Clonal hematopoiesis and inherited genetic variation in sickle cell disease

项目摘要 镰状细胞病（SCD）与慢性溶血、全身性内皮功能障碍、 炎症和血管闭塞。这种复杂的病理生理学导致剧烈疼痛， 进行性多器官损伤和过早死亡，中位寿命为48年， 收入国家。我们和其他人已经确定，患有渐进性心脏，肺， 和肾损伤，无论是单独或组合，在早产儿的风险特别高， 死亡许多患有SCD的个体是高风险治疗的候选者， 消除症状和阻止器官损伤，包括异基因造血干细胞 (HSC)移植和各种形式的自体HSC基因治疗。但几 接受这些治疗的个体已经发展为急性髓性白血病或其他 骨髓肿瘤在许多情况下，血癌是由自体的，癌前病变引起的。 治疗前存在体细胞“克隆造血”（CH）突变的HSC。 我们和其他人已经证明，在没有SCD的个体中，CH突变会导致生长 有利于老化的HSC，不仅易患髓性白血病，而且易患血管内 影响心脏、肺和肾的疾病。从去除身份数据中获得的其他初步数据 基因组或外显子序列表明，SCD个体在比正常人更早的年龄发展CH。 普通人的生活。基于这些数据，我们假设患有SCD的个体 CH的患病率增加，这加速了心脏，肺， 和肾脏疾病。我们将通过首先确定患病率来检验这一假设， 在三个特征良好的多中心队列中， SCD组（n= 2645）和匹配对照组（n= 7935，Aim 1）。我们将使用一种新颖的，可扩展的，成本- 一种有效的纠错测序检测方法，可检测低水平（0.1%）体细胞CH 突变。接下来，我们将确定CH突变是否与心脏、肺或 这些队列中的肾脏疾病（目标2）。我们的团队已经完成了 通过NIH NHLBI Trans-Omics for Precision Medicine（TOPMed）对队列进行测序 计划，这将使我们能够研究CH突变和种系之间的遗传相互作用 已知影响SCD结果的变异。我们的项目将提供新的见解， CH作为SCD患者心脏、肺和肾脏疾病危险因素的重要性， 可以从个体化的器官保护策略中受益的个体 前瞻性地，并推动未来的研究，以确定CH是否倾向于发展 异基因造血干细胞移植或SCD基因治疗后的髓系白血病。

Project Summary Sickle cell disease (SCD) is associated with chronic hemolysis, systemic endothelial dysfunction, inflammation and vascular occlusion. This complex pathophysiology leads to severe pain, progressive multi-organ damage and premature death with a median lifespan of 48 years in high- income countries. We and others have determined that young adults with progressive heart, lung, and kidney damage, either individually or in combination, are at particularly high risk for premature death. Many individuals with SCD are candidates for high-risk treatments that can potentially eliminate symptoms and arrest organ damage, including allogeneic hematopoietic stem cell (HSC) transplantation and various forms of autologous HSC gene therapy. However, several individuals who received these treatments have developed acute myeloid leukemia or other myeloid neoplasms. In many cases, the blood cancer arose from an autologous, premalignant HSC harboring a somatic “clonal hematopoiesis” (CH) mutation that was present before therapy. We and others have shown in individuals without SCD that CH mutations confer a growth advantage to aging HSCs, predisposing to not only myeloid leukemia, but also endovascular disease affecting the heart, lung and kidney. Additional preliminary data derived from deidentified genomic or exonic sequences indicate that individuals with SCD develop CH at earlier ages than that of the general population. Based on these data, we hypothesize that individuals with SCD have an increased prevalence of CH, which accelerates the development of heart, lung, and kidney disease. We will test this hypothesis by first determining the prevalence and incidence of CH in three well-characterized multi-center cohorts of older children and adults with SCD (n= 2645) and matched controls (n= 7935, Aim 1). We will use a novel, scalable, cost- effective, error-corrected sequencing assay that can detect low-level (0.1%) somatic CH mutations. Next, we will determine whether CH mutations are associated with heart, lung or kidney disease in these cohorts (Aim 2). Our team has already completed whole-genome sequencing of the cohorts through the NIH NHLBI Trans-Omics for Precision Medicine (TOPMed) program, which will allow us to study genetic interactions between CH mutations and germline variants that are known to influence SCD outcomes. Our project will provide novel insights into the importance of CH as a risk factor for heart, lung, and kidney disease in SCD, identify individuals who could benefit from individualized strategies for organ protection administered prospectively, and fuel future studies to determine whether CH predisposes to the development of myeloid leukemia after allogeneic HSC transplantation or gene therapy for SCD.