Childhood trauma and adulthood inflammation: A meta-analysis of peripheral C-reactive protein, Interleukin-6 and Tumour Necrosis Factor-α

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Abstract

Childhood trauma confers higher risk of adulthood physical and mental illness, however the biological mechanism mediating this association remains largely unknown. Recent research has suggested dysregulation of the immune system as a possible biological mediator. The present paper conducted a meta-analysis in order to establish whether early life adversity contributes to potentially pathogenic pro-inflammatory phenotypes in adult individuals. A systematic search of Pubmed, PsycINFO, EMBASE, Scopus and Medline identified 25 articles for the meta-analysis, including 18 studies encompassing a sample of 16,870 individuals for C-reactive protein (CRP), 15 studies including 3,751 individuals for interleukin-6 (IL-6), and 10 studies including 881 individuals for tumour necrosis factor-α (TNF-α). Random-effects meta-analysis showed that individuals exposed to childhood trauma had significantly elevated baseline peripheral levels of CRP (Fisher’s z = 0.10, 95% confidence interval [CI] = 0.05 – 0.14), IL-6 (z = 0.08, 95% CI = 0.03 - 0.14) and TNF-α (z = 0.23, 95% CI = 0.14 – 0.32). Subgroup analyses for specific types of trauma (sexual, physical or emotional abuse) revealed that these impact differentially the single inflammatory markers. Moreover, meta-regression revealed greater effect sizes in clinical samples for the association between childhood trauma and CRP but not for IL-6 or TNF-α. Age, BMI and gender had no moderating effects. The analysis demonstrates that childhood trauma contributes to a pro-inflammatory state in adulthood, with specific inflammatory profiles depending on the specific type of trauma.

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Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.

Torsten Klengel, Divya Mehta, Christoph Anacker … (2013)

Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.

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Relationship between multiple forms of childhood maltreatment and adult mental health in community respondents: results from the adverse childhood experiences study.

Vincent Felitti, Judson Edwards, Robert Anda … (2003)

This study examined the prevalence of a history of various combinations of childhood maltreatment types (physical abuse, sexual abuse, and witnessing of maternal battering) among adult members of a health maintenance organization (HMO) and explored the relationship with adult mental health of the combinations of types of childhood maltreatment and emotional abuse in the childhood family environment. A total of 8,667 adult members of an HMO completed measures of childhood exposure to family dysfunction, which included items on physical and sexual abuse, witnessing of maternal battering, and emotional abuse in the childhood family environment. The adults' current mental health was assessed by using the mental health scale of the Medical Outcomes Study 36-item Short-Form Health Survey. The prevalences of sexual abuse, physical abuse, and witnessing of maternal violence were 21.6%, 20.6%, and 14.0%, respectively, when the maltreatment types were considered separately. Among respondents reporting any of the maltreatment types, 34.6% reported more than one type of maltreatment. Lower mean mental health scores were associated with higher numbers of abuse categories (mean=78.5, 75.5, 72.8, and 69.9 for respondents with no, one, two, and three abuse types, respectively). Both an emotionally abusive family environment and the interaction of an emotionally abusive family environment with the various maltreatment types had a significant effect on mental health scores. Childhood physical and sexual abuse, as well as witnessing of maternal battering, were common among the adult members of an HMO in this study. Among those reporting any maltreatment, more than one-third had experienced more than one type of maltreatment. A dose-response relation was found between the number of types of maltreatment reported and mental health scores. In addition, an emotionally abusive family environment accentuated the decrements in mental health scores. Future research examining the effects of childhood maltreatment on adult mental health should include assessments of a wide range of abusive experiences, as well as the family atmosphere in which they occur.

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Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder.

Torsten Klengel, Wilson K. Smith, Bekh Bradley … (2013)

Childhood maltreatment is likely to influence fundamental biological processes and engrave long-lasting epigenetic marks, leading to adverse health outcomes in adulthood. We aimed to elucidate the impact of different early environment on disease-related genome-wide gene expression and DNA methylation in peripheral blood cells in patients with posttraumatic stress disorder (PTSD). Compared with the same trauma-exposed controls (n = 108), gene-expression profiles of PTSD patients with similar clinical symptoms and matched adult trauma exposure but different childhood adverse events (n = 32 and 29) were almost completely nonoverlapping (98%). These differences on the level of individual transcripts were paralleled by the enrichment of several distinct biological networks between the groups. Moreover, these gene-expression changes were accompanied and likely mediated by changes in DNA methylation in the same loci to a much larger proportion in the childhood abuse (69%) vs. the non-child abuse-only group (34%). This study is unique in providing genome-wide evidence of distinct biological modifications in PTSD in the presence or absence of exposure to childhood abuse. The findings that nonoverlapping biological pathways seem to be affected in the two PTSD groups and that changes in DNA methylation appear to have a much greater impact in the childhood-abuse group might reflect differences in the pathophysiology of PTSD, in dependence of exposure to childhood maltreatment. These results contribute to a better understanding of the extent of influence of differences in trauma exposure on pathophysiological processes in stress-related psychiatric disorders and may have implications for personalized medicine.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9607835

Journal ID (pubmed-jr-id): 20545

Journal ID (nlm-ta): Mol Psychiatry

Journal ID (iso-abbrev): Mol. Psychiatry

Title: Molecular psychiatry

ISSN (Print): 1359-4184

ISSN (Electronic): 1476-5578

Publication date Nihms-submitted: 5 May 2015

Publication date (Electronic): 02 June 2015

Publication date (Print): May 2016

Publication date PMC-release: 01 November 2016

Volume: 21

Issue: 5

Pages: 642-649

Affiliations

[1 ]Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Department of Psychological Medicine, London, UK

[2 ]Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Department of Psychology, London, UK

[3 ]University College London, Department of Psychology, London, UK

[4 ]Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Department of Psychosis Studies, London, UK

[5 ]National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley, NHS Foundation Trust and King’s College London, London, UK

Author notes

Correspondence to: Dr Valeria Mondelli, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Department of Psychological Medicine, The James Black Centre, 125 Coldharbour Lane, SE5 9NU, London, United Kingdom, valeria.mondelli@ 123456kcl.ac.uk , Phone: +44 (0) 20 7848 0352, Fax: + 44 (0) 20 7848 0986

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Manuscript ID: EMS63150

DOI: 10.1038/mp.2015.67

PMC ID: 4564950

PubMed ID: 26033244

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Childhood trauma and adulthood inflammation: A meta-analysis of peripheral C-reactive protein, Interleukin-6 and Tumour Necrosis Factor-α

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UCL: UN SDG 03 Good Health and Well-Being

Most cited references 80

Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.

Relationship between multiple forms of childhood maltreatment and adult mental health in community respondents: results from the adverse childhood experiences study.

Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder.

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