Genetic Epidemiology of HAD Susceptibility Genes

描述（由申请人提供）：越来越多的证据表明，个体的宿主基因组成不仅强烈影响 HIV 传播和进展为 AIDS 的风险，而且在特定 AIDS 定义疾病（如 HIV 相关痴呆 (HAD)）的发展中也发挥着关键作用。为了支持这一假设，我们最近证明单核细胞趋化蛋白 1 (MCP-1) 基因的 GA/GA 基因型与患 HAD 的风险显着增加相关。然而，很少有研究系统地确定宿主基因型与 HAD 发生之间的关系。在这项合作研究中，我们将测试以下假设。目标 1 将检验总体假设，即已知促进或促进单核细胞募集的候选基因的表达将改变 HAD 风险。为此，我们将研究趋化因子 MIP-1alphaP 的基因剂量和 MMP-9 的变异在 HAD 发病机制中的遗传贡献。目标 #2 将检验以下假设：候选细胞因子或神经毒素基因（例如 TNFα）的表达是 MP 介导的针对 HIV 感染的大脑炎症反应的一部分，会改变 HAD 的风险。目标 #3 将检验以下假设：神经元对 MP 介导的炎症损伤的易感性与 APOE 基因型有关。该提案有两个显着优势：首先，为了直接解决 HAD 宿主遗传的重要性，我们将利用在美国单个医疗中心跟踪的最大的 HIV-1 血清阳性个体（1,132 名受试者）队列。一些独特的流行病学特征，包括该队列中大量的白人和非裔美国人，为我们提供了研究遗传多态性对 HAD 的影响的能力。其次，我们将结合流行病学研究设计来解决每个具体目标。例如，除了传统的队列研究之外，我们还会使用巢式病例对照研究、病例队列研究来剖析不同基因型对人群水平的影响。这项研究意义重大，因为 (1) 它将使用强大的遗传学方法来解决可以说是世界上 40 岁以下个体痴呆症最常见原因的机制，即 HAD； （2）它有可能建立一个广泛适用的范式，用于剖析其他复杂的多病因疾病的遗传基础，在这些疾病中，多种基因的产物彼此相互作用并与环境因素相互作用。例如，鉴于与 HAD、多发性硬化症等自身免疫性疾病以及 AD 和帕金森病等退行性疾病相关的炎症过程的相似性，我们的研究结果可能提供在这组不同疾病的发病机制中发挥作用的常见病因或遗传网络的证据。因此，本提案寻求资金支持一项合作研究，通过合并两个不同研究团队（即遗传学 (UTHSCSA) 和流行病学/病毒学/统计学 (WHMC)）的独特技能和资源，探索 HAD 易感性的遗传机制。这项研究将利用预先存在的、匿名的、无关联的人类标本。 IRB 对这些标本进行基因研究的批准之前已根据 45 CFR 46.110 授权的快速审查获得。我们已提交添加新副标题的请求：“艾滋病毒相关痴呆的遗传流行病学”。

DESCRIPTION (provided by applicant): There is growing evidence that the host genetic make-up of an individual not only strongly influences risk of HIV-transmission and progression to AIDS but also plays a critical role in the development of specific AIDS defining illnesses such as HIV-associated dementia (HAD). In support of this hypothesis, we recently demonstrated that the GA/GA genotype for the monocyte chemoattractant protein 1 (MCP-1) gene is associated with a significantly increased risk of developing HAD. However, there are very few studies that have systematically determined the association between host genotype and development of HAD. In this collaborative study, we will test the following hypotheses. Aim # 1 will test the overall hypothesis that expression of candidate genes that are known to promote or facilitate monocyte recruitment will alter risk of HAD. In this aim, we will investigate the genetic contribution of gene dosage of the chemokine MIP-1alphaP and variation in MMP-9 in HAD pathogenesis. Aim #2 will test the hypothesis that expression of candidate cytokine or neurotoxin genes (e.g. TNFalpha) that are part of the MP-mediated inflammatory response to HIV infection in the brain alter the risk of HAD. Aim #3 will test the hypothesis that neuronal susceptibility to MP-mediated inflammatory damage is linked to APOE genotypes. There are two significant strengths of this proposal: First, to address directly the importance of the host genetic of HAD, we will capitalize on the largest cohort of HIV-1 seropositive individuals (1,132 subjects) followed at a single U.S. medical center. Several unique epidemiological features, including the large number of Caucasians and African-Americans in this cohort, provide us the power to study the effects of genetic polymorphisms in HAD. Second, we will use a combination of epidemiologic study designs tailored to address each specific aim. For example, we will use the nested case-control study, the case-cohort study in addition to the traditional cohort study to dissect out the population level effects of various genotypes. The research is significant because (1) it will use the powerful approach of genetics to address the mechanisms underlying what arguably is the most common cause of dementia in the world in individuals less than the age of 40, namely HAD; (2) it has the potential for establishing a broadly applicable paradigm for approaches to dissect the genetic basis for other complex, multi-etiologic disorders in which the products of a multiplicity of genes interact with each other and with environmental factors. For example, given the similarities in the inflammatory processes associated with HAD, autoimmune diseases such as multiple sclerosis, and degenerative diseases such as AD and Parkinson's disease, our findings may provide evidence of common etiologic factors or genetic networks that play a role in the pathogenesis of this diverse group of diseases. Thus, this proposal seeks funds to support a collaborative study to explore the genetic mechanisms underlying HAD susceptibility by amalgamating the unique skills and resources of two different research teams, namely genetics (UTHSCSA) and epidemiology/virology/statistics (WHMC). This study will utilize pre-existing, anonymous, unlinked human specimens. IRB approval for genetic study of these specimens has been previously obtained under expedited review authorized by 45 CFR 46.110. We have submitted a request for addition of a new subtitle: "Genetic epidemiology of HIV-associated dementia".