Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder
Open accessAbstract
DNA methylation may mediate persistent changes in gene function following chronic stress. To examine this hypothesis, we evaluated African American subjects matched by age and sex, and stratified into four groups by post‐traumatic stress disorder (PTSD) diagnosis and history of child abuse. Total Life Stress (TLS) was also assessed in all subjects. We evaluated DNA extracted from peripheral blood using the HumanMethylation27 BeadChip and analyzed both global and site‐specific methylation. Methylation levels were examined for association with PTSD, child abuse history, and TLS using a linear mixed model adjusted for age, sex, and chip effects. Global methylation was increased in subjects with PTSD. CpG sites in five genes (TPR, CLEC9A, APC5, ANXA2, and TLR8) were differentially methylated in subjects with PTSD. Additionally, a CpG site in NPFFR2 was associated with TLS after adjustment for multiple testing. Notably, many of these genes have been previously associated with inflammation. Given these results and reports of immune dysregulation associated with trauma history, we compared plasma cytokine levels in these subjects and found IL4, IL2, and TNFα levels associated with PTSD, child abuse, and TLS. Together, these results suggest that psychosocial stress may alter global and gene‐specific DNA methylation patterns potentially associated with peripheral immune dysregulation. Our results suggest the need for further research on the role of DNA methylation in stress‐related illnesses. © 2011 Wiley‐Liss, Inc.
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Elevated expression of pro-inflammatory cytokines after traumatic stress exposure is probably regulated by multiple epigenetic mechanisms, including dysregulation of microRNA expression.
“Further human PTSD research suggested that elevated expression of pro-inflammatory cytokines after traumatic stress exposure is probably regulated by multiple epigenetic mechanisms, including dysregulation of microRNA expression (216–218).”
From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [216]
The Introduction suggests epigenetic alterations may contribute to inflammatory dysregulation in PTSD, and the Discussion reports increased plasma TNFα associated with child abuse and higher lifetime stress. The paper examines DNA methylation, but does not establish that it regulates the cytokine increase or address the claimed dysregulation of microRNA expression or multiple epigenetic mechanisms. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMethylation of mannosidase, alpha class 2C, member 1 (MAN2C1), acid phosphatase 5 (ACP5), and toll-like receptor (TLR) 8 is altered in PTSD.
“Methylation of mannosidase, alpha class 2C, member 1 (MAN2C1), acid phosphatase 5 (ACP5), and tolllike receptor (TLR) 8, which are genes involved in immune function, was found to be altered in PTSD (Smith et al, 2011;Uddin et al, 2011).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Smith et al, 2011
The Results section (‘Gene-Specific Changes in DNA Methylation’; page unavailable) reports increased methylation at CpG sites in ACP5 and TLR8 in subjects with PTSD compared with controls. It does not identify MAN2C1 among the genes whose CpG sites met its experiment-wide criteria, and a search for MAN2C1 and its full name found no supporting passage in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn some studies, concentrations of IL-8 and IL-4 are lower in individuals with PTSD.
“In some studies, concentrations of IL-8 (Jergovic et al, 2015;Song et al, 2007b) and IL-4 (Smith et al, 2011;von Kanel et al, 2007) are lower in individuals with PTSD.”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Smith et al, 2011
Differential levels of DNA methylation of genes related to stress reactivity have already been associated with PTSD and early life stress.
“Differential levels of DNA methylation of genes related to stress reactivity have already been associated with PTSD and early life stress [93-95].”
From Efficacy of oxytocin administration early after psychotrauma in preventing the development of PTSD: study protocol of a randomized controlled trial (2014) · cites this paper as [93]
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- Authors
- Smith, A. K., Conneely, K. N., Kilaru, V., Mercer, K. B., Weiss, T. E., Bradley, B., Tang, Y., Gillespie, C. F., Cubells, J. F., & Ressler, K. J.
- Affiliations
- Emory University (US)
- Howard Hughes Medical Institute (US)
- Atlanta VA Medical Center (US)
- Corresponding author
- Ressler, Kerry J.
- ORCID
- Venue
- American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
- Publisher
- Wiley
- Published
- 2011-06-28
- Volume
- 156
- Issue
- 6
- Pages
- 700-708
- ISSN
- 1552-4841 (ISSN-L)
- 1552-485X
- PMC
- PMC3292872
- OpenAlex
- W2055238656
- Semantic Scholar
- a7e19ae9a62e52335346d57782e25eaa2074277f
- Cited by
- 355
- References
- 62
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 19 · 2023: 19 · 2022: 28 · 2021: 24 · 2020: 22 · 2019: 18 · 2018: 24 · 2017: 36 · 2016: 25 · 2015: 27 · 2014: 39 · 2013: 32 · 2012: 16
- FWCI
- 31.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000454)
- National Institute of Mental Health (K23MH082256, MH082256, MH 071537, K01MH085806, R01MH071537, MH085806, R56MH071537)
- National Center for Research Resources (M01-RR00039, M01RR000039)
- National Center for Advancing Translational Sciences
- Topics
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- post-traumatic stress disorder, DNA methylation, child abuse, immune dysregulation, cytokines, inflammation, African Americans, TLR8, CLEC9A, annexin A2, TPR, IL-4, interleukin-2, TNF-α, psychosocial stress, epigenetics
- MeSH terms
- Black or African American, DNA, Humans, Stress Disorders, Post-Traumatic, Stress, Psychological, Cytokines, CpG Islands, DNA Methylation, Adult Survivors of Child Abuse
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