Clonal hematopoiesis and inherited genetic variation in sickle cell disease

镰状细胞病的克隆造血和遗传变异

基本信息

批准号：
10638404
负责人：
Alexander Bick
金额：
$ 81.76万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638404
关键词：
APOL1 gene Acceleration Acute Myelocytic Leukemia Address Adult Affect Age Allogenic American Autologous Benefits and Risks Biological Assay Blood Blood Cells Blood Pressure Blood Vessels Cell division Cessation of life Child Childhood Chronic Clinical Clonal Hematopoietic Stem Cell Complex Country DNA DNMT3a Data Development Disease Disease Outcome Disease susceptibility Early Intervention Functional disorder Future General Population Genes Genetic Genetic Variation Genetic study Genomics Genotype Germ-Line Mutation Goals Growth Heart Heart Diseases Hematological Disease Hematopoiesis Hematopoietic Neoplasms Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hemoglobin Hemolysis Incidence Income Individual Inflammation Inherited JAK2 gene Kidney Kidney Diseases Life Link Longevity Lung Lung diseases Measurement Morbidity - disease rate Multiple Organ Failure Mutation Myeloid Leukemia Myeloproliferative disease National Heart, Lung, and Blood Institute Organ Outcome Pain Patient Selection Patients Phenotype Predisposition Premature Mortality Prevalence Prevalence Study Probability Pulmonary Function Test/Forced Expiratory Volume 1 Pulmonary Hypertension Renal function Risk Risk Factors Sampling Severities Sickle Cell Anemia Somatic Mutation Statistical Models Symptoms System TP53 gene Technology Testing Therapeutic Trans-Omics for Precision Medicine United States National Institutes of Health Variant Work adverse outcome alpha-Thalassemia cohort comorbidity cost effective curative treatments design driver mutation emerging adult endothelial dysfunction exome sequencing gene therapy genetic variant genome sequencing heart damage hematopoietic stem cell aging high risk individualized medicine innovation insight lung injury mortality multiorgan damage novel personalized strategies premalignant premature programs prospective public health relevance renal damage sex stem cell gene therapy treatment risk whole genome young adult

项目摘要

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.

项目摘要镰状细胞疾病（SCD）与慢性溶血，全身内皮功能障碍有关炎症和血管阻塞。这种复杂的病理生理学导致严重疼痛，渐进的多器官损害和过早死亡，中位寿命为48年，高收入国家。我们和其他人已经确定，有进步心脏的年轻人，肺，肾脏损伤是单独或结合的，尤其是过早的高风险死亡。许多患有SCD的人是高风险治疗的候选者消除症状并有组织的损害，包括同种异体造血干细胞（HSC）移植和各种形式的自体HSC基因治疗。但是，有几个接受这些治疗的个人已经发展出急性髓样白血病或其他髓样肿瘤。在许多情况下，血液癌来自自体癌 HSC具有在治疗前提出的体细胞“克隆造血”（CH）突变。我们和其他人在没有SCD的个人中表明CH突变会导致A增长衰老HSC的优势，不仅容易发生髓样白血病，而且还易于血管内影响心脏，肺和肾脏的疾病。从去识别得出的其他初步数据基因组或外显子序列表明，患有SCD的个体在早期的年龄较早而不是普通人群。基于这些数据，我们假设患有SCD的人 CH的患病率增加，这加速了心脏，肺的发展和肾脏疾病。我们将通过首先确定患病率和 CH的发病率是三个特征良好的多中心队列的年龄较大的儿童和成人的发病率 SCD（n = 2645）和匹配的控件（n = 7935，AIM 1）。我们将使用一种小说，可扩展，成本 - 有效的，错误校正的测序测定法可以检测低水平（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（AIM 2）。我们的团队已经完成了全基因组通过NIH NHLBI Trans-Omics进行精密医学的同伙测序（TopMed）程序，这将使我们能够研究CH突变与种系之间的遗传相互作用已知会影响SCD结果的变体。我们的项目将提供新颖的见解 CH作为SCD心脏，肺和肾脏疾病的危险因素的重要性，确定可以从管理器官保护的个性化策略中受益的个人前瞻性并助长了未来的研究，以确定CH是否容易发展 SCD同种异体HSC移植或基因治疗后的髓样白血病。