Multi-omic Predictors of Renal Function among HIV-infected Individuals of African Ancestry

项目概要/摘要 虽然抗逆转录病毒疗法（ART）成功地抑制了艾滋病毒和减少艾滋病 艾滋病毒感染者（PLWH）经历慢性病的发病率更高， 预期寿命。慢性肾脏病（CKD），这是一种常见的并发症， 感染及其治疗一直是艾滋病毒携带者寿命缩短的一个关键原因。艾滋病病毒的发病机制- 相关的CKD是多因素的，与直接暴露于HIV病毒血症、重复感染、全身免疫缺陷、 对感染和ART方案的反应，以及对传统CKD风险因素的反应。遗传和 环境因素在CKD的发生和发展中起作用，并影响生物学功能 和多个分子水平的途径。研究继续表明，表观遗传变化可能发挥作用， 在CKD和HIV感染的病理学中起关键作用。与其他分子层整合，如宿主 表观基因组和转录组，表观基因组可以介导遗传，环境和生理效应，并可以 可能影响肾功能。然而，表观基因组和多组学对肾功能的影响， 疾病尚未在人群水平上进行调查，特别是在非洲血统的人中， CKD负担高，但在多组学研究中代表性不足。我们将识别并复制 使用纵向表观全基因组方法的肾功能表观遗传预测因子（目的1）。我们将 还检查与表观遗传学和肾脏疾病相关的遗传因素，以阐明调解， 遗传学、DNAm和肾功能之间的修饰和因果推断（Aim 2）。我们会进行 整合多组学分析与eGFR相关的基因、通路和分子系统（目的3）。 从这项研究中学到的知识将有可能改善PLWH的长期临床结局，促进 艾滋病毒治疗的精确医学，并支持艾滋病毒/艾滋病研究中的高优先主题。

PROJECT SUMMARY/ABSTRACT Although antiretroviral therapy (ART) results in successful suppression of HIV and a decrease of AIDS progression, people living with HIV (PLWH) experience a higher incidence of chronic diseases and shorter expectancy of life. Chronic kidney disease (CKD), which emerged as a common complication of both HIV infection and its treatment, has been a critical cause of shortened life span in PLWH. The pathogenesis of HIV- related CKD is multifactorial, linked to direct exposure to HIV viremia, superinfections, the systemic immune response to infection and ART regiments, as well as to traditional CKD risk factors. Both genetic and environmental factors play a role in the development and progression of CKD, and affect biological functions and pathways at multiple molecular levels. Research continues to suggest that epigenetic changes may play a pivotal role in the pathology of CKD and HIV infection. Integrated with other molecular layers, such as host genome and transcriptome, epigenome can mediate genetic, environmental and physiological effects, and can potentially influence kidney function. However, the epigenomic and multi-omic impacts on kidney function and disease have not been investigated at population level, particularly among people of African ancestry who experience high burden of CKD but underrepresented in multi-omics research. We will identify and replicate epigenetic predictors of kidney function using a longitudinal epigenome-wide approach (Aim 1). We will also examine genetic factors associated with epigenetics and kidney disease to elucidate mediation, modification and causal inference between genetics, DNAm and kidney function (Aim2). We will conduct integrative multi-omics analyses to genes, pathways and molecular system related to eGFR (Aim 3). Knowledge learned from this study will potentially improve long-term clinical outcomes of PLWH, promote precision medicine for HIV treatment, and support high priority topics in HIV/AIDS research.