Genetic Epidemiology of HAD Susceptibility Genes

HAD易感基因的遗传流行病学

• 批准号: 7322110
• 负责人: Sunil K Ahuja
• 金额: $ 39.03万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-09 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7322110
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Address; Adult; Affect; African American; Age; Agonist; Alleles; Alzheimer' s Disease; American; Animal Experiments; Animals; Apolipoprotein E; Appendix; Arts; Astrocytes; Autoimmune Diseases; Blood - brain barrier anatomy; Brain; CCR5 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Candidate Disease Gene; Caucasians; Caucasoid Race; Cells; Central Nervous System Diseases; Cessation of life; Chemotactic Factors; Clinical Research; Cohort Studies; Columbidae; Complement; Complex; Complication; Consensus; DNA-Protein Interaction; Data; Degenerative Disorder; Dementia; Development; Disease; Dose; Endothelial Cells; Environmental Risk Factor; Epidemic; Epidemiologic Studies; Epidemiology; Etiology; European; Event; Fibrinogen; Figs - dietary; Funding; Gelatinase B; Gene Dosage; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genotype; Giant Cells; Goals; HIV; HIV Infections; HIV encephalitis; HIV-1; Haplotypes; Human; Immune; Immune response; Immunosuppression; In Vitro; Individual; Individual Differences; Infection; Infiltration; Inflammatory; Inflammatory Response; Integration Host Factors; Knock-out; Lead; Light; Link; Literature; Macrophage Inflammatory Protein-1; Macrophage Inflammatory Proteins; Matrix Metalloproteinases; Mediating; Medical center; Methods; Microglia; Modeling; Molecular; Monocyte Chemoattractant Protein-1; Monocyte Chemoattractant Proteins; Mononuclear; Multiple Sclerosis; Mus; Mutation; Nervous System Trauma; Nested Case-Control Study; Neuraxis; Neurodegenerative Disorders; Neuronal Dysfunction; Neuronal Injury; Neurons; Neurotoxins; Nodule; Nucleic Acid Regulatory Sequences; Numbers; Organ; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Penetration; Personal Satisfaction; Phagocytes; Phenotype; Physicians; Play; Population; Population Biology; Predisposition; Process; Production; Property; Protein Isoforms; Protein Overexpression; Proteins; Publishing; Rate; Recruitment Activity; Research; Research Design; Research Ethics Committees; Research Personnel; Resort; Resources; Risk; Role; Route; Satellite Viruses; Scientist; Serum; Single Nucleotide Polymorphism; Specimen; Staging; Stimulus; Stress; Susceptibility Gene; T-Lymphocyte; Tail; Testing; Therapeutic immunosuppression; Thinking; Toxin; Translating; Variant; Viral; Viremia; Virus; Virus Diseases; Work; age related; base; beta-Chemokines; brain tissue; chemokine; cohort; cytokine; driving force; genetic association; genetic epidemiology; genetic risk factor; in vivo; innovation; interest; migration; monocyte; nonhuman primate; peripheral blood; protein expression; research study; response; skills; statistics; tool; trafficking; transmission process; virology

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".

描述（由申请人提供）：越来越多的证据表明，个体的宿主遗传构成不仅强烈影响艾滋病毒传播和向艾滋病的发展风险，而且在定义诸如HIV相关痴呆等疾病的特定艾滋病的发展中起着至关重要的作用。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基因型与发育中的风险显着增加有关。但是，很少有研究系统地确定宿主基因型与HAD的发展之间的关联。在这项合作研究中，我们将检验以下假设。 AIM＃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会改变HAD的风险。在此目标中，我们将研究趋化因子MIP-1Alphap的基因剂量和MMP-9的变异的遗传贡献。 AIM＃2将检验以下假设：候选细胞因子或神经毒素基因（例如TNFALPHA）的表达是MP介导的对大脑中HIV感染的炎症反应的一部分，这会改变HAT的风险。 AIM＃3将检验以下假设：MP介导的炎症损伤的神经元易感性与APOE基因型有关。该提案有两个重要的优势：首先，要直接解决HAD的宿主遗传的重要性，我们将利用最大的HIV-1血清阳性个体（1,132名受试者）在美国单一的医疗中心之后。几个独特的流行病学特征，包括大量的高加索人和该队列中的非裔美国人，为我们提供了研究遗传多态性hAT的影响的能力。其次，我们将使用量身定制的流行病学研究设计的组合来解决每个特定目标。例如，我们将使用嵌套的病例对照研究，除了传统的队列研究外，病例研究研究还可以剖析各种基因型的种群水平效应。这项研究很重要，因为（1）它将使用遗传学的有力方法来解决什么是在40岁以下的个体中，可以说是世界上最常见的痴呆症原因，即； （2）它具有建立广泛适用的范式的方法，以剖析其他复杂的，多性疾病的遗传基础，其中多种基因的产物相互相互作用以及与环境因素相互作用。例如，鉴于与HAD相关的炎症过程中的相似性，自身免疫性疾病（如多发性硬化症）以及AD和帕金森氏病等退行性疾病，我们的发现可能提供常见的病因学因素或遗传网络的证据，这些因素或遗传网络在这种多样性疾病的病原体中起着作用。因此，该提案寻求资金来支持一项协作研究，以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）（UTHSCSA）和流行病学/病毒学/统计局（WHMC），从而探索了遗传机制的易感性。这项研究将利用现有的，匿名的，未连接的人类标本。 IRB对这些标本的遗传研究的批准先前已在45 CFR 46.110授权的快速审查下获得。我们提出了添加新字幕的请求：“与HIV相关痴呆的遗传流行病学”。