Understanding and treating trauma and violence-related pathologies in South African townships : emergence and modifiability of epigenetic and neural memories of traumatic stressors and appetitive offending

Xulu, Khethelo Richman (2018-12)

Thesis (PhD)--Stellenbosch University, 2018.

Thesis

ENGLISH SUMMARY : Prolonged exposure to traumatic stress results in sustained activation of biological responses, which affect shared similar pathways, leading to posttraumatic stress disorder (PTSD), a serious mental illness; and behavioural problems such as appetitive aggression. Appetitive aggression is the perpetration of violence that induces feelings of arousal and excitement. Chronic exposure to stress can modify mechanisms such as DNA methylation and telomere length, which are environmentally sensitive. DNA methylation and telomere length, including genetic variants have been implicated in the aetiology of both aggression and PTSD. Therefore, studying DNA methylation, telomeres, and genetic variation is essential to better understand appetitive aggression and PTSD. The overarching aim of this study was to investigate DNA methylation, telomere length and genetic variation in association with appetitive aggression and PTSD. The secondary aim was to investigate changes in DNA methylation and telomere length that may be involved in the effectiveness of psychotherapeutic interventions by identifying key biological markers related to appetitive aggression and PTSD symptom severity in Xhosa Black South African men. The third aim was to investigate the association between appetitive aggression and genetic variations of both the serotonin transporter in the promoter region (5-HTTLPR) and monoamine oxidase A (MAOA). Recruited participants with higher levels of appetitive aggression and higher PTSD symptom severity, as measured by the Appetitive Aggression Scale (AAS) and the PTSD Symptom Scale-Interview (PSS-1), respectively, were randomised to receive either Narrative Exposure Therapy for Forensic Offender Rehabilitation (FORNET), Cognitive Behavioural Therapy (CBT) and controls. Saliva collection occurred before the intervention (baseline) and at 8 and 16 months post-intervention, and genomic DNA was extracted at subsequent follow-up visits. The Human Mental Disorders EpiTect Methyl II Signature PCR Array was used to quantify DNA methylation. Telomere length was determined using quantitative polymerase chain reaction (qPCR). PCR was used for genotyping. The data were analysed using regression models, repeated measures of analysis of variance (ANOVA), mixed models and Fisher’s least significant difference (LSD). No significant changes in methylation were observed in the FORNET group. However, methylation in both autism susceptibility candidate 2 (AUTS2) (p=0.000) and reelin (RELN) (p=0.023) genes decreased significantly in the CBT group between first and second follow-up visits. In the catechol-o-methyltransferase (COMT) gene, methylation significantly decreased between baseline and first follow-up (p=0.007), while between first and second follow-up visits there was a significant increase (p=0.038). Methylation in the RELN (r=0.38, p=0.02) gene exhibited strong positive correlation with appetitive aggression, while methylation in the COMT gene correlated with PTSD symptom severity (r=0.35, p=0.01). No significant correlation between appetitive aggression and telomere length (r=0.09, p= 0.121) was observed; however, increased telomere length correlated with higher PTSD symptom severity (r=0.13, p=0.039). The STin2 VNTR 12-repeat homozygous genotype and L’-STin2.12/STin2.12 were associated with appetitive aggression (p=0.003 and p=8.00 x 10–8, respectively). This research provides insights into the biological mechanisms that may play a significant role in appetitive aggression and PTSD. DNA methylation and telomere length may be biological markers that are responsive to psychotherapeutic interventions. The STin2 VNTR 12-repeat may be a distinguishing marker of appetitive and reactive forms of aggression. These biological mechanisms provided preliminary insights into appetitive aggression and PTSD.

AFRIKAANSE OPSOMMING : Langdurige blootstelling aan traumatiese stres het volgehoue aktivering van biologiese response tot gevolg, wat gedeelde soortgelyke paaie beïnvloed. Dit lei tot posttraumatiese stresversteuring (PTSV), ʼn ernstige geestesiekte, en gedragsprobleme soos dranggedrewe aggressie. Dranggedrewe aggressie is geweldpleging wat gevoelens van stimulering en opwinding veroorsaak. Chroniese blootstelling aan stres kan meganismes soos DNS-metilering en telomeerlengte, wat omgewingsensitief is, verander. DNS-metilering en telomeerlengte, wat genetiese variante insluit, speel ʼn rol in die etiologie van sowel aggressie as PTSV. Daarom is die bestudering van DNS-metilering, telomere en genetiese afwykings noodsaaklik vir ʼn beter begrip van dranggedrewe aggressie en PTSV. Die oorkoepelende oogmerk van die huidige navorsing was om DNS-metilering, telomeerlengte en genetiese afwyking met betrekking tot dranggedrewe aggressie en PTSV te ondersoek. Die sekondêre oogmerk was om die veranderinge in DNS-metilering en telomeerlengte wat by psigoterapeutiese intervensie betrokke is, te ondersoek deur belangrike biologiese merkers wat met dranggedrewe aggressie en intensiteit van PTSV-simptome in Xhosa swart Suid-Afrikaanse mans verband hou, te identifiseer. Die derde oogmerk was om ʼn verband tussen dranggedrewe aggressie en genetiese afwykings in sowel serotonientransport in die promotorgebied (5-HTTLPR) as monoamienoksidase-A (MAOA) te ondersoek. Gewerfde deelnemers met sowel hoër dranggedrewe aggressie as hoër intensiteit van PTSV-simptome, onderskeidelik gemeet deur die Skaal vir Dranggedrewe Aggressie (AAS) en die Skaal vir PTSV-simptome – onderhoudsweergawe (PSS-i), is verewekansig om verhalende blootstellingterapie vir rehabilitering van forensiese oortreders (FORNET), kognitiewe gedragsterapie (KGT) en kontroles te ontvang. Speeksel is voor die intervensie versamel (basislyn) en 8 en 16 maande ná intervensie is genomiese DNS by opvolgsessies onttrek. Die Human Mental Disorders EpiTect Methyl II Signature PKR-toets is gebruik om DNS-metilering te kwantifiseer. Telomeerlengte is deur middel van kwantitatiewe polimerase-kettingreaksie (kPKR) bepaal. PKR is vir genotipering gebruik. Die data is deur middel van regressiemodelle, herhaalde-meting-variansieontleding (ANOVA), gemengde modelle en Fisher se kleinste betekenisvolle verskil (LSD) ontleed. Daar was geen beduidende veranderinge in metilering in die FORNET-groep nie. Metilering in sowel die outisme-ontvanklikheidskandidaat-2- (AUTS2-) geen (p=0.000) en reelin- (RELN-)geen (p=0.023) het egter beduidend in die KGT-groep afgeneem tussen die eerste en tweede opvolgsessie. In die katesjol-O-metieltransferase- (COMT-) geen het metilering tussen die basislyn en die eerste opvolgsessie beduidend afgeneem (p=0.007), terwyl dit tussen die eerste en tweede opvolgsessie beduidend toegeneem het (p=0.038). Metilering in die RELN-geen het sterk positiewe korrelasie met dranggedrewe aggressie getoon (r=0.38, p=0.02), terwyl metilering in die COMT-geen met intensiteit van PTSV-simptome gekorreleer het (r=0.35, p=0.01). Daar is geen beduidende korrelasie tussen dranggedrewe aggressie en telomeerlengte (r=0.09, p=0.121) waargeneem nie; groter telomeerlengte het egter met hoër intensiteit van PTSV-simptome gekorreleer (r=0.13, p=0.039). Die intron 2 (STin2) veranderlike getal tandem herhalings (VNTR) 12-herhaling homosigotiese genotipe en L’-STin2.12/STin2.12 het met dranggedrewe aggressie geassosieer (p=0.003 en p=8.00 x 10–8 onderskeidelik). Hierdie navorsing het insig gebied in die begrip van biologiese meganismes wat moontlik ʼn belangrike rol in dranggedrewe aggressie en PTSV speel. DNS-metilering en telomeerlengte kan in wese merkers wees wat op psigoterapeutiese intervensies reageer. Die STin2 VNTR 12-herhaling kan tussen dranggedrewe en reaktiewe aggressie onderskei. Hierdie biologiese meganismes bied voorbereidende insig in die begrip van dranggedrewe aggressie en PTSV.

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