Dopamine receptor D3 genetic polymorphism (rs6280TC) is associated with rates of cognitive impairment in methamphetamine-dependent men with HIV: preliminary findings

• Published in: Journal of neurovirology Vol. 17; no. 3; pp. 239 - 247
• Main Authors: Gupta, Saurabh, Bousman, Chad A., Chana, Gursharan, Cherner, Mariana, Heaton, Robert K., Deutsch, Reena, Ellis, Ronald J., Grant, Igor, Everall, Ian P.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.06.2011; Springer
• Subjects: Adult; Alleles; Amphetamine-Related Disorders - etiology; Amphetamine-Related Disorders - genetics; Amphetamine-Related Disorders - metabolism; Amphetamine-Related Disorders - psychology; Amphetamine-Related Disorders - virology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cognition Disorders - etiology; Cognition Disorders - genetics; Cognition Disorders - metabolism; Cognition Disorders - psychology; Cognition Disorders - virology; Dopamine - metabolism; Genetic Predisposition to Disease; Genotype; HIV - physiology; HIV Infections - complications; HIV Infections - genetics; HIV Infections - metabolism; HIV Infections - virology; Human immunodeficiency virus; Human viral diseases; Humans; Immunology; Infectious Diseases; Male; Medical sciences; Methamphetamine - adverse effects; Methamphetamine - pharmacology; Neurology; Neuropsychological Tests; Neurosciences; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptors, Dopamine D3 - genetics; Receptors, Dopamine D3 - metabolism; Retrospective Studies; Risk Factors; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Viral diseases of the nervous system; Virology; HIV; SNP; Dopamine D3 receptor; Methamphetamine; Cognitive impairment; Human; Drug addiction; Nervous system diseases; Cognitive disorder; Metamfetamine; D3 Dopamine receptor; Infection; Viral disease; Polymorphism
• DOI: 10.1007/s13365-011-0028-3
• ISSN: 1355-0284; 1538-2443

Macrophages are one of HIV-1’s principal targets and chiefly responsible for translocating HIV into the central nervous system (CNS). Previous research suggested an increase in macrophages being infected by HIV in the presence of methamphetamine (METH) or increased extracellular dopamine (DA). Experimental studies indicate that this is mediated by DA receptors, including DA receptor D3 (DRD3), which is expressed in macrophages. A single nucleotide polymorphism (SNP) of the DRD3 gene (rs6280TC) modulates its dopamine binding affinity, resulting in the possibility that inheriting a variant of this SNP increases macrophage susceptibility to HIV infection in the presence of METH and DA, particularly in the CNS where METH is sequestered, leading to cognitive impairment (CI). Thus, we conducted a retrospective clinical investigation to evaluate whether rs6280TC is associated with CI among HIV-positive METH users. We stratified 310 males by HIV serostatus (HIV-positive, -negative) and METH dependence (METH-positive, -negative) and then by rs6280TC genotype (CC, CT, and TT). Genotypic groups within each of four HIV/METH groups were compared for rates of CI. We hypothesized that only HIV-positive/METH-positive carriers of the C allele, which increases the DRD3’s binding to DA, would be more likely to develop CI. Cochran–Armitage test for trends in proportions yielded significant ( p  < 0.05) association between three genotypes and impairment rates in the hypothesized order, but only among HIV-positive/METH-positive subjects. The results also confirmed that C allele carriers (CC and CT, 53.3%) in this group had higher impairment rates ( p  = 0.05) than TT carriers (33.3%). These findings support the theory that rs6280TC influences the frequency of CI in HIV-positive/METH-positive males.