Functional polymorphisms in dopamine-related genes: Effect on neurocognitive functioning in HIV+ adults

Abstract

Dopaminergic dysfunction is a putative mechanism underlying HIV-associated neurocognitive disorders. Dopamine transporter (DAT), brain-derived neurotrophic factor (BDNF), and catechol-O-methyltransferase (COMT) have been specifically implicated. We report analyses examining the main effects of functional polymorphisms within dopamine-modulating genes, as well as their interactive effects with disease severity, upon neurocognitive functioning in HIV+ adults. Method A total of 184 HIV+ adults were included in the analysis. Three polymorphisms were examined within dopamine-modulating genes: COMT val158met, BDNF val66met, and the DAT 3 variable number tandem repeat. Separate hierarchical regression analyses for five neurocognitive domains (working memory, processing speed, learning, memory, motor) were conducted. Predictor variables were age, ethnicity, gender, education, CD4+ T-cell count, current depression, genotype, and an interaction term capturing genotype and disease severity (CD4). Results None of the polymorphisms or HIV disease variables significantly improved the hierarchical regression models. Younger age, higher education, and Caucasian ethnicity were almost invariably associated with better functioning across all five cognitive domains. A trend was noted for current depression as a predictor of motor and learning ability. Conclusion This study did not find evidence to support direct or interactive effects of dopamine-related genes and HIV disease severity on neurocognitive functioning.

The longitudinal and interactive effects of HIV status, stimulant use, and host genotype upon neurocognitive functioning

“…This likely reflects the multifaceted nature of HAND pathogenesis, which is influenced by numerous cytokines, chemokines, and other immunological factors. Consistent with findings from another cohort(Levine et al 2012b), DA-related genetic differences do not appear to influence the longitudinal neurocognitive functioning of HIV+ individuals, despite significant evidence for the role of DA dysfunction in HAND. Further, in the pre-HAART era, improvement of processing speed and decline of motor functioning over time among HIV+ individuals was consistently observed, and an unrelated decline in motor functioning due to stimulant use (regardless of HIV status) was also consistently observed.…”

Genetic predictor of working memory and prefrontal function in women with HIV

“…Consistent with our findings, a study of 192 HIV-infected, non-methamphetamine users found an association between the Met/Met genotype and better executive function (Bousman et al, 2010b). Conversely, a study of 184 HIV-infected individuals (87% male) in more advanced stages of HIV (mean CD4=219) found no effect of COMT genotype on the Letter-Number Sequencing test (LNS) and the Paced Auditory Serial Addition Test (Levine et al, 2012). The discrepancy between that study and the others might be due to the inclusion of individuals with more advanced disease where the effect of disease might mask any COMT effect (Stout et al, 1995; York et al, 2001), the use of the LNS which might be less sensitive than the N-back to COMT (Bousman et al, 2010b) or to low female representation (13%).…”

“…Two previous studies investigated the effect of COMT genotype on executive function in HIV, but involved predominantly male cohorts and did not include HIV-uninfected controls (Bousman et al, 2010b; Levine et al, 2012). Consistent with our findings, a study of 192 HIV-infected, non-methamphetamine users found an association between the Met/Met genotype and better executive function (Bousman et al, 2010b).…”

Interactions of HIV and Drugs of Abuse

“…A likely reason may be that the deletion of CXCR4 or its cognate ligand SDF-1/CXCL12 is lethal (Ma et al, 1998; Zou, Kottmann, Kuroda, Taniuchi, & Littman, 1998). Combined mutations in multiple HIV co-receptors and/or in the cognate ligands of these co-receptors can interact to confer more or less protection against HIV infectivity or subsequent pathogenesis (Shapshak et al, 2004b; Gelman et al, 2012; Levine, Sinsheimer, Bilder, Shapshak, & Singer, 2012). Lastly, “elite suppressors” or “controllers” is the term given a subset of individuals who maintain plasma HIV copy numbers below 50 copies/mL (Han et al, 2008).…”

“…An examination of specific human gene polymorphisms, especially genes for drug receptors (Bond et al, 1998; Kreek, Nielsen, Butelman, & LaForge, 2005; Kreek et al, 2005; Kreek et al, 2012), enzymes affecting drug metabolism (Meyer & Zanger, 1997), and/or neurochemical systems thought to underlie addiction (Lachman et al, 1996; Nebert, McKinnon, & Puga, 1996; Li et al, 2004; Kreek et al, 2005; Levine et al, 2012), has identified significant correlative relationships between gene polymorphisms and substance abuse (Kreek et al, 2005; Yuferov, Levran, Proudnikov, Nielsen, & Kreek, 2010; Crystal et al, 2012; Manini, Jacobs, Vlahov, & Hurd, 2013; Jacobs, Murray, Byrd, Hurd, & Morgello, 2013). Because addiction is principally a CNS disorder with neurobehavioral/neuropsychiatric underpinnings (Leshner, 1997; Volkow, Wang, Fowler, & Tomasi, 2012), examining substance abuse-HIV interactions in the brain seems a logical direction.…”