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艾滋病毒传播和发展为艾滋病的风险，而且在特定艾滋病定义疾病（如艾滋病毒相关痴呆（HAD））的发展中起着关键作用。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HAD发病风险显著增加相关。然而，很少有研究系统地确定宿主基因型与HAD发展之间的关系。在本次合作研究中，我们将检验以下假设。目的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的风险。在这个目的中，我们将研究趋化因子mmp - 1alphap的基因剂量和MMP-9的变异在HAD发病中的遗传作用。Aim #2将测试候选细胞因子或神经毒素基因（如TNFalpha）的表达，这些基因是脑内mp介导的HIV感染炎症反应的一部分，可以改变HAD的风险。Aim #3将验证神经元对mp介导的炎症损伤的易感性与APOE基因型有关的假设。这个建议有两个显著的优势：首先，为了直接解决HAD宿主基因的重要性，我们将利用在美国一个医疗中心跟踪的最大的HIV-1血清阳性个体队列（1132名受试者）。几个独特的流行病学特征，包括该队列中大量的白种人和非裔美国人，为我们研究HAD遗传多态性的影响提供了力量。其次，我们将结合流行病学研究设计来解决每个特定的目标。例如，我们将使用巢式病例对照研究、病例队列研究以及传统队列研究来剖析不同基因型的群体水平效应。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能是世界上40岁以下人群中最常见的痴呆原因（即HAD）的潜在机制；(2)它有可能建立一种广泛适用的范式，用于剖析其他复杂的多病因疾病的遗传基础，其中多种基因的产物相互作用并与环境因素相互作用。例如，考虑到HAD、自身免疫性疾病（如多发性硬化症）和退行性疾病（如阿尔茨海默病和帕金森病）相关炎症过程的相似性，我们的研究结果可能为共同的病因或遗传网络在这类不同疾病的发病机制中发挥作用提供证据。因此，本提案寻求资金支持一项合作研究，通过整合两个不同研究团队的独特技能和资源，即遗传学（UTHSCSA）和流行病学/病毒学/统计学（WHMC），探索HAD易感性的遗传机制。这项研究将利用已有的、匿名的、没有关联的人类样本。IRB先前已根据45 CFR 46.110授权的快速审查获得了对这些标本进行遗传研究的批准。我们已经提交了一份申请，要求增加一个新的副标题：“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".