Studies of the Natural History of Sickle Cell Disease

镰状细胞病自然史的研究

基本信息

批准号：
10253904
负责人：
Swee Lay Thein
金额：
$ 95.44万
依托单位：
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10253904
关键词：
10 year old 2 year old Affect African Basic Science Biochemical Biological Specimen Banks Blood Blood Transfusion Bone Marrow Transplantation Bone necrosis Brain Brain Infarction Cardiopulmonary Caring Cell Culture Techniques Cell Separation Cerebrovascular Disorders Characteristics Child Clinic Clinical Clinical Data Clinical Management Complication Data Databases Development Disease Disease model District of Columbia Early Intervention Eligibility Determination Enrollment Fetal Hemoglobin Future General Anesthesia Generations Genes Genetic Genetic Markers Genome Scan Genomics Genotype Health Health system Healthcare Heart Hematological Disease Hemoglobin concentration result Hospitals Human Iatrogenesis Impaired cognition In Vitro Individual Infarction Informed Consent Inherited Kidney Lead Life Liver Longevity Lung Magnetic Resonance Imaging Medical Minority Molecular Morbidity - disease rate Natural History Nucleic Acids Organ Other Genetics Outcome Pathogenesis Patients Performance Phenotype Population Premenopause Procedures Process Protocols documentation Public Health Pulmonary Hypertension Quality of life Recording of previous events Research Research Methodology Research Project Grants Sampling Scanning Schools Science Severities Severity of illness Sickle Cell Sickle Cell Anemia Single Nucleotide Polymorphism Site Stroke Stroke prevention Transfusion Translational Research United States National Institutes of Health Variant Vascular Diseases Woman alpha-Thalassemia biobank cerebrovascular clinical center clinical phenotype clinical predictors comorbidity exome sequencing experience follow-up genetic variant genome sequencing genome wide association study gonad function high risk improved improved outcome lung injury middle cerebral artery novel novel therapeutics prevent renal damage reproductive function reproductive tract research study stroke incidence stroke risk therapy outcome whole genome

项目摘要

Sickle cell disease (SCD) is rapidly emerging as a public health issue globally. It is an inherited blood disorder that occurs predominantly in individuals of African descent; it affects about 100,000 individuals in the USA with one in 365 black children in the US born with SCD. A characteristic feature of SCD is the extremely variable disease severity which presents major challenges in clinical management. With improved general medical care and increased life span, the disparate clinical outcome will become more apparent with increasingly variable emerging complications affecting kidneys, brain, liver, heart and lungs. Bone marrow transplantation remains the only cure but it is a high-risk procedure, appropriate for a minority of patients and often performed too late after a major complication, such as stroke, has occurred. It is clear that the genetic background and co-inheritance of other genes have a great influence on the severity of SCD. For example, studies have shown that patients who can produce high levels of fetal hemoglobin (HbF) have a milder disease and a lower risk of stroke. The brain is a major site of morbidity in children with SCD, overt stroke affects about 6% of ten year olds, with the highest stroke incidence in 2 year olds. Early cerebrovascular disease can be detected by Transcranial Doppler (TCD) scanning demonstrating increased blood velocity in the middle cerebral artery and studies have shown that starting blood transfusions at this stage can prevent progressive vasculopathy and stroke. However some children are transfused unnecessarily as 40% are predicted to remain stroke-free without transfusion 10 years after abnormal TCD, and others develop stroke despite a normal TCD scan. Further, a recent study suggested that some children, despite receiving regular blood transfusion therapy for secondary stroke prevention, continue to experience cerebrovascular damage. Ideally, one would like to identify children at high risk of cerebrovascular disease before the TCD becomes abnormal, because at that stage damage has already occurred. In addition to overt stroke, silent brain infarcts affect up to 20% of children with SCD in whom there has been no clear history of stroke but brain MRI shows small infarcts. These silent infarcts also start to occur in the first few years of life, and are associated with cognitive impairment and poor school performance. They cannot easily be detected without brain MRI which is difficult to perform routinely in young children because of the need for general anesthesia. An unmet healthcare need in SCD is the ability to predict disease severity to facilitate early intervention thereby minimizing organ damage and improving patient quality of life. Currently, there are two established genetic modifiers fetal hemoglobin (HbF) levels and co-inheritance of alpha thalassemia but these 2 genetic variants do not explain all the variability in the disease spectrum. Identification of other genetic variants may also allow prediction of other complications such as osteonecrosis, renal and lung damage which are often clinically silent until irreversible damage has occurred. Genotype-phenotype association studies are useful in identifying novel genetic modifiers. Additionally, whole genome and exome sequencing could identify novel variants and add to our understanding of the genetic modifiers of this disease. This protocol will allow the development of a biorepository of samples and clinical data from patients with SCD receiving medical care at Childrens National Health System (CNHS) and the National Institutes of Health (NIH). Utilizing this database we will determine to what extent current genetic markers (single nucleotide polymorphisms, SNPs) can predict the clinical phenotypes and disease severity in subjects with sickle cell SCD. We also propose to derive new genetic markers using whole genome-wide association studies (GWAS) utilizing whole genome scan, whole genome sequencing (WGS) and whole exome sequencing. The information collected collaboratively will be useful in assessing clinical needs of this population as well as developing research projects for better understanding of the disease which could lead to development of novel therapies and improving outcomes for individuals living with SCD. The protocol is actively accruing patients from the NIH clinical center and Childrens National Hospital in DC, Washington, DC. Currently, 146 (61 NIH, 85 CNMC) new patients in 2019 have been evaluated under the natural history protocol. To date a total of 864 (743 NIH, 121 CNMC) patients enrolled. 855 (734 NIH, 121 CNMC) subjects enrolled during for the last CR and 9 new enrollments since CR

镰状细胞病（SCD）正在迅速成为全球公共卫生问题。这是一种遗传性血液疾病，主要发生在非洲人后裔中；它影响了美国约 100,000 人，其中每 365 名黑人儿童中就有 1 名出生时患有 SCD。 SCD 的一个典型特征是疾病严重程度差异极大，这给临床治疗带来了重大挑战。随着一般医疗保健的改善和寿命的延长，不同的临床结果将变得更加明显，影响肾脏、大脑、肝脏、心脏和肺部的并发症越来越多。骨髓移植仍然是唯一的治疗方法，但它是一种高风险手术，只适合少数患者，并且在发生中风等主要并发症后往往为时已晚。很明显，遗传背景和其他基因的共同遗传对SCD的严重程度有很大影响。例如，研究表明，能够产生高水平胎儿血红蛋白（HbF）的患者病情较轻，中风的风险较低。大脑是SCD儿童的主要发病部位，大约6%的10岁儿童患有明显的中风，其中2岁儿童的中风发病率最高。早期脑血管疾病可以通过经颅多普勒（TCD）扫描发现，显示大脑中动脉血流速度增加，研究表明，在这个阶段开始输血可以预防进行性血管病变和中风。然而，一些儿童进行了不必要的输血，因为预计 40% 的儿童在 TCD 异常后 10 年后无需输血即可保持无中风，而其他儿童尽管 TCD 扫描正常但仍会发生中风。此外，最近的一项研究表明，一些儿童尽管定期接受输血治疗以预防中风，但仍会出现脑血管损伤。理想情况下，人们希望在 TCD 变得异常之前识别出脑血管疾病高危儿童，因为在那个阶段损伤已经发生。除了明显的中风外，高达 20% 的 SCD 儿童还受到无症状脑梗塞的影响，这些儿童没有明确的中风病史，但脑 MRI 显示有小梗塞。这些无症状的梗塞也会在生命的最初几年开始发生，并与认知障碍和学习成绩不佳有关。如果没有脑部核磁共振检查，就很难检测到它们，而由于需要全身麻醉，脑部核磁共振检查很难在幼儿中常规进行。 SCD 中未满足的医疗保健需求是能够预测疾病严重程度，以促进早期干预，从而最大限度地减少器官损伤并提高患者的生活质量。目前，有两种已确定的遗传修饰因子胎儿血红蛋白 (HbF) 水平和 α 地中海贫血的共同遗传，但这两种遗传变异并不能解释疾病谱的所有变异性。其他遗传变异的识别还可以预测其他并发症，例如骨坏死、肾损伤和肺损伤，这些并发症在临床上通常是无症状的，直到发生不可逆转的损伤。基因型-表型关联研究有助于识别新的遗传修饰因子。此外，全基因组和外显子组测序可以识别新的变异，并增加我们对这种疾病的遗传修饰因素的理解。该协议将允许开发一个生物储存库，其中包含在国家儿童卫生系统 (CNHS) 和国立卫生研究院 (NIH) 接受医疗护理的 SCD 患者的样本和临床数据。利用该数据库，我们将确定当前遗传标记（单核苷酸多态性，SNP）在多大程度上可以预测镰状细胞性 SCD 受试者的临床表型和疾病严重程度。我们还建议利用全基因组关联研究（GWAS）利用全基因组扫描、全基因组测序（WGS）和全外显子组测序来衍生新的遗传标记。合作收集的信息将有助于评估该人群的临床需求，以及开发研究项目以更好地了解该疾病，从而开发新疗法并改善 SCD 患者的治疗结果。该协议正在积极招募来自华盛顿特区 NIH 临床中心和儿童国家医院的患者。目前，已有 146 名（61 名 NIH、85 名 CNMC）2019 年新患者接受了自然史方案的评估。迄今为止，共有 864 名患者（743 名 NIH，121 名 CNMC）入组。 855 名受试者（734 名 NIH，121 名 CNMC）在上次 CR 期间注册，自 CR 以来有 9 名新注册受试者