Reduced DNA methylation of FKBP5 in Cushing’s syndrome

Eugenia Resmini, Alicia Santos, Anna Aulinas, Susan M. Webb, Yolanda Vives-Gilabert, Olivia Cox, Gary S Wand, Richard Lee

Research output: Contribution to journalArticle

Abstract

FKBP5 encodes a co-chaperone of HSP90 protein that regulates intracellular glucocorticoid receptor sensitivity. When it is bound to the glucocorticoid receptor complex, cortisol binds with lower affinity to glucocorticoid receptor. Cushing’s syndrome is associated with memory deficits, smaller hippocampal volumes, and wide range of cognitive impairments. We aimed at evaluating blood DNA methylation of FKBP5 and its relationship with memory and hippocampal volumes in Cushing’s syndrome patients. Polymorphism rs1360780 in FKBP5 has also been assessed to determine whether genetic variations can also govern CpG methylation. Thirty-two Cushing’s syndrome patients and 32 matched controls underwent memory tests, 3-Tesla MRI of the brain, and DNA extraction from total leukocytes. DNA samples were bisulfite treated, PCR amplified, and pyrosequenced to assess a total of 41CpG-dinucleotides in the introns 1, 2, 5, and 7 of FKBP5. Significantly lower intronic FKBP5 DNA methylation in CS patients compared to controls was observed in ten CpG-dinucleotides. DNA methylation at these CpGs correlated with left and right HV (Intron-2-Region-2-CpG-3: LHV, r = 0.73, p = 0.02; RHV, r = 0.58, p = 0.03). Cured and active CS patients showed both lower methylation of intron 2 (92.37, 91.8, and 93.34 %, respectively, p = 0.03 for both) and of intron 7 (77.08, 73.74, and 79.71 %, respectively, p = 0.02 and p < 0.01) than controls. Twenty-two subjects had the CC genotype, 34 had the TC genotype, and eight had the TT genotype. Lower average DNA methylation in intron 7 was observed in the TT subjects compared to CC (72.5vs. 79.5 %, p = 0.02) and to TC (72.5 vs. 79.0 %, p = 0.03). Our data demonstrate, for the first time, a reduction of intronic DNA methylation of FKBP5 in CS patients.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalEndocrine
DOIs
StateAccepted/In press - Sep 23 2016

Fingerprint

Cushing Syndrome
DNA Methylation
Introns
Glucocorticoid Receptors
Genotype
Methylation
DNA
Memory Disorders
Hydrocortisone
Leukocytes
Polymerase Chain Reaction
Brain
Proteins

Keywords

  • 3Tesla MRI
  • Cushing’s syndrome
  • FKBP5 DNA methylation
  • FKBP5 polymorphism
  • Glucocorticoid resistance
  • Hypercortisolism

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Resmini, E., Santos, A., Aulinas, A., Webb, S. M., Vives-Gilabert, Y., Cox, O., ... Lee, R. (Accepted/In press). Reduced DNA methylation of FKBP5 in Cushing’s syndrome. Endocrine, 1-10. https://doi.org/10.1007/s12020-016-1083-6

Reduced DNA methylation of FKBP5 in Cushing’s syndrome. / Resmini, Eugenia; Santos, Alicia; Aulinas, Anna; Webb, Susan M.; Vives-Gilabert, Yolanda; Cox, Olivia; Wand, Gary S; Lee, Richard.

In: Endocrine, 23.09.2016, p. 1-10.

Research output: Contribution to journalArticle

Resmini, E, Santos, A, Aulinas, A, Webb, SM, Vives-Gilabert, Y, Cox, O, Wand, GS & Lee, R 2016, 'Reduced DNA methylation of FKBP5 in Cushing’s syndrome', Endocrine, pp. 1-10. https://doi.org/10.1007/s12020-016-1083-6
Resmini E, Santos A, Aulinas A, Webb SM, Vives-Gilabert Y, Cox O et al. Reduced DNA methylation of FKBP5 in Cushing’s syndrome. Endocrine. 2016 Sep 23;1-10. https://doi.org/10.1007/s12020-016-1083-6
Resmini, Eugenia ; Santos, Alicia ; Aulinas, Anna ; Webb, Susan M. ; Vives-Gilabert, Yolanda ; Cox, Olivia ; Wand, Gary S ; Lee, Richard. / Reduced DNA methylation of FKBP5 in Cushing’s syndrome. In: Endocrine. 2016 ; pp. 1-10.
@article{c194f18869754a96b505071fb491d077,
title = "Reduced DNA methylation of FKBP5 in Cushing’s syndrome",
abstract = "FKBP5 encodes a co-chaperone of HSP90 protein that regulates intracellular glucocorticoid receptor sensitivity. When it is bound to the glucocorticoid receptor complex, cortisol binds with lower affinity to glucocorticoid receptor. Cushing’s syndrome is associated with memory deficits, smaller hippocampal volumes, and wide range of cognitive impairments. We aimed at evaluating blood DNA methylation of FKBP5 and its relationship with memory and hippocampal volumes in Cushing’s syndrome patients. Polymorphism rs1360780 in FKBP5 has also been assessed to determine whether genetic variations can also govern CpG methylation. Thirty-two Cushing’s syndrome patients and 32 matched controls underwent memory tests, 3-Tesla MRI of the brain, and DNA extraction from total leukocytes. DNA samples were bisulfite treated, PCR amplified, and pyrosequenced to assess a total of 41CpG-dinucleotides in the introns 1, 2, 5, and 7 of FKBP5. Significantly lower intronic FKBP5 DNA methylation in CS patients compared to controls was observed in ten CpG-dinucleotides. DNA methylation at these CpGs correlated with left and right HV (Intron-2-Region-2-CpG-3: LHV, r = 0.73, p = 0.02; RHV, r = 0.58, p = 0.03). Cured and active CS patients showed both lower methylation of intron 2 (92.37, 91.8, and 93.34 {\%}, respectively, p = 0.03 for both) and of intron 7 (77.08, 73.74, and 79.71 {\%}, respectively, p = 0.02 and p < 0.01) than controls. Twenty-two subjects had the CC genotype, 34 had the TC genotype, and eight had the TT genotype. Lower average DNA methylation in intron 7 was observed in the TT subjects compared to CC (72.5vs. 79.5 {\%}, p = 0.02) and to TC (72.5 vs. 79.0 {\%}, p = 0.03). Our data demonstrate, for the first time, a reduction of intronic DNA methylation of FKBP5 in CS patients.",
keywords = "3Tesla MRI, Cushing’s syndrome, FKBP5 DNA methylation, FKBP5 polymorphism, Glucocorticoid resistance, Hypercortisolism",
author = "Eugenia Resmini and Alicia Santos and Anna Aulinas and Webb, {Susan M.} and Yolanda Vives-Gilabert and Olivia Cox and Wand, {Gary S} and Richard Lee",
year = "2016",
month = "9",
day = "23",
doi = "10.1007/s12020-016-1083-6",
language = "English (US)",
pages = "1--10",
journal = "Endocrine",
issn = "1355-008X",
publisher = "Humana Press",

}

TY - JOUR

T1 - Reduced DNA methylation of FKBP5 in Cushing’s syndrome

AU - Resmini, Eugenia

AU - Santos, Alicia

AU - Aulinas, Anna

AU - Webb, Susan M.

AU - Vives-Gilabert, Yolanda

AU - Cox, Olivia

AU - Wand, Gary S

AU - Lee, Richard

PY - 2016/9/23

Y1 - 2016/9/23

N2 - FKBP5 encodes a co-chaperone of HSP90 protein that regulates intracellular glucocorticoid receptor sensitivity. When it is bound to the glucocorticoid receptor complex, cortisol binds with lower affinity to glucocorticoid receptor. Cushing’s syndrome is associated with memory deficits, smaller hippocampal volumes, and wide range of cognitive impairments. We aimed at evaluating blood DNA methylation of FKBP5 and its relationship with memory and hippocampal volumes in Cushing’s syndrome patients. Polymorphism rs1360780 in FKBP5 has also been assessed to determine whether genetic variations can also govern CpG methylation. Thirty-two Cushing’s syndrome patients and 32 matched controls underwent memory tests, 3-Tesla MRI of the brain, and DNA extraction from total leukocytes. DNA samples were bisulfite treated, PCR amplified, and pyrosequenced to assess a total of 41CpG-dinucleotides in the introns 1, 2, 5, and 7 of FKBP5. Significantly lower intronic FKBP5 DNA methylation in CS patients compared to controls was observed in ten CpG-dinucleotides. DNA methylation at these CpGs correlated with left and right HV (Intron-2-Region-2-CpG-3: LHV, r = 0.73, p = 0.02; RHV, r = 0.58, p = 0.03). Cured and active CS patients showed both lower methylation of intron 2 (92.37, 91.8, and 93.34 %, respectively, p = 0.03 for both) and of intron 7 (77.08, 73.74, and 79.71 %, respectively, p = 0.02 and p < 0.01) than controls. Twenty-two subjects had the CC genotype, 34 had the TC genotype, and eight had the TT genotype. Lower average DNA methylation in intron 7 was observed in the TT subjects compared to CC (72.5vs. 79.5 %, p = 0.02) and to TC (72.5 vs. 79.0 %, p = 0.03). Our data demonstrate, for the first time, a reduction of intronic DNA methylation of FKBP5 in CS patients.

AB - FKBP5 encodes a co-chaperone of HSP90 protein that regulates intracellular glucocorticoid receptor sensitivity. When it is bound to the glucocorticoid receptor complex, cortisol binds with lower affinity to glucocorticoid receptor. Cushing’s syndrome is associated with memory deficits, smaller hippocampal volumes, and wide range of cognitive impairments. We aimed at evaluating blood DNA methylation of FKBP5 and its relationship with memory and hippocampal volumes in Cushing’s syndrome patients. Polymorphism rs1360780 in FKBP5 has also been assessed to determine whether genetic variations can also govern CpG methylation. Thirty-two Cushing’s syndrome patients and 32 matched controls underwent memory tests, 3-Tesla MRI of the brain, and DNA extraction from total leukocytes. DNA samples were bisulfite treated, PCR amplified, and pyrosequenced to assess a total of 41CpG-dinucleotides in the introns 1, 2, 5, and 7 of FKBP5. Significantly lower intronic FKBP5 DNA methylation in CS patients compared to controls was observed in ten CpG-dinucleotides. DNA methylation at these CpGs correlated with left and right HV (Intron-2-Region-2-CpG-3: LHV, r = 0.73, p = 0.02; RHV, r = 0.58, p = 0.03). Cured and active CS patients showed both lower methylation of intron 2 (92.37, 91.8, and 93.34 %, respectively, p = 0.03 for both) and of intron 7 (77.08, 73.74, and 79.71 %, respectively, p = 0.02 and p < 0.01) than controls. Twenty-two subjects had the CC genotype, 34 had the TC genotype, and eight had the TT genotype. Lower average DNA methylation in intron 7 was observed in the TT subjects compared to CC (72.5vs. 79.5 %, p = 0.02) and to TC (72.5 vs. 79.0 %, p = 0.03). Our data demonstrate, for the first time, a reduction of intronic DNA methylation of FKBP5 in CS patients.

KW - 3Tesla MRI

KW - Cushing’s syndrome

KW - FKBP5 DNA methylation

KW - FKBP5 polymorphism

KW - Glucocorticoid resistance

KW - Hypercortisolism

UR - http://www.scopus.com/inward/record.url?scp=84988723514&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84988723514&partnerID=8YFLogxK

U2 - 10.1007/s12020-016-1083-6

DO - 10.1007/s12020-016-1083-6

M3 - Article

SP - 1

EP - 10

JO - Endocrine

JF - Endocrine

SN - 1355-008X

ER -