Serotonin-Related Gene Polymorphisms and Asymptomatic Neurocognitive Impairment in HIV-Infected Alcohol Abusers

Abstract

HIV-infected individuals continue to experience neurocognitive deterioration despite virologically successful treatments. While the cause remains unclear, evidence suggests that HIV-associated neurocognitive disorders (HAND) may be associated with neurobehavioral dysfunction. Genetic variants have been explored to identify risk markers to determine neuropathogenesis of neurocognitive deterioration. Memory deficits and executive dysfunction are highly prevalent among HIV-infected adults. These conditions can affect their quality of life and HIV risk-taking behaviors. Single nucleotide polymorphisms in the SLC6A4, TPH2, and GALM genes may affect the activity of serotonin and increase the risk of HAND. The present study explored the relationship between SLC6A4, TPH2, and GALM genes and neurocognitive impairment in HIV-infected alcohol abusers. A total of 267 individuals were genotyped for polymorphisms in SLC6A4 5-HTTLPR, TPH2 rs4570625, and GALM rs6741892. To assess neurocognitive functions, the Short Category and the Auditory Verbal Learning Tests were used. TPH2 SNP rs4570625 showed a significant association with executive function in African American males (odds ratio 4.8, 95% CI, 1.5–14.8; P = 0.005). Similarly, GALM SNP rs6741892 showed an increased risk with African American males (odds ratio 2.4, 95% CI, 1.2–4.9; P = 0.02). This study suggests that TPH2 rs4570625 and GALM rs6741892 polymorphisms may be risk factors for HAND.

Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics

“…Although these were found to have small effects, they may have more significant impact with pre-existing cognitive deficits, such as in HAND [ 60 ]. In view of this, several studies have investigated the effect of genetic polymorphisms related to dopamine and serotonin neurotransmission on cognitive functions in HAND [ 60 , 61 , 62 ].…”

“…Two SNPs of serotonin-related genes have been associated with NCI in HIV-positive(+) adults, particularly in African American males [ 61 , 63 ]. A homozygous TT genotype in the SNP rs4570625 was associated with poorer executive functioning in HIV+ individuals, most of whom were with ANI, while a small proportion had MNI (HAD was not found in any participants), as assessed by Frascati criteria [ 61 ]. This SNP is located in the transcriptional region for the gene encoding tryptophan hydroxylase 2 ( TPH2 ), the rate-limiting enzyme in serotonin biosynthesis, and affects the transcription rate of TPH2 [ 61 ].…”

“…A homozygous TT genotype in the SNP rs4570625 was associated with poorer executive functioning in HIV+ individuals, most of whom were with ANI, while a small proportion had MNI (HAD was not found in any participants), as assessed by Frascati criteria [ 61 ]. This SNP is located in the transcriptional region for the gene encoding tryptophan hydroxylase 2 ( TPH2 ), the rate-limiting enzyme in serotonin biosynthesis, and affects the transcription rate of TPH2 [ 61 ]. The same study further found that the polymorphism GALM rs6741892 of the galactose mutarotase gene ( GALM ), which indirectly increases local serotonin release, was linked to impaired memory in the same participants [ 61 ].…”

“…This SNP is located in the transcriptional region for the gene encoding tryptophan hydroxylase 2 ( TPH2 ), the rate-limiting enzyme in serotonin biosynthesis, and affects the transcription rate of TPH2 [ 61 ]. The same study further found that the polymorphism GALM rs6741892 of the galactose mutarotase gene ( GALM ), which indirectly increases local serotonin release, was linked to impaired memory in the same participants [ 61 ]. The SLC6A4 5-HTTLPR polymorphism, associated with serotonin transport, had no significant effect.…”

Effects of HIV-1 TAT protein and methamphetamine exposure on visual discrimination and executive function in mice

“…Most evidence suggests that serotonin level/function is decreased after HIV infection. For example, polymorphisms that reduce serotonin function impair cognitive performance in HIV-positive subjects [41] and Simian Immunodeficiency Virus infection in Macaques decreases serotonin levels [42]. This provides further evidence that the global effects of HIV disease are the result of multiple factors in combination and individual proteins/responses represent only one contributing factor in the symptom profile of HIV disease.…”