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

描述（由申请人提供）：在拟议的研究中，我们将研究非法兴奋剂使用如何影响人类免疫缺陷病毒（HIV）感染者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过程。虽然已经确定，艾滋病毒感染和兴奋剂的使用导致神经认知障碍，这些影响是累加的，甚至是协同的，这两个因素之间的相互作用关系，因为它随着时间的推移演变还没有被检查。此外，虽然宿主遗传学在HIV/AIDS进展中的作用在过去几年中受到越来越多的关注，但其对神经认知缺陷随时间的进展和特征的贡献仍有待确定。为了解决这个问题，我们将采用两种遗传关联方法。首先，我们将利用一个候选基因的方法与大样本（N = 1000）的HIV+和HIV-的个人，将重点放在多态性，影响多巴胺（DA）的代谢和活性。这种神经递质与HIV相关的神经认知障碍（HAND）和慢性兴奋剂滥用的认知后遗症的神经发病机制有关。此外，研究表明，DA相关基因的功能多态性可以通过改变潜在的神经生理学来影响神经心理功能，并且这种情况发生在与神经艾滋病受影响的大脑区域相似的大脑区域。因此，检查DA相关的多态性可能会增加一个关键层的知识，解释个体间的差异，在神经心理学的结果和艾滋病毒+吸毒者的进展。在这项探索性研究中，我们还将研究与神经生物学和免疫功能相关的其他基因的变体，包括ApoE，脑源性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名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HAND的进展和诊断。如此大规模的HAND神经发病机制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（MACS），这是一项对HIV+个体的自然史和临床结局进行的纵向研究。神经心理学，精神病学和病毒学的数据，主要是白人，男同性恋者的队列收集定期。艾滋病毒阳性和艾滋病毒阴性的人以及使用兴奋剂方式各不相同的人都有数据。液体可用于DNA提取和基因分型。拟议的研究小组由精神病遗传学，神经心理学，神经艾滋病和统计学方面的专家组成，他们成功地进行了类似的研究并使用MACS数据。这些研究的结果将导致更好地了解HAND的神经发病机制，确定药物靶点，并最终提高HIV感染者的生活质量。这些调查的结果将立即转化为公共卫生工作。具体来说，他们将进一步阐明理解的神经发病机制的手。此外，鉴定HAND神经发病机制中的宿主遗传因素将能够开发特定的药物治疗，最终导致HIV感染者的生活质量更高。

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.