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: 10013809
• 负责人: Vincent Charles Marconi
• 金额: $ 70.53万
• 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/10013809
• 关键词: AIDS-Associated Nephropathy; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Affect; African; African American; 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; Methods; Modeling; Modification; Molecular; Outcome; Pathogenesis; Pathology; Pathway interactions; Physiological; Play; Population; Prevention; Randomized; Regimen; Renal function; Research; Risk; Risk Factors; Risk stratification; Role; Site; Structure of molecular layer of cerebellar cortex; 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; outcome forecast; precision medicine; 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.

项目摘要/摘要 尽管抗逆转录病毒疗法(ART)成功地抑制了艾滋病毒并减少了艾滋病 随着疾病的发展，艾滋病毒携带者(PLWH)的慢性病发病率更高，时间更短 预期寿命。慢性肾脏疾病(CKD)，这是两种艾滋病毒的常见并发症 感染及其治疗一直是PLWH患者寿命缩短的关键原因。HIV的致病机制-- 相关的CKD是多因素的，与直接暴露于HIV病毒血症、双重感染、全身免疫有关 对感染和抗逆转录病毒疗法以及传统的慢性肾脏病危险因素的反应。无论是遗传还是 环境因素在慢性肾脏病的发生发展中起作用，并影响生物功能。 和多个分子水平上的途径。研究继续表明，表观遗传变化可能会对 在慢性肾脏病和艾滋病毒感染的病理中起关键作用。与其他分子层整合，如宿主 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 可能会影响肾功能。然而，表观基因组和多基因组对肾功能和 尚未在人口一级调查疾病，特别是在非洲血统的人中 经历了CKD的高负担，但在多组学研究中的代表性不足。我们将识别并复制 使用纵向表观基因组方法预测肾功能的表观遗传学指标(目标1)。我们会 还要检查与表观遗传学和肾脏疾病相关的遗传因素，以阐明调节作用， 遗传学、dNaM与肾功能之间的修饰和因果推断(AIM2)。我们将进行 与EGFR相关的基因、途径和分子系统的综合多组学分析(目标3)。 从这项研究中学到的知识将潜在地改善PLWH的长期临床结果，促进 用于艾滋病毒治疗的精准医学，并支持艾滋病毒/艾滋病研究中的高度优先主题。