Genetic Epidemiology of HAD Susceptibility Genes

描述(申请人提供)：越来越多的证据表明，个人的宿主基因构成不仅强烈影响艾滋病毒传播和发展为艾滋病的风险，而且在特定艾滋病的发展中发挥关键作用，这些疾病包括艾滋病毒相关痴呆症(HAD)。为了支持这一假设，我们最近证明了单核细胞趋化蛋白1(MCP-1)基因的GA/GA基因型与发生HAD的风险显著增加有关。然而，很少有研究系统地确定宿主基因与HAD发病的关系。在这项合作研究中，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。为此，我们将研究趋化因子MIP-1αP的基因剂量和基质金属蛋白酶-9的变异在HAD发病机制中的遗传贡献。目的#2将验证一个假设，即作为MP介导的炎症反应的一部分的候选细胞因子或神经毒素基因(例如，TNFpha)的表达改变了HAD的风险。目的#3将验证神经元对MP介导的炎性损伤的易感性与APOE基因相关的假设。这项提议有两个显著的优点：第一，为了直接解决HAD宿主基因的重要性，我们将利用在一个美国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)。一些独特的流行病学特征，包括这个队列中大量的高加索人和非裔美国人，为我们提供了研究遗传多态对HAD影响的力量。其次，我们将使用针对每个特定目标量身定做的流行病学研究设计的组合。例如，我们将在传统队列研究的基础上，使用嵌套病例对照研究、病例队列研究来剖析各种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世界上40岁以下人群患痴呆症的最常见原因，即HAD的潜在机制；(2)它有可能为剖析其他复杂的、多病因疾病的遗传基础的方法建立一个广泛适用的范例，在这些疾病中，多种基因的产物相互作用并与环境因素相互作用。例如，考虑到与HAD、自身免疫性疾病(如多发性硬化症)以及退行性疾病(如AD和帕金森氏病)相关的炎症过程的相似性，我们的发现可能提供在这一不同疾病组的发病机制中发挥作用的共同病因或遗传网络的证据。因此，这项建议寻求资金支持一项合作研究，通过合并遗传学(UTHSCSA)和流行病学/病毒学/统计学(WHMC)两个不同研究团队的独特技能和资源来探索HAD易感性的遗传机制。这项研究将利用预先存在的、匿名的、没有关联的人类标本。IRB对这些标本进行遗传研究的批准此前已在45 CFR 46.110授权的快速审查下获得。我们已经提交了增加一个新副标题的请求：“艾滋病毒相关性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".