Longitudinal changes of telomere length and epigenetic age related to traumatic stress and post-traumatic stress disorder
Introduction
In addition to a wealth of literature about the molecular sequelae of exposure to traumatic stress in humans, recent studies have identified telomere shortening as one of the alterations associated to traumatic stress, (for review see (Shalev et al., 2013)).
Telomeres are repeats of the nucleotides TTAGGG about 3–20 kB long at the end of chromosomes and have a function in protecting functional genetic code of the chromosomes against shortening due to duplication of DNA by DNA-polymerase that is part of normal cell division. Telomere length decreases with age, and the renewed interest in telomeres is partly due its association with longevity. Another age indicator that has recently been developed is the age estimator based of methylation of CpG sequences in the genome (Horvath et al., 2012, Horvath, 2013). DNA methylation is an epigenetic mechanism that plays a role in tissue type specification and is strongly related to ageing (Boks et al., 2009, Horvath et al., 2012). Recently Horvath (Horvath, 2013) identified 353 CpG loci that are routinely investigated in commercial available DNA methylation arrays that predict age with high accuracy. Interestingly, recent studies have firmly established that DNA methylation also plays a role in several diseases and is associated to environmental exposures and particularly traumatic stress (for reviews see [Vinkers, submitted]).
Considering that both telomere length and epigenetic age may be associated to trauma exposure, it is of interest to investigate this in a longitudinal design, which, in contrast to previous cross sectional studies, provide a higher level of evidence for a causal relationship. However, from the perspective of clinical utility, it is even more interesting to incorporate development of post-traumatic stress disorder (PTSD) symptoms as outcome in such an analysis in order to interpret the role of any trauma related changes in age-related parameters in disease aetiology of this psychiatric disorder. We hypothesised that both telomere shortening and accelerated epigenetic age would be positively associated with trauma exposure, and that development of PTSD symptoms would be associated with an even stronger acceleration of these ageing parameters.
Section snippets
Subjects
We analysed longitudinal changes in a selected subgroup from a large, prospective cohort of 1032 Dutch military personnel deployed to Afghanistan, (see van Zuilen et al., 2011). Blood samples and standardised measures of Posttraumatic Stress Disorder (PTSD) symptoms were collected before and 6 months after deployment. The Self-Rating Inventory for PTSD (SRIP) was used to measure the presence of PTSD symptoms. The SRIP has a good reliability (Cronbach's alpha between 0.90 and 0.94) and validity
Association of trauma and PTSD with change in telomere length
Trauma exposure and increase in telomere length were not significantly associated (B = −10.17, p = 0.528). However, increase in PTSD symptoms was associated with lengthening of telomeres (B = 1.91, p = 0.018) in the mixed model analysis. Table 2 shows the full model for the analysis of change in telomere length. Figure 1 shows the relationship between change in telomere length and change in PTSD symptoms.
Association of trauma and PTSD with change in epigenetic ageing (DNAm age)
As a second measure of age acceleration we analysed change in DNAm age. We found a pattern
Discussion
In this unique longitudinal study in Dutch military personnel before and after deployment to a combat zone in Afghanistan, we studied an age indicator derived from DNA methylation levels (DNAm age) and telomere length. We found that trauma was not associated with decrease in telomere length, but was associated with accelerated DNAm ageing. Therefore the association of these measures with trauma are in the expected direction as previous studies that have reported similar association of decreased
Conflict of interest statement
None declared.
Acknowledgements
We are grateful to the participants of the study. Christiaan Vinkers is supported by a Netherlands Organisation for Scientific Research VENI grant (451-13-001) and a Netherlands Brain Foundation Fellowship (F2013(1)-216).
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