Childhood trauma and genetic variation in the DAT 40-bp VNTR contribute to HIV-associated neurocognitive disorders

Abstract

HIV/AIDS is a major public health burden in South Africa, currently affecting an estimated 13.5% of the population. Despite improved access to antiretroviral therapies, HIV-associated neurocognitive disorders (HAND), characterised by a spectrum of neurocognitive impairment, emotional disturbances and motor abnormalities, continue to persist. Gene-environment interactions contribute to HAND pathophysiology and previous research has identified childhood trauma as an environmental risk factor. Dopaminergic signalling in the prefrontal cortex plays a key role in cognitive function. Thus, variants in genes encoding the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT), which are responsible for dopamine transport and metabolism, could represent genetic risk factors for HAND. This study investigated whether the DAT variable number of tandem repeats (VNTR) and COMT Val158Met (rs4680) polymorphisms are associated with longitudinal change in cognitive function in the context of childhood trauma and HIV. Participants (n = 49 HIV-negative and n = 64 HIV-positive women) completed the Childhood Trauma Questionnaire - Short Form (CTQ-SF) and provided blood for genetic analyses. Global cognitive scores were generated from baseline and one-year follow-up assessments. Following polymerase chain reaction, genotypes were determined using gel electrophoresis and confirmed by Sanger sequencing. Baseline global cognitive scores, genotype, HIV status and CTQ-SF scores were regressed on one-year global cognitive scores in regression models. Analysis of variance was used to examine the effect of including predictor variable interactions on model fit. HIV seropositivity was associated with poorer cognitive performance at one-year follow-up (p = 2.46 ×10^-4). The combination of HIV and DAT 10-repeat homozygosity (DAT 10/10) was associated with reduced global cognitive scores in longitudinal models (p = 0.010). Including the interaction between DAT 10/10, childhood trauma, and HIV explained significantly more of the variance in longitudinal cognitive scores (p = 0.008). There were no significant associations with the COMT genotype. Our research indicates that childhood trauma and genetic variation in DAT contribute toward the aetiology of HAND. Future studies in larger cohorts are warranted to verify these results.

Keywords: COMT, Catechol-O-methyltransferase; Catechol-O-methyltransferase; Childhood trauma; DAT, Dopamine transporter; Dopamine transporter; HAND, HIV-associated neurocognitive disorders; HIV; HIV, Human immunodeficiency virus; HIV-associated neurocognitive disorders.

Fig. 1

: a) COMT genotyping using a 15% acrylamide gel. Samples were genotyped for the COMT rs4680 variant using acrylamide gel electrophoresis. The different genotypes can be clearly seen on the gel. GG describes the Val/Val genotype; AG describes the Val/Met genotype; and GG describes the Met/Met genotype. A 25 bp molecular marker is used as a reference. b) COMT Sanger sequencing for COMT rs4680. (i) a homozygous GG (Val/Val) genotype; (ii) a heterozygous AG (Val/Met) genotype; (iii) a homozygous AA (Met/Met) genotype using Sanger sequencing. c) DAT genotyping using a 1.5% agarose gel. DAT 40 bp VNTR variants were genotyped on an agarose gel stained with Condasafe. The electrophoresis was carried out at 70 V for 2.5 h. Lane 4 = */* ; lanes 5 and 6 = */10; and lanes 2, 3, and 7 – 10/10 genotype. Lane 1 represents the negative control. d) DAT-VNTR sequence chromatogram using Sanger sequencing.

Fig. 2

Scatter plot showing the interaction between DAT 10/10 genotype and HIV status significantly associated with follow-up global cognitive scores (HNRC battery). HIV seropositivity and DAT 10-repeat homozygosity was associated with significantly lower cognitive scores in longitudinal models (p = 0.010). The regression model was generated using age and education adjusted z-scores and data is displayed as raw data points. The figure shows a shaded 95% confidence interval with trend lines.

Fig. 3

Scatter plot showing the relationship between DAT 10/10, childhood trauma (CTQ-SF) and HIV status trend towards association with longitudinal cognitive scores (p = 0.08). Including the interaction between DAT 10-repeat homozygosity, childhood trauma and HIV status explained significantly more of the variation in follow-up cognitive scores (p = 0.008). Childhood trauma is displayed categorically with scores less than or equal to 31 being categorized as “No Childhood Trauma” group and scores more than or equal to 41 being categorized as the “Childhood Trauma” group. The regression model was generated using age and education adjusted z-scores and data is displayed as raw data points. The figure shows a shaded 95% confidence interval with trend lines.

Fig. 4

Scatter plot showing the relationship between COMT genotype and HIV status with longitudinal cognitive scores (p = 0.5105). The regression model was generated using age and education adjusted z scores, and data is displayed as raw data points. The figure shows a shaded 95% confidence interval with trend lines.