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

• 批准号: 7933511
• 负责人: Eric Otto Johnson
• 金额: $ 8.82万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933511
• 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

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）：响应RFA DA-08-009：药物使用群体和模式生物中的HIV-1和宿主遗传学，本项目的总体目标是通过进行：1)HIV-1感染（阳性/阴性）的病例/对照全基因组关联（GWA）研究，在非洲裔美国人和欧美注射吸毒者（IDU）的大样本中确定和表征HIV-1易感性和耐药性的遗传决定因素；2) HIV阳性注射吸毒者病毒载量的GWA研究。宿主基因研究有望确定影响人类对HIV-1反应的基因变异。这些变异将有助于确定人类对HIV-1反应的各个方面，这些方面可能是开发HIV-1疫苗的最佳目标。HIV-1感染的遗传研究正在取得进展。然而，几乎所有报道的发现都来自候选基因研究，这只能解释HIV-1感染变异性的一小部分。遗传研究的大型相关队列有限，尽管非洲裔美国人在该社区的艾滋病毒负担不成比例，但目前的遗传研究中缺少非洲裔美国人，以及对IDU人群的有限关注限制了该领域识别影响HIV-1感染的遗传变异的能力，并强烈要求对HIV-1感染表型进行大规模GWA研究。拟议的研究将使用来自城市健康研究（UHS）的现有样本和数据，这是对北美街头招募的注射吸毒者进行的持续时间最长的研究，以实现以下目标：目的1：评估非洲裔美国人和欧洲裔美国注射吸毒者中HIV-1易感性/耐药性与HIV-1易感性/耐药性的遗传关系。将对非洲裔美国人和欧洲裔美国注射吸毒者（n= 5,583和3,864）进行单独的GWA分析。目的1a：使用倾向评分方法，量化和平衡HIV阳性病例和高风险HIV阴性对照者的HIV风险水平，为GWA研究做准备。目的1b：探索与HIV-1状态相关的顶级snp的HIV风险相互作用基因。目的2：评估非裔美国人和欧裔美国人HIV阳性注射吸毒者中病毒载量的遗传关联。目的3：重复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，后者是艾滋病疾病进展和发展的重要预测因子。这将是第一个包括非裔美国人的基因研究，这一群体在美国遭受了不成比例的艾滋病毒负担。这项研究的结果可能为开发HIV-1疫苗确定重要的生物学途径和靶点。