Browsing by Author "Kalungi, Allan"

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    The 5-HTTLPR-rs25531 S-A-S-A haplotype and chronic stress moderate the association between acute stress and internalizing mental disorders among HIV+ children and adolescents in Uganda
    (Frontiers, 2021-04-23) Kalungi, Allan; Womersley, Jacqueline S.; Kinyanda, Eugene; Joloba, Moses L.; Ssembajjwe, Wilber; Nsubuga, Rebecca N.; Seedat, Soraya, 1966-; Hemmings, Sian M.
    Background: Internalizing mental disorders (IMDs) among HIV-positive (HIV+) children and adolescents are associated with poor disease outcomes, such as faster HIV disease progression. Although it has been suggested that the development of IMDs is moderated by interaction of stressful life events and vulnerability factors, the underlying etiology is largely unknown. Serotonin transporter gene [solute carrier family 6 member A4 (SLC6A4)] and human tryptophan hydroxylase 2 gene (TPH2) polymorphisms have been implicated in the development of IMDs. This study investigated the association between acute stress and IMDs, and moderation by chronic stress and genetic variants in SLC6A4 and TPH2. Hypothesis: Acute stress acts through genetic and environmental vulnerability factors to increase the risk of developing IMDs. Methods: Polymorphisms in SLC6A4 (5-HTTLPR, rs25531, 5-HTTLPR-rs25531, and STin2 VNTR) and TPH2 (rs1843809, rs1386494, rs4570625, and rs34517220) were genotyped in 368 HIV+ children and adolescents (aged 5–17 years) with any internalizing mental disorder (depression, anxiety disorders, or posttraumatic stress disorder), and 368 age- and sex-matched controls, who were also HIV+. Chronic and acute stress categories were derived by hierarchical cluster analysis. Logistic regression analysis was used to assess the independent moderating effect of chronic stress and each selected polymorphism on the association between acute stress and IMDs. Results: We observed a statistically significant association between severe acute stress and IMDs (p = 0.001). Children and adolescents who experienced severe acute stress were twice as likely to develop IMDs, compared to children and adolescents who experienced mild acute stress (p = 0.001). Chronic stress interacted with severe acute stress to increase the risk of IMDs (p = 0.033). Acute stress was found to interact with 5-HTTLPR-rs25531 S-A-S-A haplotype to increase the risk for IMDs among Ugandan HIV+ children and adolescents (p = 0.049). We found no evidence for a combined interaction of acute stress, chronic stress, and 5-HTTLPR-rs25531 on IMDs. Conclusion: The odds of having an internalizing mental disorder (IMD) were higher among HIV+ children and adolescents who experienced severe acute stress compared to HIV+ children and adolescents who experienced mild acute stress. Chronic stress and 5-HTTLPR-rs25531 independently moderated the association between acute stress and IMDs.
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    Association between serotonin transporter gene polymorphisms and increased suicidal risk among HIV positive patients in Uganda
    (BioMed Central, 2017-07-25) Kalungi, Allan; Seedat, Soraya; Hemmings, Sian M. J.; Van der Merwe, Lize; Joloba, Moses L.; Nanteza, Ann; Nakassujja, Noeline; Birabwa, Harriet; Serwanga, Jennifer; Kaleebu, Pontiano; Kinyanda, Eugene
    Background: Persons living with HIV/AIDS (PLWHA) are at an increased risk of suicide. Increased suicidal risk is a predictor of future attempted and completed suicides and has been associated with poor quality of life and poor adherence with antiretroviral therapy. Clinical risk factors have low predictive value for suicide, hence the interest in potential neurobiological correlates and specific heritable markers of suicide vulnerability. The serotonin transporter gene has previously been implicated in the aetiology of increased suicidal risk in non-HIV infected study populations and its variations may provide a platform for identifying genetic risk for suicidality among PLWHA. The present cross-sectional study aimed at identifying two common genetic variants of the serotonin transporter gene and their association with increased suicidal risk among human immunodeficiency virus (HIV)-positive adults in Uganda. Results: The prevalence of increased suicidal risk (defined as moderate to high risk suicidality on the suicidality module of the Mini Neuropsychiatric Interview (M.I.N.I) was 3.3% (95% CI, 2.0–5.3). The 5-HTTLPR was found to be associated with increased suicidal risk before Bonferroni correction (p-value = 0.0174). A protective effect on increased suicidal risk was found for the 5-HTTLPR/rs25531 S A allele (p-value = 0.0046)- which directs reduced expression of the serotonin transporter gene (5-HTT). Conclusion: The S A allele at the 5-HTTLPR/rs25531 locus is associated with increased suicidal risk among Ugandan PLWHA. Further studies are needed to validate this finding in Ugandan and other sub-Saharan samples.
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    Internalizing mental disorders and accelerated cellular aging among perinatally HIV-infected youth in Uganda
    (Frontiers Media, 2019) Kalungi, Allan; Womersley, Jacqueline S.; Kinyanda, Eugene; Joloba, Moses L.; Ssembajjwe, Wilber; Nsubuga, Rebecca N.; Levin, Jonathan; Kaleebu, Pontiano; Kidd, Martin; Seedat, Soraya, 1966-; Hemmings, Sian M. J.
    Introduction: Internalizing mental disorders (IMDs) in HIV+ children and adolescents are associated with impaired quality of life and non-adherence to anti-retroviral treatment. Telomere length is a biomarker of cellular aging, and shorter telomere length has been associated with IMDs. However, the nature of this association has yet to be elucidated. Objective: We determined the longitudinal association between IMDs and relative telomere length (rTL) and the influence of chronic stress among Ugandan perinatally HIV-infected youth (PHIY). Methods: IMDs (depressive disorders, anxiety disorders, and post-traumatic stress disorder) and IMDs were assessed using the locally adapted Child and Adolescent Symptom Inventory-5. In 368 PHIY with any IMD and 368 age- and sex-matched PHIY controls without any psychiatric disorder, rTL was assessed using quantitative polymerase chain reaction. Hierarchical cluster analysis was used to generate the three chronic stress classes (mild, moderate, and severe). t-tests were used to assess the difference between baseline and 12 month rTL and the mean difference in rTL between cases and controls both at baseline and at 12 months. Linear regression analysis was used to model the effects of chronic stress on the association between IMDs and rTL, controlling for age and sex. Results: We observed longer rTL among cases of IMDs compared with controls (p < 0.001). We also observed a statistically significant reduction in rTL between baseline and 12 months in the combined sample of cases and controls (p < 0.001). The same statistical difference was observed when cases and controls were individually analyzed (p < 0.001). We found no significant difference in rTL between cases and controls at 12 months (p = 0.117). We found no significant influence of chronic stress on the association between IMDs and rTL at both baseline and 12 months. Conclusion: rTL is longer among cases of IMDs compared with age- and sex-matched controls. We observed a significant attrition in rTL over 12 months, which seems to be driven by the presence of any IMDs. There is a need for future longitudinal and experimental studies to understand the mechanisms driving our findings.
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    Internalizing mental disorders in HIV : the role of environment, telomere length and selected genetic variants
    (Stellenbosch : Stellenbosch University, 2020-03) Kalungi, Allan; Hemmings, Sian M. J.; Kinyanda, Eugene; Seedat, Soraya, 1966-; Womersley, Jacqueline S.; Joloba, Moses; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Psychiatry.
    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.
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    TERT rs2736100 and TERC rs16847897 genotypes moderate the association between internalizing mental disorders and accelerated telomere length attrition among HIV+ children and adolescents in Uganda
    (BMC (part of Springer Nature), 2021-01-06) Kalungi, Allan; Kinyanda, Eugene; Womersley, Jacqueline S.; Joloba, Moses L.; Ssembajjwe, Wilber; Nsubuga, Rebecca N.; Kaleebu, Pontiano; Levin, Jonathan; Kidd, Martin; Seedat, Soraya; Hemmings, Sian M. J.
    Background: Internalizing mental disorders (IMDs) (depression, anxiety and post-traumatic stress disorder) have been associated with accelerated telomere length (TL) attrition; however, this association has not been investigated in the context of genetic variation that has been found to influence TL. We have previously reported an association between IMDs and accelerated TL attrition among Ugandan HIV+ children and adolescents. This study investigated the moderating effects of selected single nucleotide polymorphisms in the telomerase reverse transcriptase gene (TERT) (rs2736100, rs7726159, rs10069690 and rs2853669) and the telomerase RNA component gene (TERC) (rs12696304, rs16847897 and rs10936599) on the association between IMDs and TL, among Ugandan HIV+ children (aged 5–11 years) and adolescents (aged 12–17 years). Results: We found no significant interaction between IMDs as a group and any of the selected SNPs on TL at baseline. We observed significant interactions of IMDs with TERT rs2736100 (p = 0.007) and TERC rs16847897 (p = 0.012), respectively, on TL at 12 months. Conclusions: TERT rs2736100 and TERC rs16847897 moderate the association between IMDs and TL among Ugandan HIV+ children and adolescents at 12 months. Understanding the nature of this association may shed light on the pathophysiological mechanisms underlying advanced cellular aging in IMDs.