Internalizing mental disorders in HIV : the role of environment, telomere length and selected genetic variants
Date
2020-03
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Stellenbosch : Stellenbosch University
Abstract
ENGLISH SUMMARY : Background: HIV+ children and adolescents (CA-HIV) suffer from a considerable burden of internalizing mental disorders (IMDs), which are associated with negative outcomes, such as poor academic functioning and faster HIV disease progression. IMDs are complex disorders with unknown etiology, despite significant research efforts. This PhD study aimed to investigate whether acute stress interacts with vulnerability factors (genetic, acquired or a combination of both) to influence the occurrence of IMDs.
Methods: The study used data from 736 Ugandan CA-HIV who were recruited into a larger study examining mental health among children and adolescents living with HIV/AIDS in Kampala and Masaka districts of Uganda (CHAKA Study). Cases (n = 368) were CA-HIV who had any internalizing mental disorder (IMD) (depressive disorders, anxiety disorders and PTSD). Controls (n = 368) were CA-HIV who did not have these disorders and were matched with cases on age, site, socio-economic status and sex. Psychiatric disorders were assessed using the Child and Adolescent Symptom Inventory-5 (CASI-5) and the Youth Inventory-4R. Chronic and acute stress classes were determined by hierarchical cluster analysis using an index derived from data on social disadvantage variables. DNA extracted from blood was used for targeted genetic investigations. Specifically, variants in the serotonin transporter gene (SLC6A4: 5-HTTLPR, rs25531, 5-HTTLPR/rs25531 and STin2 VNTR), and tryptophan hydroxylase gene (TPH2: (rs1843809, rs1386494, rs4570625 and rs345177220) were determined. Relative telomere length (TL) was also determined using these samples.
Statistical analysis: Socio-demographic variables were compared between cases and controls. Linear regression was used to determine the association between TL and IMDs. Logistic regression was used to: i) determine the association between acute stress and IMDs, and ii) assess the moderating effect of each of the vulnerability factors on the associations identified in (i).
Results: Presence of IMDs was associated with accelerated TL attrition over a 12-month period. The T-allele of TERT rs2736100 and the C-allele of TERC rs16847897 were associated with accelerated TL attrition among cases of IMDs (p = 0.007 and p = 0.012, respectively). CA-HIV who experienced severe acute stress were twice as likely to have an IMD compared to CA-HIV who experienced mild acute stress (p = 0.001). Acute stress significantly interacted with chronic stress (p = 0.033) and 5-HTTLPR/rs25531 haplotype (p = 0.049) to influence the likelihood of having an IMD. CA-HIV who experienced severe acute stress and severe chronic stress were four times more likely to be a case of IMDs as compared to those under mild acute stress and mild chronic stress. CA-HIV who possessed the S-A-S-A haplotype and experienced moderate or severe acute stress were respectively fifteen and twelve times more likely to be diagnosed with an IMD compared to CA-HIV who possessed the L-A-L-A haplotype and experienced mild acute stress.
Conclusions: IMDs were associated with accelerated TL attrition. Severe chronic stress and 5-HTTLPR/rs25531 haplotype independently interacted with acute stress to increase risk for IMDs among Ugandan CA-HIV. These data support previously identified relationships between IMDs and accelerated biological aging, and provide evidence for the role of serotonin gene-environment interactions in the risk of developing IMDs among CA-HIV in Uganda.
AFRIKAANSE OPSOMMING : Agtergrond: MIV+ kinders asook adolessente (KA-MIV) lei aan hoë vlakke van internaliserende geestesversteurings (IGVs), wat geassosieer word met negatiewe uitkomstes soos swak akademiese prestasie en vinniger MIV vordering. IGVs is ‘n komplekse groep toestande, met ‘n onbekende etiologie, ten spyte van onlangse vordering in die navorsing. In hierdie PhD studie ondersoek ons of akute stres kan kombineer met ander kwesbaarheid faktore (geneties, verworwe of beide) om na ‘n verhoogde voorkoms van IGVs te lei. Metode: Die huidige studie vorm deel van ‘n groter projek wat geestesgesondheid in 736 kinders en adolessente met MIV/VIGS in Kampala en Masaka distrikte in Uganda (CHAKA studie) ondersoek. Gevalle (n=368) is positief vir KA-MIV en ly aan ‘n IGV (depressie, angs- en/of post-traumatiese stres versteurings). Kontroles is vry van geestesversteurings met vergelykbare ouderdom, perseel, sosio-ekonomiese status en geslag. Psigiatriese toestande was ondersoek met die “Child and Adolescent Symptom Inventory-5 (CASI-5)” en die “Youth Inventory-4R”. Beide kroniese en onlangse stres groepe was bepaal deur ‘n hiërargiese groepontleding. Sosiale benadeling veranderlikes was gebruik as ‘n indeks in die analise. Bloed DNS was gebruik in gerigte genetiese analises. Meer spesifiek, variante in die serotonienvervoerder geen (SLC6A4: 5-HTTLPR, rs25531, 5-HTTLPR/rs25531 en STin2 VNTR), en tryptofaan-hidroksilase geen (TPH2: (rs1843809, rs1386494, rs4570625 en rs345177220) was bepaal. Relatiewe telomeer lengte (TL) was ook bepaal met dieselfde bloedmonsters. Statistiese analise: Sosio-demografiese veranderlikes was vergelyk tussen gevalle en kontroles. ‘n Lineêre regressie analise was gebruik om die assosiasie tussen TL en IGVs te bepaal. ‘n Logistieke regressie model was gebruik om: i) die assosiasie tussen onlangse stres en IGVs te bepaal, en ii) die modererende effek van elk van die kwesbaarheid faktore op assosiasies wat geïdentifiseer was in (i). Resultate: Die teenwoordigheid van IGVs was geassosieer met ‘n versnelde TL-verkorting oor ‘n 12 maande periode. Die T-aliel van TERT rs2736100 en die C-aliel van TERC rs16847897 was geassosieer met ‘n versnelde TL-verkorting in IGV gevalle (p = 0.007 en p = 0.012, onderskeidelik). KA-MIV wat erge akute stress ondervind het was twee keer meer geneig om ‘n IGV te hê in vergelyking met KA-MIV wat ‘n ligte akute stres ervaring gehad het (p = 0.001). Akute stres het ‘n beduidende interaksie gehad met kroniese stres (p = 0.033) en 5-HTTLPR/rs25531 haplotipe (p = 0.049) wat bepaal het hoe waarskynlik die teenwoordigheid van ‘n IGV was. KA-MIV wie erge akute en kroniese stres ervaar het was vier keer meer geneig om ‘n IGV geval te gewees het, in vergelyking met ligte akute stres asook ligte kroniese stres. KA-MIV wie ‘n S-A-S-A haplotipe gehad het en wie matige of erge stres ervaar het was onderskeidelik vyftien en twaalf keer meer geneig om ‘n diagnose van ‘n IGV te gehad het, in vergelyking met KA-MIV wie ‘n L-A-L-A haplotipe en ligte akute stres ervaar het. Slotsom: IGVs was geassosieer met ‘n versnelde TL verkorting. Erge kroniese stres en 5-HTTLPR/rs25531 haplotipe toon ‘n onafhanklike interaksie met akute stres en verhoogte risiko vir IGVs onder KA-MIV van Uganda. Die data ondersteun ‘n verhouding tussen IGVs en versnelde biologiese veroudering wat al van te vore geïdentifiseer is, en verskaf bewyse vir ‘n interaksie tussen serotonien geen en die omgewing in die kwesbaarheid vir IGVs onder KA-MIV in Uganda.
AFRIKAANSE OPSOMMING : Agtergrond: MIV+ kinders asook adolessente (KA-MIV) lei aan hoë vlakke van internaliserende geestesversteurings (IGVs), wat geassosieer word met negatiewe uitkomstes soos swak akademiese prestasie en vinniger MIV vordering. IGVs is ‘n komplekse groep toestande, met ‘n onbekende etiologie, ten spyte van onlangse vordering in die navorsing. In hierdie PhD studie ondersoek ons of akute stres kan kombineer met ander kwesbaarheid faktore (geneties, verworwe of beide) om na ‘n verhoogde voorkoms van IGVs te lei. Metode: Die huidige studie vorm deel van ‘n groter projek wat geestesgesondheid in 736 kinders en adolessente met MIV/VIGS in Kampala en Masaka distrikte in Uganda (CHAKA studie) ondersoek. Gevalle (n=368) is positief vir KA-MIV en ly aan ‘n IGV (depressie, angs- en/of post-traumatiese stres versteurings). Kontroles is vry van geestesversteurings met vergelykbare ouderdom, perseel, sosio-ekonomiese status en geslag. Psigiatriese toestande was ondersoek met die “Child and Adolescent Symptom Inventory-5 (CASI-5)” en die “Youth Inventory-4R”. Beide kroniese en onlangse stres groepe was bepaal deur ‘n hiërargiese groepontleding. Sosiale benadeling veranderlikes was gebruik as ‘n indeks in die analise. Bloed DNS was gebruik in gerigte genetiese analises. Meer spesifiek, variante in die serotonienvervoerder geen (SLC6A4: 5-HTTLPR, rs25531, 5-HTTLPR/rs25531 en STin2 VNTR), en tryptofaan-hidroksilase geen (TPH2: (rs1843809, rs1386494, rs4570625 en rs345177220) was bepaal. Relatiewe telomeer lengte (TL) was ook bepaal met dieselfde bloedmonsters. Statistiese analise: Sosio-demografiese veranderlikes was vergelyk tussen gevalle en kontroles. ‘n Lineêre regressie analise was gebruik om die assosiasie tussen TL en IGVs te bepaal. ‘n Logistieke regressie model was gebruik om: i) die assosiasie tussen onlangse stres en IGVs te bepaal, en ii) die modererende effek van elk van die kwesbaarheid faktore op assosiasies wat geïdentifiseer was in (i). Resultate: Die teenwoordigheid van IGVs was geassosieer met ‘n versnelde TL-verkorting oor ‘n 12 maande periode. Die T-aliel van TERT rs2736100 en die C-aliel van TERC rs16847897 was geassosieer met ‘n versnelde TL-verkorting in IGV gevalle (p = 0.007 en p = 0.012, onderskeidelik). KA-MIV wat erge akute stress ondervind het was twee keer meer geneig om ‘n IGV te hê in vergelyking met KA-MIV wat ‘n ligte akute stres ervaring gehad het (p = 0.001). Akute stres het ‘n beduidende interaksie gehad met kroniese stres (p = 0.033) en 5-HTTLPR/rs25531 haplotipe (p = 0.049) wat bepaal het hoe waarskynlik die teenwoordigheid van ‘n IGV was. KA-MIV wie erge akute en kroniese stres ervaar het was vier keer meer geneig om ‘n IGV geval te gewees het, in vergelyking met ligte akute stres asook ligte kroniese stres. KA-MIV wie ‘n S-A-S-A haplotipe gehad het en wie matige of erge stres ervaar het was onderskeidelik vyftien en twaalf keer meer geneig om ‘n diagnose van ‘n IGV te gehad het, in vergelyking met KA-MIV wie ‘n L-A-L-A haplotipe en ligte akute stres ervaar het. Slotsom: IGVs was geassosieer met ‘n versnelde TL verkorting. Erge kroniese stres en 5-HTTLPR/rs25531 haplotipe toon ‘n onafhanklike interaksie met akute stres en verhoogte risiko vir IGVs onder KA-MIV van Uganda. Die data ondersteun ‘n verhouding tussen IGVs en versnelde biologiese veroudering wat al van te vore geïdentifiseer is, en verskaf bewyse vir ‘n interaksie tussen serotonien geen en die omgewing in die kwesbaarheid vir IGVs onder KA-MIV in Uganda.
Description
Thesis (PhD)--Stellenbosch University, 2020.
Keywords
HIV-positive youth -- Mental health -- Environmental aspects, HIV-positive youth -- Mental health -- Physiological aspects, HIV-positive children -- Mental health -- Environmental aspects, HIV-positive children -- Mental health -- Physiological aspects, HIV-positive persons -- Psychological aspects, UCTD