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

描述(申请人提供)：针对RFA DA-08-009：吸毒人群和模式生物中的艾滋病毒-1和宿主遗传学，该项目的总体目标是通过以下方式在非裔美国人和欧洲美国人注射吸毒者的大样本中确定和表征艾滋病毒-1易感性和耐药性的遗传决定因素：1)艾滋病毒-1感染(阳性/阴性)的病例/对照基因组关联研究；2)艾滋病毒+注射吸毒者病毒载量的病例-对照全基因组关联研究。宿主基因研究有望识别影响人类对HIV-1反应的基因变异。这些变异将有助于确定人类对艾滋病毒-1的反应方面，这些方面可能是开发艾滋病毒-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，几乎所有报道的发现都来自候选基因研究，这些研究只解释了HIV-1感染的一小部分变异性。可用于基因研究的大型相关队列有限，尽管该社区的艾滋病毒负担不成比例，但目前的基因研究中没有非裔美国人，以及对注射吸毒者人群的关注有限，限制了该领域识别影响艾滋病毒-1感染的遗传变异的能力，并强烈主张有必要对艾滋病毒-1感染表型进行大规模的全球艾滋病研究。这项拟议的研究将使用城市健康研究(UHS)的现有样本和数据，该研究是北美对街头招募的注射吸毒者进行的时间最长的研究，以实现以下目标：目标1：评估非裔美国人和欧洲裔美国注射吸毒者中艾滋病毒-1易感性/耐药性与高危艾滋病毒阴性对照的遗传关联。将在非洲裔美国人和欧洲裔美国人注射吸毒者(分别为5583人和3864人)中进行单独的GWA分析。目的1a：在为全球艾滋病研究做准备时，使用倾向计分方法来量化和平衡HIV阳性病例和高危HIV阴性对照中的HIV风险水平。目的1b：探索与HIV-1状态相关的顶级SNPs与HIV风险的基因交互作用。目的2：评估非洲裔美国人和欧洲裔美国人HIV阳性注射吸毒者病毒载量的遗传相关性。目的3：复制HIV疫苗免疫学中心(CHAVI)队列的主要研究结果。公共卫生相关性：这项针对注射吸毒者的研究将确定与艾滋病毒-1感染和艾滋病毒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。这将是第一次包括非裔美国人的基因研究，非裔美国人在美国遭受着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。

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.