Genome-Wide Association Study of HIV-1 Host Genetics Among Injection Drug Users

注射吸毒者中 HIV-1 宿主遗传学的全基因组关联研究

基本信息

批准号：
7880028
负责人：
Eric Otto Johnson
金额：
$ 72.34万
依托单位：
RESEARCH TRIANGLE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7880028
关键词：
Accounting Acquired Immunodeficiency Syndrome Acute Affect African American American Animal Model Arts Attention Behavioral Biological Biology Candidate Disease Gene Case-Control Studies Clinical Cohort Studies Communities DNA Data Detection Development Disease Disease Progression Drug abuse Drug usage Equilibrium Europe European Genes Genetic Genetic Determinism Genetic Risk Genetic Variation Genotype Goals HIV HIV Antibodies HIV Infections HIV Seropositivity HIV vaccine HIV-1 HLA-C Antigens Heterogeneity Human Immunology Infection Inherited Injecting drug user Intervention Joints Life Malawi Measures Medical Modeling Needle Sharing North America Outcome Pathway interactions Patients Phase Phenotype Population Predisposition Preparation Probability Publishing Recruitment Activity Reporting Research Research Personnel Resistance Resistance to infection Risk Risk Behaviors Risk Estimate Running Sampling Scoring Method Screening procedure Serum Shares syringes Single Nucleotide Polymorphism Susceptibility Gene Testing United States Urban Health Variant Viral Load result Virus Work case control cohort condoms consistent condom use demographics disorder risk genetic analysis genetic association genetic variant genome wide association study high risk member novel public health relevance response sex success transmission process vaccine development willingness

项目摘要

DESCRIPTION (provided by applicant): In response to RFA DA-08-009: HIV-1 and Host Genetics in Drug Using Populations and Model Organisms, the overarching goal of this project is to identify and characterize genetic determinants of HIV-1 susceptibility and resistance in large samples of African American and European American injection drug users (IDU) by conducting: 1) a case/control genome-wide association (GWA) study of HIV-1 infection (positive / negative); 2) a case-only GWA study of viral load among HIV+ IDUs. Host genetic studies hold out the promise of identifying genetic variants that influence the human response to HIV-1. Such variants would help determine aspects of the human response to HIV-1 that may be the best targets for developing a vaccine against HIV-1. Progress is being made in genetic studies of HIV-1 infection. However, nearly all reported findings are from candidate gene studies, which explain only a fraction of the variability of HIV-1 infection. The limited availability of large relevant cohorts for genetic study, the absence of African Americans from current genetic studies despite the disproportionate HIV burden in this community, and the limited attention to the IDU population limit the field's ability to identify genetic variants affecting HIV-1 infection and strongly argue for the need to conduct large-scale GWA studies of HIV-1 infection phenotypes. The proposed study will use existing samples and data from Urban Health Study (UHS), the longest- running study of street-recruited IDUs in North America to achieve the following aims: Aim 1: To evaluate genetic associations for HIV-1 susceptibility/resistance in HIV+ cases and high risk HIV negative controls among African American and European American IDUs. Separate GWA analyses will be conducted among African American and European American IDUs (n= 5,583 and 3,864, respectively). Aim 1a: To quantify and balance the level of HIV risk among HIV positive cases and high-risk HIV negative controls using Propensity Score Methods in preparation for GWA studies. Aim 1b: To explore gene by HIV risk interactions for top SNPs associated with HIV-1 status. Aim 2: To evaluate genetic associations of viral load among African American and European American HIV positive IDUs. Aim 3: To replicate primary findings in Center for HIV Vaccine Immunology (CHAVI) cohorts. PUBLIC HEALTH RELEVANCE: This study of injection drug users will identify genes associated with HIV-1 infection and HIV viral load, the latter being an important predictor of disease progression and development of AIDS. This will be the first genetic study to include African Americans, a group who suffers a disproportionate HIV burden in the United States. The results of this study may identify important biological pathways and targets for developing a vaccine against HIV-1.

描述（由申请人提供）：为了回应 RFA DA-08-009：吸毒人群和模式生物中的 HIV-1 和宿主遗传学，该项目的首要目标是识别和表征 HIV-1 易感性的遗传决定因素和通过以下方式对非裔美国人和欧洲裔美国人注射吸毒者 (IDU) 的大样本进行耐药性检测： 1) HIV-1 感染（阳性/阴性）的病例/对照全基因组关联 (GWA) 研究； 2) 一项针对 HIV+ 注射吸毒者病毒载量的仅病例 GWA 研究。宿主遗传学研究有望确定影响人类对 HIV-1 反应的遗传变异。这些变异将有助于确定人类对 HIV-1 反应的各个方面，这可能是开发 HIV-1 疫苗的最佳目标。 HIV-1 感染的遗传学研究正在取得进展。然而，几乎所有报告的发现都来自候选基因研究，这些研究只能解释 HIV-1 感染变异性的一小部分。用于基因研究的大型相关队列的可用性有限，尽管该社区的艾滋病毒负担不成比例，但当前的基因研究中缺乏非洲裔美国人，以及对注射吸毒者人群的有限关注限制了该领域识别影响 HIV-1 感染的基因变异的能力并强烈主张需要对 HIV-1 感染表型进行大规模 GWA 研究。拟议的研究将使用城市健康研究 (UHS) 的现有样本和数据来实现以下目标：目标 1：评估 HIV-1 易感性/耐药性的遗传关联。非洲裔美国人和欧洲裔美国人注射吸毒者中的艾滋病毒阳性病例和高风险艾滋病毒阴性对照。将对非洲裔美国人和欧洲裔美国人注射吸毒者（分别为 5,583 名和 3,864 名）进行单独的 GWA 分析。目标 1a：使用倾向评分方法量化和平衡 HIV 阳性病例和高风险 HIV 阴性对照之间的 HIV 风险水平，为 GWA 研究做准备。目标 1b：通过 HIV 风险相互作用探索与 HIV-1 状态相关的主要 SNP 的基因。目标 2：评估非洲裔美国人和欧洲裔美国人 HIV 阳性注射吸毒者中病毒载量的遗传关联。目标 3：复制 HIV 疫苗免疫学中心 (CHAVI) 队列的主要发现。公共卫生相关性：这项针对注射吸毒者的研究将确定与 HIV-1 感染和 HIV 病毒载量相关的基因，后者是疾病进展和艾滋病发展的重要预测因素。这将是第一项针对非裔美国人的基因研究，该群体在美国承受着不成比例的艾滋病毒负担。这项研究的结果可能会确定开发 HIV-1 疫苗的重要生物学途径和目标。