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Endocrine Abstracts (2015) 37 GP02.06 | DOI: 10.1530/endoabs.37.GP.02.06

ECE2015 Guided Posters Adrenal (1) (8 abstracts)

DNA methylation of FKBP5 and its relationship with hippocampal volumes in Cushing's syndrome patients

Eugenia Resmini 1, , Alicia Santos 1, , Anna Aulinas 1, , Susan Webb 1, , Beatriz Gómez-Anson 2, , Olivia Cox 4 & Richard Lee 4


1Endocrinology/Medicine Departments, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), IIB‐Sant Pau, ISCIII, Hospital Sant Pau, Barcelona, Spain; 2Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; 3Neuroradiology Unit, Hospital Sant Pau, and IIB‐Sant Pau, Barcelona, Spain; 4Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.


Introduction: FKBP5 is a protein that regulates glucocorticoid receptor sensitivity, via an ultra-short negative feedback mechanism. Variations in the FKBP5 gene can influence the response to glucocorticoids (GC). Hypercortisolaemia plays a role on impairment of brain function and could be mediated by epigenetic variations of the FKBP5 gene. Cushing’s syndrome (CS), a disease characterized by hypercortisolaemia, is associated with memory deficits, lower hippocampal volumes and a wide range of cognitive impairments. Recently, it has been demonstrated that GC-induced methylation changes in FKBP5 observed in blood DNA can serve as a proxy to both methylation and expression changes in the brain. We aimed at evaluating DNA methylation of FKBP5 in blood and its relationship with memory and hippocampal volumes (HV) in CS patients.

Patients and methods: 33 CS patients with memory impairments (nine active and 24 cured) and 33 matched healthy controls were included. Memory tests, 3Tesla MRI of the brain, and DNA extraction from total leukocytes was carried out in all subjects. DNA from CS patients and healthy controls were bisulfite treated, PCR amplified, and pyrosequenced to assess a total of 34 CpG dinucleotides in introns 1, 2, and 5 of the FKBP5 gene.

Results: We observed lower methylation in introns 2 and 5, in both cured and active CS patients compared to controls (P<0.001 and P<0.05 respectively). We also observed a positive correlation between the total methylation values and hippocampal volumes in active patients (r=0.86, P<0.01 left HV and r=0.80, P=0.01 right HV), but not with memory tests. However, there were multiple correlations between single CpG dinucleotides and memory test variables (P<0.01).

Conclusion: As lower DNA methylation in FKBP5 is associated with higher GC exposure and gene expression, our results demonstrate a relationship between blood DNA methylation and GC-induced brain impairments in CS patients.

Disclosure: This work was supported by Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (MICINN, FIS080302).

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