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（GWAS）和基因表达来确定HIV获得的新宿主遗传因素，从而推动HIV发病机制领域的发展。我们最初的GWAS和拟议的工作取得成功的关键是：(1)将高度暴露的艾滋病毒对照者与艾滋病毒阳性病例进行比较；(2)样本量大；(3)功能生物学与统计关联结果的整合。50%的HIV易感性变异可归因于宿主遗传。确定这些遗传因素对于了解HIV发病机制和靶向药物开发至关重要。唯一与HIV获得相关的基因变异（CCR5的缺失）背后的机制导致了抗逆转录病毒药物maraviroc的产生。在随后的17年中，直到现在，宿主遗传的获得几乎没有取得什么进展。我们的初始GWAS （n= 3136）鉴定并独立复制了FERM和PDZ结构域含有1个基因（FRMPD1）的变体与HIV获取之间的新关联。利用基因表达数据和文献，我们提出了单核苷酸多态性（SNP） rs4878712在HIV获得中发挥保护作用的机制。这一统计证据和与HIV的生物学上似是而非的联系的结合，为在拟议的研究中深入研究HIV获得的宿主遗传学提供了坚实的基础。目的1：在高度暴露的HIV对照组和HIV阳性病例（N= 9291）的扩展GWAS中，确定与HIV获得的新的遗传关联。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，该方法考虑了基因与hiv暴露风险的相互作用，提高了统计能力，并建立了复制分析。目的2：鉴定HIV阳性病例和高度暴露的HIV对照者之间差异表达的基因，以表征导致HIV易感性的生物学途径。利用基因表达数据，我们将确定与HIV阳性病例相比，高度暴露的HIV对照组中上调或下调的基因，这将确定影响HIV-1感染易感性的生物学途径。目的3：确定驱动HIV阳性病例和高度暴露的HIV对照组之间差异基因表达的变异，并测试它们与HIV获得的关系。我们将绘制Aim 2中HIV状态差异表达基因的表达数量性状位点（eqtl）图谱，评估与Aim 1中HIV获得相关的变异的潜在功能，并在集中的荟萃分析中测试未包括在Aim 1结果中的前10,000个eqtl与HIV获得的关联。了解艾滋病毒的发病机制对于开发新的、更有效的治疗方法和预防性药物至关重要。宿主遗传学是HIV发病机制的核心。将这些工具应用于拟议队列中的艾滋病毒感染可能会产生新的发现，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.