Clonal hematopoiesis of indeterminate potential and HIV in the REPRIEVE trial

项目摘要/摘要 这项提议的目标是了解造血干细胞获得性突变之间的关系。 艾滋病毒携带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，是艾滋病毒携带者的主要健康问题。这个 感染艾滋病毒的人患冠心病的风险似乎明显高于未感染艾滋病毒的人，至少通过 炎症加剧，但这种差异的根本原因尚不清楚。癌前病变 显示与普通人群中的CHD几率通过炎症途径有关。筹码更多 在炎性生物标志物升高的普通人群中很常见。以前的和新的 初步工作表明，芯片可能与HIV中的CHD特别相关，HIV中的CHD被认为是炎症 在冠心病等加速衰老现象中发挥特别大的作用。在这里，我们建议定义 大规模国际4期艾滋病毒芯片感染的流行率、危险因素和临床后果 艾滋病病毒感染者的心血管疾病预防临床试验(暂缓)这将是第一次 HIV中CHIP的广泛分析以及他汀类药物对CHIP相关CHD的影响。缓刑是 对患有严格判定的心血管疾病的HIV患者进行的最大规模的安慰剂对照他汀类试验 事件，广泛的暴露数据，以及密集的纵向表型，包括成像和生物标志物 子群。在目标1中，我们将使用整个外显子组在5000名缓刑参与者中识别芯片携带者 对循环中的白细胞进行测序，并确定一般的和HIV特有的芯片风险因素。在目标2中，我们 将评估CHIP与意外心血管结局和死亡的关系，以及纵向关系 炎症和影像生物标记物。在目标3中，我们将发现切屑与 通过因果中介分析以及生殖系基因和端粒的HIV相关结果 分析结果与约15万名未感染艾滋病毒的人进行了比较。完成这些目标将产生新的见解 CHD生物学和预防用于针对艾滋病毒的CHD预防，包括推进新的发现 治疗靶点。

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.