Defining the impact of injection drug use on antiretroviral therapy and HIV treatment outcomes: an (epi)genomic approach

定义注射吸毒对抗逆转录病毒治疗和艾滋病毒治疗结果的影响：（表观）基因组方法

• 批准号: 10216209
• 负责人: Bradley E Aouizerat
• 金额: $ 36.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216209
• 关键词: Affect; Aging; Biological; Biological Markers; Blood; Candidate Disease Gene; Cohort Studies; DNA; DNA Methylation; Data; Disease; Drug usage; Epigenetic Process; Gene Combinations; Gene Expression; Gene Expression Regulation; Genes; Genetic Variation; Genomic approach; Genomics; Genotype; Goals; HIV; HIV Infections; Health; Individual; Injecting drug user; Knowledge; Link; Machine Learning; Medical; Mendelian randomization; Modeling; Outcome; Patients; Pharmacogenomics; Plasma; Positioning Attribute; Prediction of Response to Therapy; Public Health; Role; Signal Transduction; Single Nucleotide Polymorphism; Testing; Tissue-Specific Gene Expression; Treatment outcome; Variant; Veterans; Women' s Interagency HIV Study; Work; antiretroviral therapy; bead chip; biomarker identification; clinically relevant; cohort; comorbidity; differential expression; epigenome; epigenome-wide association studies; epigenomics; frailty; gene function; genetic approach; genetic variant; genome-wide; genomic signature; indexing; injection drug use; intravenous drug use; methylome; mortality; non-drug; outcome prediction; pharmacokinetics and pharmacodynamics; potential biomarker; predictive modeling; response; transcriptome; transcriptome sequencing; transcriptomics; uptake

Although uptake of combination antiretroviral therapy (cART) in people who inject drugs (PWID) infected with HIV has increased dramatically in the past decade, poor health outcomes including non-AIDS-related comorbidity and mortality in HIV-infected PWID on cART remains a significant public health problem. A crucial knowledge gap is a lack of the understanding about how injection drug use (IDU) impacts the course of HIV disease. Differences in gene regulation affected by IDU and non-adherence to cART are likely to affect the pharmacokinetics and pharmacodynamics of these treatments that may result in poor outcomes. Thus, there is an urgent need to identify genomic signatures for PWID and to link PWID-associated genomic signals to HIV outcomes in the context of cART exposure (i.e., levels in plasma). Our overall hypothesis is that PWID accrue DNA methylation (DNAm) and transcriptome variations that impact on health outcomes, and which may be explained in part by variability in cART exposure. This hypothesis is built on our previous findings showing that IDU significantly altered the blood DNA methylome in HIV-infected individuals. Furthermore, DNAm signatures associated with IDU differentiated less and greater HIV disease frailty. To test this hypothesis, our approach will first perform epigenome-wide DNAm association analysis and transcriptome-wide association analysis in HIV-infected PWID as compared to HIV-infected non-PWID who are treated with cART in two independent cohorts. Second, we will test the relationship between PWID-associated differentially methylated positions (DMP) or regions (DMR) and differential gene expression (DGE) on cART variability in plasma and also their relationships with HIV frailty and mortality. Last, we propose to integrate genetic variation (single nucleotide polymorphism [SNP]), DNAm, and gene expression that differs by HIV-infected PWID/non-PWID status. Our goal is to identify DMP or DMR and DGE between HIV-infected PWID and non-PWID in the context of cART and to apply epigenetic and transcriptomic signatures as biomarkers to predict HIV frailty and mortality. The application proposes the first integrative pharmacogenomic approach of genetic variants, epigenomic and transcriptomic associations for HIV-infected PWID in the context of cART. We expect to identify PWID- associated genes that can predict HIV cART treatment outcomes. The predictive model resulting from this project can inform biomarker identification for HIV outcomes. The proposal is the first step towards the understanding of pharmacogenomics and pharamcoepigenomics in PWID with HIV infection. The results will fill the knowledge gap of the biological basis of IDU effects on HIV outcomes and provide evidence to prioritize genes for future research of their functions in HIV progression.

虽然注射毒品（PWID）感染者接受联合抗逆转录病毒治疗（cART）， 在过去十年中，艾滋病毒急剧增加，包括非艾滋病相关的不良健康结果 接受cART治疗的HIV感染PWID的合并症和死亡率仍然是一个重大的公共卫生问题。一个关键 知识差距是缺乏对注射毒品（IDU）如何影响艾滋病毒进程的理解 疾病受IDU和不依从cART影响的基因调控差异可能会影响 这些治疗的药代动力学和药效学可能会导致不良结果。由此可见，有 迫切需要确定PWID的基因组特征，并将PWID相关的基因组信号与HIV联系起来 在cART暴露的情况下的结果（即，血浆水平）。我们的总体假设是PWID 累积DNA甲基化（DNAm）和转录组变异，影响健康结果， 部分原因是cART暴露的可变性。这一假设是建立在我们先前的发现基础上的， IDU显著改变了HIV感染者的血液DNA甲基化组。此外，DNA 与IDU相关的特征区分了艾滋病毒疾病脆弱性的程度。为了验证这一假设，我们 该方法将首先进行表观基因组范围的DNAm关联分析和转录组范围的关联分析， 与在两个国家接受cART治疗的HIV感染非PWID相比，HIV感染PWID的分析 独立的群体。第二，我们将测试PWID相关的差异甲基化 位置（DMR）或区域（DMR）和差异基因表达（DGE）对血浆中cART变异性的影响， 以及它们与艾滋病毒脆弱性和死亡率的关系。最后，我们建议整合遗传变异（单个 核苷酸多态性[SNP]）、DNAm和因HIV感染的PWID/非PWID而不同的基因表达 status.我们的目标是确定HIV感染的PWID和非PWID之间的DMR和DGE， cART的背景下，并应用表观遗传和转录组学特征作为生物标志物来预测HIV脆弱性， mortality. 该申请提出了遗传变异、表观基因组和 cART背景下HIV感染PWID的转录组学关联。我们希望能找到PWID- 可以预测HIV cART治疗结果的相关基因。由此产生的预测模型 项目可以为HIV结果的生物标志物鉴定提供信息。该提案是迈向 了解药物基因组学和药物表观基因组学在PWID与HIV感染中的作用。结果将填补 关于注射吸毒对艾滋病毒结果的生物学基础的知识差距，并提供证据， 基因，以便将来研究它们在HIV进展中的功能。