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

非洲血统 HIV 感染者肾功能的多组学预测因子

• 批准号: 10360539
• 负责人: Vincent Charles Marconi
• 金额: $ 70.96万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360539
• 关键词: AIDS-Associated Nephropathy; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Affect; African American population; African ancestry; Aging; Apolipoproteins; Biological; Biological Markers; Biological Process; Body mass index; Chronic Disease; Chronic Kidney Failure; Clinical; Cohort Studies; Complication; Cross-Sectional Studies; DNA Methylation; Data; Development; Diabetes Mellitus; Diagnosis; Disease Outcome; End stage renal failure; Environment; Environmental Risk Factor; Epigenetic Process; Exposure to; Filtration; Future; Gene Expression; Genes; Genetic; Genetic Variation; Genome; Genomics; Glomerular Filtration Rate; HIV; HIV Infections; HIV-2; Human; Hypertension; Immune response; Incidence; Individual; Infection; Kidney; Kidney Diseases; Knowledge; Life Expectancy; Link; Longevity; Longitudinal Studies; Measures; Mediating; Mediation; Mendelian randomization; Methods; Modeling; Modification; Molecular; Outcome; Pathogenesis; Pathology; Pathway interactions; Persons; Physiological; Play; Population; Prevention; Prognosis; Regimen; Renal function; Research; Risk; Risk Factors; Role; Site; System; Therapeutic; Time; Variant; Veterans; Viremia; antiretroviral therapy; biological systems; cigarette smoking; co-infection; comorbidity; design; epigenetic marker; epigenetic variation; epigenome; epigenome-wide association studies; epigenomics; experience; functional genomics; high risk; human disease; improved; inter-individual variation; kidney dysfunction; longitudinal analysis; mortality; multiple omics; novel; precision medicine; risk stratification; risk variant; superinfection; transcriptome; transcriptome sequencing; transcriptomics

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.

项目概要/摘要 尽管抗逆转录病毒疗法 (ART) 成功抑制了 HIV 并减少了 AIDS 发病率 随着艾滋病毒感染者 (PLWH) 的进展，慢性病发病率更高，患病时间更短。 预期寿命。慢性肾脏病 (CKD)，这是艾滋病毒和艾滋病毒的常见并发症 感染及其治疗一直是PLWH寿命缩短的重​​要原因。 HIV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 对感染和 ART 治疗以及传统 CKD 危险因素的反应。无论是遗传还是 环境因素在CKD的发生、发展中发挥作用，并影响生物功能 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 感染的病理学中发挥着关键作用。与其他分子层集成，例如主体 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，并且可以 可能影响肾功能。然而，表观基因组和多组学对肾功能和 该疾病尚未在人群层面进行调查，特别是在非洲血统的人群中 经历着 CKD 的沉重负担，但在多组学研究中代表性不足。我们将识别并复制 使用纵向全表观基因组方法对肾功能进行表观遗传预测（目标 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中介作用， 遗传学、DNAm 和肾功能之间的修饰和因果推断（Aim2）。我们将进行 对 eGFR 相关基因、通路和分子系统进行综合多组学分析（目标 3）。 从这项研究中学到的知识将有可能改善 PLWH 的长期临床结果，促进 艾滋病毒治疗的精准医学，并支持艾滋病毒/艾滋病研究的高度优先课题。