Clonal hematopoiesis of indeterminate potential and HIV in the REPRIEVE trial

REPRIEVE 试验中不确定潜力的克隆造血和 HIV

• 批准号: 10249348
• 负责人: Pradeep Natarajan
• 金额: $ 60.87万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249348
• 关键词: Aging; Atherosclerosis; Biological Markers; Biology; Blood; Blood Cells; Blood Circulation; Blood Vessels; Cardiovascular system; Cessation of life; Clinical; Consent; Coronary heart disease; DNA; Data; Data Set; Enrollment; Event; Funding; General Population; Genes; Genetic; Genotype; Goals; HIV; Health; Hematology; Hematopoiesis; Hematopoietic stem cells; Incidence; Individual; Inflammation; Inflammatory; International; Investigation; Length; Leukocytes; Lipoproteins; Malignant Neoplasms; Mediation; Mediator of activation protein; Morbidity - disease rate; Mus; Mutation; National Heart, Lung, and Blood Institute; Outcome; Participant; Pathway interactions; Phase; Phenotype; Placebos; Play; Positioning Attribute; Precancerous Conditions; Prevalence; Prevention; Prevention strategy; Preventive; Primary Prevention; Randomized Controlled Clinical Trials; Risk; Risk Factors; Risk Reduction; Role; Science; Signal Transduction; Site; Source; Subgroup; Testing; Tissues; Trans-Omics for Precision Medicine; United States National Institutes of Health; Work; adjudicate; age related; biobank; cardiovascular disorder prevention; cardiovascular effects; cardiovascular imaging; cardiovascular risk factor; exome; exome sequencing; follow-up; heart disease prevention; heart disease risk; imaging biomarker; immune activation; immunoregulation; inflammatory marker; insight; mortality; new therapeutic target; novel; premalignant; prevent; prevention clinical trial; public health relevance; randomized trial; telomere; therapeutic target

PROJECT SUMMARY / ABSTRACT The goal of this proposal is to understand the relationship between acquired mutations in hematopoietic stem cells and coronary heart disease (CHD) among individuals living with HIV. With advances in HIV management, now non-AIDS-defining illnesses, particularly CHD, are major health issues for individuals living with HIV. The risk of CHD appears to be notably higher among those with HIV versus those without HIV, at least through heightened inflammation, but the fundamental reasons for the difference is not well-understood. Pre-cancerous shown to associate with CHD odds in the general population through inflammatory pathways. CHIP is more common among those in the general population who have elevated inflammatory biomarkers. Prior and new preliminary work suggest that CHIP may be particularly relevant to CHD in HIV, where inflammation is believed to play a particularly large role in accelerated aging phenomena such as CHD. Here, we propose to define the prevalence, risk factors, and clinical consequences of CHIP in HIV within a large, international, phase 4 cardiovascular disease prevention clinical trial among individuals with HIV (REPRIEVE) this will be the first extensive analyses of CHIP in HIV as well as the influence of statins on CHIP-associated CHD. REPRIEVE is the largest placebo-controlled statin trial among individuals with HIV with rigorously adjudicated cardiovascular events, extensive exposure data, and dense longitudinal phenotyping including imaging and biomarkers in a subgroup. In Aim 1, we will identify carriers of CHIP among 5,000 REPRIEVE participants using whole exome sequencing of circulation white blood cells and define general and HIV-specific CHIP risk factors. In Aim 2, we will estimate the relationship of CHIP with incident cardiovascular outcomes and death, as well as longitudinal inflammatory and imaging biomarkers. In Aim 3, we will discover the mechanistic relationships of CHIP with HIV-associated outcomes through causal mediation analyses as well as germline genotype and telomere analyses compared with ~150,000 individuals without HIV. Completion of these aims will yield novel insights in CHD biology and prevention for tailored CHD prevention in HIV, including advancing the discovery of new therapeutic targets.

项目概要/摘要 该提案的目标是了解造血干获得性突变之间的关系 HIV感染者中的细胞和冠心病（CHD）。随着艾滋病毒管理的进步， 现在，非艾滋病定义的疾病，特别是冠心病，是艾滋病毒感染者的主要健康问题。这 与未感染艾滋病毒的人相比，艾滋病毒感染者患冠心病的风险似乎明显更高，至少通过 炎症加剧，但造成这种差异的根本原因尚不清楚。癌前期 研究表明，它通过炎症途径与普通人群中的冠心病发病率相关。芯片更多 在炎症生物标志物升高的普通人群中很常见。以前的和新的 初步研究表明，CHIP 可能与 HIV 感染的先天性心脏病 (CHD) 特别相关，据信该病存在炎症 在先心病等加速衰老现象中发挥着特别重要的作用。在这里，我们建议定义 在大型国际 4 期研究中，HIV 中 CHIP 的患病率、危险因素和临床后果 HIV 感染者的心血管疾病预防临床试验 (REPRIEVE) 这将是第一个 对 HIV 中的 CHIP 以及他汀类药物对 CHIP 相关冠心病的影响进行了广泛分析。缓刑是 最大的安慰剂对照他汀类药物试验，对象是患有严格心血管疾病的艾滋病毒感染者 事件、广泛的暴露数据和密集的纵向表型分析，包括成像和生物标志物 子组。在目标 1 中，我们将使用全外显子组在 5,000 名 REPRIEVE 参与者中识别 CHIP 携带者 对循环白细胞进行测序并确定一般和 HIV 特异性 CHIP 风险因素。在目标 2 中，我们 将估计 CHIP 与心血管事件事件和死亡的关系，以及纵向 炎症和成像生物标志物。在目标 3 中，我们将发现 CHIP 与 通过因果中介分析以及种系基因型和端粒分析艾滋病毒相关结果 与约 150,000 名未感染 HIV 的个体进行比较。完成这些目标将产生新的见解 冠心病生物学和预防，针对艾滋病毒定制冠心病预防，包括推进新药物的发现 治疗目标。