Genetic Epidemiology of HAD Susceptibility Genes

越来越多的证据表明，个体的宿主遗传组成不仅强烈影响HIV传播和进展为AIDS的风险，而且在特定AIDS定义疾病（如HIV相关痴呆症（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发生风险显著增加相关[PNAS，2002]。然而，很少有研究系统地确定宿主基因型和HAD发展之间的关联。在这项合作研究中，我们将检验以下假设：目标#1”将检验HAD是一种炎性疾病，特别是由HIV-1感染的MP的分泌产物引起的脑病的假设。在这个目标中，我们将调查特定的趋化因子/细胞因子/MMPs和TNF α在HAD发病机制中的遗传贡献。目的#2将检验CXCR 4-SDF轴（被认为在HIV-Env介导神经元功能障碍和细胞凋亡中起关键作用）将改变HAD风险的假设。目标#3将检验阿尔茨海默病和HAD之间存在共同遗传机制联系的假设。该提案有两个显著的优势：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一医疗中心随访的最大的HIV-1血清阳性个体队列（1，132名受试者）。几个独特的流行病学特征，包括大量的白人和非洲裔美国人在这个队列中，为我们提供了权力，研究遗传多态性在HAD的影响。第二，我们将结合流行病学研究设计，以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的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，多病因疾病，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，考虑到与HAD、自身免疫性疾病（如多发性硬化症）和退行性疾病（如AD和帕金森病）相关的炎症过程的相似性，我们的研究结果可能提供共同病因因素或遗传网络的证据，这些因素或遗传网络在这组不同疾病的发病机制中发挥作用。因此，这项建议寻求资金，以支持一项合作研究，通过合并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（NHMC），探索HAD易感性的遗传机制。本研究将使用既存、匿名、未关联的人体标本。先前已根据45 CFR 46 110授权的快速审查获得IRB对这些标本进行遗传学研究的批准。我们已提出请求，要求增加一个新的副标题：“艾滋病毒相关痴呆症的遗传流行病学”。

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 [PNAS, 2002]. 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 hypothesis that HAD is an inflammatory disease, specifically an encephalopathy perpetrated by secretory products of HIV-l-infected MPs. In this aim, we will investigate the genetic contribution of specific chemokines/cytokines/MMPs and TNFalpha in HAD pathogenesis. Aim #2 will test the hypothesis that the CXCR4-SDF axis that is thought to play a critical role in mediating neuronal dysfunction and apoptosis by the HIV-Env will alter risk of HAD. Aim #3 will test the hypothesis that there are common genetic-mechanistic links between Alzheimer's disease and HAD. 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 (NHMC). 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".