engleski

Hypermethylation of the monoamine oxidase A gene – a new epigenetic marker for posttraumatic stress disorder?

Posttraumatic Stress Disorder (PTSD) can develop after experiencing or witnessing any severe traumatic event such as combat. Point prevalence rates in war-affected regions, e.g. Bosnia- Herzegovina and Kosovo, range from 18% to 35%. Noradrenergic dysfunction as represented by e.g. elevated noradrenaline concentrations in the cerebrospinal fluid of PTSD patients is known to play a substantial role in the pathogenesis of PTSD symptoms [1]. Epigenetic regulation (i.e. DNA methylation) is strongly suggested to moderate the interaction between environmental influences and a genetic predisposition. Therefore, differential methylation of genes involved in the noradrenergic system such as the monoamine oxidase A (MAOA) gene might be part of the complex biological underpinnings of a dysregulated noradrenergic system and thereby contribute to PTSD risk. The present study aimed at investigating MAOA gene methylation as a possible epigenetic marker of PTSD status and severity in a sample comprising patients with PTSD and healthy controls recruited from war- affected regions in Bosnia-Herzegovina, Croatia and Kosovo. DNA methylation levels of MAOA (exonI/intronI region) were analyzed in PTSD patients [N=216 ; m=157, age (mean±s.d.): 50.08±6.74 years], remitted PTSD patients [N=151 ; m=98, age (mean ±s.d.): 49.48±8.20 years] and healthy controls [N=349, m=232, age (mean±s.d.): 48.81±8.50 years] by direct sequencing of sodium bisulfite- treated DNA followed by semi- quantitative analysis of the sequencing results via the Epigenetic Sequencing Methylation software. Severity of PTSD symptoms was assessed by the Clinician- Administered PTSD Scale (CAPS). All participants were assessed for potential confounders of methylation (sex, age, or smoking status). Possible categorical differences were analyzed by (M)ANCOVAs with age and smoking status as covariates. Post-hoc tests (Bonferroni) were performed to test individual differences in methylation across groups. Associations between dimensional measures were analyzed performing partial correlation analyses controlled for age and smoking status. In the male subsample, analyses revealed significant methylation differences at three out of 13 CpG sites between patients with current PTSD, remitted PTSD patients, and healthy controls. Post-hoc tests showed trend- wise significant (padjusted<0.1) to significant (padjusted<0.05) hypermethylation in current PTSD patients when compared to healthy controls at CpG3 (padjusted=0.089), CpG12 (padjusted=0.011) and CpG13 (padjusted=0.086) as well as at CpG3 (padjusted=0.029), CpG12 (padjusted<0.001), and CpG13 (padjusted=0.058) when compared to remitted PTSD patients. Additionally, PTSD symptom severity (total CAPS scores) was positively correlated with average MAOA methylation (r=0.206, p=0.016), methylation at CpG3 (r=0.186, p=0.033), CpG12 (r=0.306, p<0.001), and CpG13 (r=0.277, p=0.001) in male patients with a current PTSD diagnosis. In the female subsample, we failed to observe association of MAOA methylation with either current or remitted PTSD, while there was a positive correlation between MAOA methylation and symptom severity (r=0.294, p=0.033). The results of the present study for the first time suggest MAOA hypermethylation – possibly resulting in an increased noradrenergic tonus – as a disease status and severity marker of PTSD particularly in male patients. Given robust replication, MAOA hypermethylation might thus serve as an epigenetic marker within the complex risk factor constellation of PTSD. Furthermore, applying a personalized pharmaco- therapeutic approach, anti- adrenergic agents might prove to be beneficial in counterbalancing increased noradrenergic signalling specifically in male PTSD patients displaying MAOA hypermethylation.

posttraumatic stress disorder ; MAOA gene methylation ; epigenetic marker

nije evidentirano