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

基本信息

批准号：
9297254
负责人：
Eric Otto Johnson
金额：
$ 68.01万
依托单位：
RESEARCH TRIANGLE INSTITUTE
依托单位国家：
美国
项目类别：
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/9297254
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 Disease Distal Down-Regulation Drug Targeting Drug abuse Drug usage 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 Research Design Risk Risk Behaviors Sample Size Sampling Single Nucleotide Polymorphism Testing Tissue-Specific Gene Expression Tube Up-Regulation Urban Health Variant Virus Women’s Interagency HIV Study Work case control cohort differential expression drug development effective therapy ethnic diversity genetic association genetic variant genome wide association study genome-wide improved novel population based prophylactic protective effect public health relevance risk variant success tool

项目摘要

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）：我们建议通过大规模全基因组关联研究（GWAS）和基因表达来确定艾滋病毒获得的新宿主遗传因素，从而推动艾滋病毒发病机制领域的发展。我们最初的 GWAS 和拟议工作成功的关键是：（1）将高度暴露的 HIV 对照者与 HIV+ 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。 HIV 易感性的变异 50% 可归因于宿主遗传学。识别此类遗传因素对于了解艾滋病毒发病机制和靶向药物开发至关重要。唯一与 HIV 感染相关的遗传变异（CCR5 的缺失）背后的机制产生了马拉韦罗（一种抗逆转录病毒药物）。在接下来的 17 年里，直到现在，获得的宿主遗传学几乎没有取得任何进展。我们最初的 GWAS (n=3,136) 鉴定并独立复制了包含 1 个基因 (FRMPD1) 的 FERM 和 PDZ 结构域中的变体与 HIV 获得之间的新关联。利用基因表达数据和文献，我们提出了一种机制，通过该机制，单核苷酸多态性（SNP）rs4878712对HIV感染发挥保护作用。统计证据和与艾滋病毒的生物学上合理的联系相结合，为在拟议的研究中更深入地研究艾滋病毒感染的宿主遗传学奠定了坚实的基础。目标 1：在高度暴露的 HIV 对照和 HIV+ 病例的扩展 GWAS 中确定与 HIV 感染的新遗传关联 (N=9,291)。为了扩展发现，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并提高了统计功效，并内置了复制分析。目标 2：识别 HIV+ 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 对照中上调或下调的基因，这将指定影响 HIV-1 感染易感性的生物途径。目标 3：识别驱动 HIV+ 病例和高度暴露的 HIV 对照之间差异基因表达的变异，并测试它们与 HIV 感染的关联。我们将绘制目标 2 中 HIV 状态差异表达基因的表达数量性状位点 (eQTL)，评估与目标 1 中获得 HIV 相关的变异的潜在功能，并测试目标 1 结果中未包含的前 10,000 个 eQTL一项重点荟萃分析中与艾滋病毒感染的关联。了解艾滋病毒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。宿主遗传学是艾滋病毒发病机制的核心。将这些工具应用于拟议队列中的艾滋病毒获取可能会带来对该领域产生重大影响的新发现。