Enhancing Discovery of HIV Host Genetics using Drug Abuse and other Interactions

描述(由申请人提供)：我们建议通过大规模全基因组关联研究和基因表达来识别艾滋病毒感染的新宿主遗传因素，从而推动艾滋病毒发病机制领域的向前发展。我们最初的GWAS和拟议工作的成功关键是：(1)将高度暴露的HIV控制组与HIV+病例进行比较；(2)大样本量；(3)功能生物学与统计关联结果的整合。艾滋病毒易感性的变异性50%可归因于宿主遗传。识别这些遗传因素对于了解HIV的发病机制和靶向药物开发至关重要。唯一与艾滋病毒感染有关的基因变异是CCR5的缺失，其潜在机制导致了抗逆转录病毒药物马拉韦罗的产生。在接下来的17年里，宿主获得性遗传学几乎没有取得什么进展，直到现在。我们最初的GWAS(n=3,136)发现并独立复制了FERM和包含1基因的PDZ结构域(FRMPD1)的变体与HIV感染之间的新关联。利用基因表达数据和文献，我们提出了单核苷酸多态(SNP)rs4878712对HIV感染起保护作用的机制。这一统计证据和生物学上可信的与艾滋病毒的联系的组合为拟议研究中对艾滋病毒获得性宿主遗传学的更深入研究提供了坚实的基础。目的1：在高度暴露的HIV对照和HIV+病例(N=9,291)的扩展GWA中，确定与HIV感染有关的新的基因。为了扩大发现范围，我们将把最初的GWAS发现样本量增加一倍以上，使用联合2自由度荟萃分析方法，该方法考虑了艾滋病病毒暴露风险的基因相互作用，并增加了统计能力，并内置了复制分析。目的2：确定在HIV阳性病例和高度暴露的HIV对照之间差异表达的基因，以表征导致HIV易感性的生物学途径。使用基因表达数据，我们将识别与HIV+病例相比，在高度暴露的HIV控制组中上调或下调的基因，这将提名影响HIV-1感染易感性的生物途径。目的3：在HIV阳性病例和高度暴露的HIV对照人群中找出驱动差异基因表达的变异，并测试它们与HIV感染的关系。我们将定位Aim 2中HIV状态差异表达的基因的表达数量性状基因座(EQTL)，评估Aim 1中与HIV感染相关的变异的潜在功能，并在集中荟萃分析中测试未包括在Aim 1结果中的前10,000个eQTL与HIV感染的关联。了解HIV的发病机制对于开发新的、更有效的治疗和预防药物至关重要。宿主遗传学是HIV致病机制的核心。将这些工具应用于拟议队列中的艾滋病毒获取可能会导致新的发现，这将对该领域产生重大影响。

DESCRIPTION (provided by applicant): We propose to move the field of HIV pathogenesis forward by identifying novel host genetic factors for HIV acquisition through large-scale genome-wide association studies (GWAS) and gene expression. Keys to success of our initial GWAS and the proposed work are: (1) comparing highly exposed HIV- controls to HIV+ cases; (2) large sample sizes; and (3) integration of functional biology with statistical association results. 50% o the variability in HIV susceptibility is attributable to host genetics. Identifying such genetic factors is essential to understanding HIV pathogenesis and targeting drug development. Mechanisms underlying the only genetic variant conclusively associated with HIV acquisition, a deletion in CCR5, gave rise to maraviroc, an antiretroviral drug. Host genetics of acquisition has seen little progress in the ensuing 17 years, until now. Our initial GWAS (n=3,136) identified and independently replicated a novel association between a variant in the FERM and PDZ domain containing 1 gene (FRMPD1) and HIV acquisition. Using gene expression data and literature, we proposed a mechanism by which the single nucleotide polymorphism (SNP) rs4878712 exerts a protective effect on HIV acquisition. This combination of statistical evidence and biologically plausible links to HIV provide a strong foundation for deeper investigation of host genetics of HIV acquisition in the proposed study. Aim 1: Identify novel genetic associations with HIV acquisition in an extended GWAS of highly exposed HIV- controls and HIV+ cases (N=9,291). To extend discovery we will more than double our initial GWAS discovery sample size, use the joint 2 degree-of-freedom meta-analysis method, which accounts for gene-by-HIV exposure risk interactions and increases statistical power, and build in replication analyses. Aim 2: Identify genes that are differentially expressed between HIV+ cases and highly exposed HIV- controls to characterize biological pathways that contribute to HIV susceptibility. Using gene expression data we will identify genes that are up or down regulated among highly exposed HIV- controls compared to HIV+ cases, which will nominate biological pathways affecting susceptibility to HIV-1 infection. Aim 3: Identify variants driving differential gene expression between HIV+ cases and highly exposed HIV- controls, and test their association with HIV acquisition. We will map expression quantitative trait loci (eQTLs) for the genes differentially expressed by HIV status in Aim 2, evaluate the potential function of variants associated with HIV acquisition from Aim 1, and test the top 10,000 eQTLs not included in the Aim 1 results for association with HIV acquisition in a focused meta-analysis. Understanding HIV pathogenesis is essential to developing new, more effective treatment and prophylactic medications. Host genetics are central to HIV pathogenesis. Applying these tools to HIV acquisition in the proposed cohorts is likely to lead to new discoveries that will highly impact the field.