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

利用药物滥用和其他相互作用加强艾滋病毒宿主遗传学的发现

• 批准号: 8799728
• 负责人: Eric Otto Johnson
• 金额: $ 76.35万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8799728
• 关键词: Accounting; Affect; African; Anti-Retroviral Agents; Automobile Driving; Biological; Biological Process; Biology; Blood; CCR5 gene; Cohort Studies; Collection; Complex; Coupled; Data; Development; Distal; Down-Regulation; Drug Targeting; Drug abuse; Environment; European; Exposure to; Foundations; Freedom; Frequencies; Gene Chips; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genotype; HIV; HIV Infections; HIV risk; HIV vaccine; HIV-1; Hemophilia A; Hispanics; Infection; Injecting drug user; Investigation; Joints; Lead; Link; Literature; Maps; Measures; Messenger RNA; Meta-Analysis; Methods; Molecular Profiling; Participant; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Predisposition; Probability; Process; Public Health; Quantitative Trait Loci; Reporting; Research Design; Risk; Risk Behaviors; Sample Size; Sampling; Single Nucleotide Polymorphism; Testing; Tissue-Specific Gene Expression; Tube; Up-Regulation; Urban Health; Vaccines; Variant; Virus; Woman; Work; case control; cohort; drug development; effective therapy; genetic association; genetic variant; genome wide association study; genome-wide; improved; novel; population based; prophylactic; protective effect; public health relevance; risk variant; success; tool

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.

描述（由申请人提供）：我们建议通过通过大规模基因组关联研究（GWAS）和基因表达来鉴定新的宿主遗传因素来转移HIV发病机理的领域。我们最初的GWA和拟议工作的成功关键是：（1）将高度暴露的HIV控制与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。 50％o HIV易感性的可变性归因于宿主遗传学。鉴定这种遗传因素对于理解HIV发病机理和靶向药物发育至关重要。与艾滋病毒获取（CCR5中的缺失）最终相关的唯一遗传变异的机制导致抗逆转录病毒药物Maraviroc。在随后的17年中，收购的寄主遗传学几乎没有进步。我们最初的GWA（n = 3,136）确定并独立复制了含有1个基因（FRMPD1）和HIV获取的FERM和PDZ结构域之间的新颖关联。使用基因表达数据和文献，我们提出了一种机制，单核苷酸多态性（SNP）RS4878712对HIV获取具有保护作用。在拟议的研究中，统计证据与生物学上合理的联系与HIV的合理联系为更深入研究HIV获取的宿主遗传学奠定了坚实的基础。 AIM 1：在高度暴露的HIV控制和HIV+病例的扩展GWA中确定与HIV获取的新型遗传关联（n = 9,291）。为了扩展发现，我们将最初的GWAS发现样本量增加一倍以上，请使用联合2自由度荟萃分析方法，该方法解释了基因by-HIV暴露风险相互作用并增加统计能力，并在复制分析中构建。目标2：确定在HIV+病例和高度暴露的HIV控制之间差异表达的基因，以表征有助于HIV敏感性的生物学途径。使用基因表达数据，我们将确定与HIV+病例相比，在高度暴露的HIV控制中调节的基因，该基因将提名影响对HIV-1感染易感性的生物学途径。 AIM 3：确定驱动HIV+病例和高度暴露的HIV控制之间差异基因表达的变体，并测试其与HIV获取的关联。我们将为AIM 2中通过HIV状态差异表达的基因绘制表达定量性状基因座（EQTL），评估与AIM 1中与HIV获取相关的变异的潜在功能，并测试AIM 1中未包括的前10,000个EQTL与HIV获取相关的AIM 1不包括在焦点元分析中。了解HIV发病机理对于开发新的，更有效的治疗和预防性药物至关重要。宿主遗传学对于HIV发病机理至关重要。将这些工具应用于拟议的队列中的艾滋病毒收购中，可能会导致新发现会对该领域产生重大影响。