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: 10471304
• 负责人: Pradeep Natarajan
• 金额: $ 61.51万
• 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/10471304
• 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; Persons; Phase; Phenotype; Placebo Control; 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.

项目摘要/摘要