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: 10079589
• 负责人: Pradeep Natarajan
• 金额: $ 62.6万
• 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/10079589
• 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 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.

项目总结/摘要 本提案的目的是了解造血干细胞获得性突变与 细胞和冠心病（CHD）的艾滋病毒感染者的个人。随着艾滋病毒管理的进步， 现在，非艾滋病定义疾病，特别是冠心病，是艾滋病毒感染者的主要健康问题。的 感染艾滋病毒的人患冠心病的风险明显高于未感染艾滋病毒的人，至少通过以下途径： 炎症加剧，但差异的根本原因尚不清楚。癌前 显示通过炎症途径与普通人群中的CHD几率相关。CHIP更多 在炎症生物标志物升高的普通人群中很常见。现有给药方案和新 初步研究表明，CHIP可能与HIV感染者的CHD特别相关， 在加速老化现象如冠心病中发挥特别大的作用。在这里，我们建议定义 在一个大型的、国际性的、4期研究中， 在HIV感染者中进行心血管疾病预防临床试验（REPRIEVE），这将是第一个 对HIV中CHIP的广泛分析以及他汀类药物对CHIP相关CHD的影响。保留是 在HIV感染者中进行的最大的安慰剂对照他汀类药物试验， 事件，广泛的暴露数据和密集的纵向表型，包括成像和生物标志物， 亚群在目标1中，我们将使用全外显子组在5，000名REPRIEVE参与者中鉴定CHIP携带者 对循环白色血细胞进行测序，并确定一般和HIV特异性CHIP风险因素。在目标2中， 将评估CHIP与心血管事件结局和死亡的关系，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生殖细胞基因型和端粒的HIV相关结果 与约150，000名无艾滋病毒的人进行了比较分析。这些目标的完成将产生新的见解， CHD生物学和预防，为HIV患者量身定制CHD预防，包括推进新的 治疗目标