The impact of host genetics and stimulant use on neurocognition in HIV+ adults.

宿主遗传学和兴奋剂使用对艾滋病毒成人神经认知的影响。

• 批准号: 7674588
• 负责人: ANDREW J LEVINE
• 金额: $ 12.6万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674588
• 关键词: AIDS neuropathy; Acquired Immunodeficiency Syndrome; Address; Adult; Affect; Alleles; Apolipoprotein E; Attention; Behavioral; Brain; Brain region; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Caucasians; Caucasoid Race; Characteristics; Chronic; Clinical; Code; Cognition Disorders; Cohort Studies; DNA; Data; Dementia; Development; Diagnosis; Disease; Dopamine; Drug user; Gays; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; HIV; HIV diagnosis; Impaired cognition; Impairment; Individual; Infection; Investigation; Knowledge; Lead; Liquid substance; Longitudinal Studies; Measures; Metabolism; Methodology; Methods; Natural History; Neurobiology; Neurocognition; Neurocognitive; Neurocognitive Deficit; Neurologic; Neuropathogenesis; Neuropsychology; Neurotransmitters; Outcome; Pattern; Performance; Pharmacologic Substance; Phenotype; Play; Proteins; Public Health; Quality of life; Reporting; Research; Resistance; Role; Sampling; Severities; Single Nucleotide Polymorphism; Statistical Methods; Substance abuse problem; Time; Tumor Necrosis Factor-alpha; Variant; Virus Diseases; Visit; Work; base; cohort; genetic analysis; genetic association; genome wide association study; immune function; insight; longitudinal course; male; neurophysiology; neuroprotection; neuropsychiatry; neuropsychological; novel; psychogenetics; statistics; stimulant abuse

DESCRIPTION (provided by applicant): In the proposed study we will examine how illicit stimulant use affects the longitudinal course of neurocognitive functioning in individuals infected with human immunodeficiency virus (HIV), and how host-genetic variation modulates this. While it is has been established that both HIV infection and stimulant use result in neurocognitive impairment, and that these effects are additive or even synergistic, the interactive relationship between these two factors as it evolves over time has not yet been examined. Further, while the role of host- genetics in the progression of HIV/AIDS has received growing attention during the past few years, its contribution to the progression and characteristics of neurocognitive deficits over time remains to be determined. To address this, we will employ two genetic association methods. First, we will utilize a candidate gene approach with a large sample (N = 1000) of HIV+ and HIV- individuals that will focus on polymorphisms that affect the metabolism and activity of dopamine (DA). This neurotransmitter is implicated in the neuropathogenesis of HIV- associated neurocognitive disorders (HAND) and cognitive sequelae of chronic stimulant abuse. Further, research has shown that functional polymorphisms in DA-related genes can affect neuropsychological functioning via alterations in underlying neurophysiology, and that this occurs in brain regions similar to those affected in neuroAIDS. Therefore, examination of DA-related polymorphisms may add a critical tier of knowledge for explaining inter-individual variation in neuropsychological outcomes and progression among HIV+ drug users. In this exploratory study, we will also examine variants of other genes associated with neurobiological and immune functioning, including ApoE, brain-derived neurotrophic factor, and tumor necrosis factor-alpha. In the second approach, we will examine existing data from a genome-wide association (GWA) scan of 496 HIV+ individuals. We will be able to examine over 555,000 single nucleotide polymorphisms (SNPs) in an effort to detect novel genes associated with neurocognitive phenotypes, such as progression and diagnosis of HAND. Such a large scale genetic analysis of HAND neuropathogenesis has yet to be conducted. The proposed study will use the Multicenter AIDS Cohort Study (MACS), a longitudinal study of the natural history and clinical outcomes in HIV+ individuals. Neuropsychological, psychiatric, and virologic data on cohort of largely Caucasian, gay males are collected at regular intervals. Data exist for both HIV+ and HIV- individuals, as well as individuals with varying stimulant use patterns. Fluids are available for DNA extraction and genotyping. The proposed research team consists of experts in psychiatric genetics, neuropsychology, NeuroAIDS, and statistics with proven ability by successfully carrying out similar studies and to work with MACS data. The results of these investigations will lead to greater understanding of the neuropathogenesis of HAND, identification of pharmaceutical targets, and ultimately greater quality of life for those infected with HIV. The results of these investigations will be immediately translatable to public health efforts. Specifically, they will further illuminate understanding of the neuropathogenesis of HAND. Further, the identification of host- genetic factors in the neuropathogenesis of HAND will enable development of specific pharmaceutical treatments, ultimately leading to greater quality of life for those infected with HIV.

描述（由申请人提供）：在拟议的研究中，我们将研究非法刺激的使用如何影响感染人类免疫缺陷病毒（HIV）的个体的神经认知功能的纵向过程，以及宿主遗传变异如何调节这一点。尽管已经确定HIV感染和刺激性使用会导致神经认知障碍，并且这些影响是加性甚至协同作用，但随着时间的流逝，这两个因素之间的互动关系尚未被检查。此外，尽管宿主遗传学在艾滋病毒/艾滋病进展中的作用在过去几年中受到了越来越多的关注，但随着时间的流逝，它对神经认知缺陷的进展和特征的贡献尚待确定。为了解决这个问题，我们将采用两种遗传关联方法。首先，我们将使用大量样本（n = 1000）HIV+和HIV个体的候选基因方法，该方法将重点放在影响多巴胺（DA）的代谢和活性的多态性上。该神经递质与HIV相关的神经认知疾病（手）和慢性刺激滥用的认知后遗症有关。此外，研究表明，与DA相关基因的功能多态性可以通过基础神经生理学的改变影响神经心理学功能，并且这发生在类似于与神经助剂相似的大脑区域中。因此，对DA相关的多态性的检查可能会增加知识的关键层次，以解释HIV+吸毒者之间神经心理学结局和进展的个体差异。在这项探索性研究中，我们还将检查与神经生物学和免疫功能相关的其他基因的变体，包括APOE，脑衍生的神经营养因子和肿瘤坏死因子 - α。在第二种方法中，我们将检查来自496 HIV+个体的全基因组关联（GWA）扫描的现有数据。我们将能够检查超过555,000个单核苷酸多态性（SNP），以检测与神经认知表型相关的新基因，例如手的进展和诊断。对手神经病发生的如此大规模的遗传分析尚未进行。拟议的研究将使用多中心艾滋病队列研究（MAC），这是对HIV+个体的自然史和临床结果的纵向研究。关于高加索人队列的神经心理学，精神病学和病毒学数据，同性恋男性是定期收集的。 HIV+和HIV个体以及具有不同兴奋性使用模式的个体都存在数据。流体可用于DNA提取和基因分型。拟议的研究团队由精神病遗传学，神经心理学，神经辅助和统计的专家组成，并通过成功进行类似的研究并使用MACS数据，具有可靠的能力。这些研究的结果将导致对手动的神经病发生，药物靶标的识别以及感染HIV感染者的生活质量更高的生活质量。这些调查的结果将立即转化为公共卫生工作。具体而言，他们将进一步阐明对手的神经病发生的理解。此外，在手部神经病发生中鉴定宿主遗传因素将使特定的药物治疗发展，最终导致感染HIV的人的生活质量更高。