD, 18 siblings of BD
patients, and 26 healthy controls were recruited for this study. All
subjects underwent a dexamethasone suppression test followed by analyses
associated with the HPA axis and the glucocorticoid receptor (GR).
RESULTS: Patients with BD, particularly those at a late stage of
illness, presented increased salivary post-dexamethasone cortisol levels
when compared to controls (p = 0.015). Accordingly, these patients
presented reduced ex vivo GR responsiveness (p = 0.008) and increased
basal protein levels of FK506-binding protein 51 (FKBP51, p = 0.012), a
co-chaperone known to desensitize GR, in peripheral blood mononuclear
cells. Moreover, BD patients presented increased methylation at the
FK506-binding protein 5 (FKBP5) gene. BD siblings presented
significantly lower FKBP51 protein levels than BD patients, even though
no differences were found in FKBP5 basal mRNA levels.
CONCLUSIONS: Our data suggest that the epigenetic modulation of the
FKBP5 gene, along with increased FKBP51 levels, is associated with the
GR hyporesponsiveness seen in BD patients. Our findings are consistent
with the notion that unaffected first-degree relatives of BD patients
share biological factors that influence the disorder, and that such
changes are more pronounced in the late stages of the illness.
