DNA methylation levels are associated with CRF1 receptor antagonist treatment outcome in women with post-traumatic stress disorder

Julius C. Pape, Tania Carrillo-Roa, Barbara O. Rothbaum, Charles Nemeroff, Darina Czamara, Anthony S. Zannas, Dan Iosifescu, Sanjay J. Mathew, Thomas C. Neylan, Helen S. Mayberg, Boadie W. Dunlop, Elisabeth B. Binder

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: We have previously evaluated the efficacy of the CRF1 receptor antagonist GSK561679 in female PTSD patients. While GSK561679 was not superior to placebo overall, it was associated with a significantly stronger symptom reduction in a subset of patients with probable CRF system hyperactivity, i.e., patients with child abuse and CRHR1 SNP rs110402 GG carriers. Here, we test whether blood-based DNA methylation levels within CRHR1 and other PTSD-relevant genes would be associated with treatment outcome, either overall or in the high CRF activity subgroup. Results: Therefore, we measured CRHR1 genotypes as well as baseline and post-treatment DNA methylation from the peripheral blood in the same cohort of PTSD-diagnosed women treated with GSK561679 (N = 43) or placebo (N = 45). In the same patients, we assessed DNA methylation at the PTSD-relevant genes NR3C1 and FKBP5, shown to predict or associate with PTSD treatment outcome after psychotherapy. We observed significant differences in CRHR1 methylation after GSK561679 treatment in the subgroup of patients with high CRF activity. Furthermore, NR3C1 baseline methylation significantly interacted with child abuse to predict PTSD symptom change following GSK561679 treatment. Conclusions: Our results support a possible role of CRHR1 methylation levels as an epigenetic marker to track response to CRF1 antagonist treatment in biologically relevant subgroups. Moreover, pre-treatment NR3C1 methylation levels may serve as a potential marker to predict PTSD treatment outcome, independent of the type of therapy. However, to establish clinical relevance of these markers, our findings require replication and validation in larger studies. Trial registration: NCT01018992. Registered 6 November 2009.

Original languageEnglish (US)
Article number136
JournalClinical Epigenetics
Volume10
Issue number1
DOIs
StatePublished - Nov 3 2018

Fingerprint

DNA Methylation
Post-Traumatic Stress Disorders
Methylation
Child Abuse
Therapeutics
Placebos
Hematologic Tests
CRF receptor type 1
Epigenomics
Psychotherapy
Genes
Single Nucleotide Polymorphism
Biomarkers
Genotype
NBI 77860

Keywords

  • CRF receptor antagonist
  • CRHR1
  • DNA methylation
  • Epigenetics
  • FKBP5
  • NR3C1
  • PTSD

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

Cite this

DNA methylation levels are associated with CRF1 receptor antagonist treatment outcome in women with post-traumatic stress disorder. / Pape, Julius C.; Carrillo-Roa, Tania; Rothbaum, Barbara O.; Nemeroff, Charles; Czamara, Darina; Zannas, Anthony S.; Iosifescu, Dan; Mathew, Sanjay J.; Neylan, Thomas C.; Mayberg, Helen S.; Dunlop, Boadie W.; Binder, Elisabeth B.

In: Clinical Epigenetics, Vol. 10, No. 1, 136, 03.11.2018.

Research output: Contribution to journalArticle

Pape, JC, Carrillo-Roa, T, Rothbaum, BO, Nemeroff, C, Czamara, D, Zannas, AS, Iosifescu, D, Mathew, SJ, Neylan, TC, Mayberg, HS, Dunlop, BW & Binder, EB 2018, 'DNA methylation levels are associated with CRF1 receptor antagonist treatment outcome in women with post-traumatic stress disorder', Clinical Epigenetics, vol. 10, no. 1, 136. https://doi.org/10.1186/s13148-018-0569-x
Pape, Julius C. ; Carrillo-Roa, Tania ; Rothbaum, Barbara O. ; Nemeroff, Charles ; Czamara, Darina ; Zannas, Anthony S. ; Iosifescu, Dan ; Mathew, Sanjay J. ; Neylan, Thomas C. ; Mayberg, Helen S. ; Dunlop, Boadie W. ; Binder, Elisabeth B. / DNA methylation levels are associated with CRF1 receptor antagonist treatment outcome in women with post-traumatic stress disorder. In: Clinical Epigenetics. 2018 ; Vol. 10, No. 1.
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AU - Nemeroff, Charles

AU - Czamara, Darina

AU - Zannas, Anthony S.

AU - Iosifescu, Dan

AU - Mathew, Sanjay J.

AU - Neylan, Thomas C.

AU - Mayberg, Helen S.

AU - Dunlop, Boadie W.

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N2 - Background: We have previously evaluated the efficacy of the CRF1 receptor antagonist GSK561679 in female PTSD patients. While GSK561679 was not superior to placebo overall, it was associated with a significantly stronger symptom reduction in a subset of patients with probable CRF system hyperactivity, i.e., patients with child abuse and CRHR1 SNP rs110402 GG carriers. Here, we test whether blood-based DNA methylation levels within CRHR1 and other PTSD-relevant genes would be associated with treatment outcome, either overall or in the high CRF activity subgroup. Results: Therefore, we measured CRHR1 genotypes as well as baseline and post-treatment DNA methylation from the peripheral blood in the same cohort of PTSD-diagnosed women treated with GSK561679 (N = 43) or placebo (N = 45). In the same patients, we assessed DNA methylation at the PTSD-relevant genes NR3C1 and FKBP5, shown to predict or associate with PTSD treatment outcome after psychotherapy. We observed significant differences in CRHR1 methylation after GSK561679 treatment in the subgroup of patients with high CRF activity. Furthermore, NR3C1 baseline methylation significantly interacted with child abuse to predict PTSD symptom change following GSK561679 treatment. Conclusions: Our results support a possible role of CRHR1 methylation levels as an epigenetic marker to track response to CRF1 antagonist treatment in biologically relevant subgroups. Moreover, pre-treatment NR3C1 methylation levels may serve as a potential marker to predict PTSD treatment outcome, independent of the type of therapy. However, to establish clinical relevance of these markers, our findings require replication and validation in larger studies. Trial registration: NCT01018992. Registered 6 November 2009.

AB - Background: We have previously evaluated the efficacy of the CRF1 receptor antagonist GSK561679 in female PTSD patients. While GSK561679 was not superior to placebo overall, it was associated with a significantly stronger symptom reduction in a subset of patients with probable CRF system hyperactivity, i.e., patients with child abuse and CRHR1 SNP rs110402 GG carriers. Here, we test whether blood-based DNA methylation levels within CRHR1 and other PTSD-relevant genes would be associated with treatment outcome, either overall or in the high CRF activity subgroup. Results: Therefore, we measured CRHR1 genotypes as well as baseline and post-treatment DNA methylation from the peripheral blood in the same cohort of PTSD-diagnosed women treated with GSK561679 (N = 43) or placebo (N = 45). In the same patients, we assessed DNA methylation at the PTSD-relevant genes NR3C1 and FKBP5, shown to predict or associate with PTSD treatment outcome after psychotherapy. We observed significant differences in CRHR1 methylation after GSK561679 treatment in the subgroup of patients with high CRF activity. Furthermore, NR3C1 baseline methylation significantly interacted with child abuse to predict PTSD symptom change following GSK561679 treatment. Conclusions: Our results support a possible role of CRHR1 methylation levels as an epigenetic marker to track response to CRF1 antagonist treatment in biologically relevant subgroups. Moreover, pre-treatment NR3C1 methylation levels may serve as a potential marker to predict PTSD treatment outcome, independent of the type of therapy. However, to establish clinical relevance of these markers, our findings require replication and validation in larger studies. Trial registration: NCT01018992. Registered 6 November 2009.

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