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：
10699739
负责人：
Swee Lay Thein
金额：
$ 79.04万
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/10699739
关键词：
10 year old 2 year old Affect African ancestry Basic Science Biochemical Biological Specimen Banks Blood Blood Transfusion Bone Marrow Transplantation Bone necrosis Brain Brain Infarction Caring Cell Culture Techniques Cell Separation Cerebrovascular Disorders Characteristics Child Clinical Clinical Data Clinical Management Complication 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 system Healthcare Heart Hematological Disease Hemoglobin concentration result Hospitals Human Impaired cognition In Vitro Individual Infarction Informed Consent Inherited Kidney Lead Life Liver Longevity Lung Medical Minority Molecular Morbidity - disease rate Natural History Nucleic Acids Organ Other Genetics Outcome Patients Performance Phenotype Population Procedures Process Protocols documentation Public Health 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 alpha-Thalassemia biobank brain magnetic resonance imaging cerebrovascular clinical center clinical phenotype clinical predictors comorbidity exome sequencing experience follow-up genetic variant genome sequencing genome wide association study high risk improved improved outcome lung injury middle cerebral artery novel novel therapeutics prevent renal damage 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. To date a total of 990 (827 NIH, 163 CNMC) patients have been enrolled.

镰状细胞病（SCD）在全球范围内迅速成为公共卫生问题。这是一种遗传性血液疾病，主要发生在非洲血统的个体中。它在美国影响了约100,000人，其中有365个黑人儿童在美国出生。 SCD的一个特征是极度可变的疾病严重程度，在临床管理中面临着主要的挑战。随着一般医疗保健的改善和寿命的提高，随着影响肾脏，大脑，肝脏，心脏和肺部越来越多的新兴并发症，不同的临床结果将变得更加明显。骨髓移植仍然是唯一的治疗方法，但它是一种高风险手术，适合少数患者，并且在发生重大并发症（例如中风）后经常进行得太晚。显然，其他基因的遗传背景和共同介绍对SCD的严重程度有很大影响。例如，研究表明，可以产生高水平的胎儿血红蛋白（HBF）的患者患有较轻的疾病和较低的中风风险。大脑是SCD儿童的主要发病率，公开中风会影响十岁的6％，中风的发病率最高。可以通过经颅多普勒（TCD）扫描发现早期脑血管疾病，表明大脑中动脉的血液速度增加，研究表明，在此阶段开始输血可以预防渐进的血管疾病和中风。但是，有些儿童被不必要地输血了，因为预计在异常TCD后10年，预计40％的儿童将保持无中风，而尽管有正常的TCD扫描，但有些儿童仍会出现中风。此外，最近的一项研究表明，尽管有定期接受预防中风的血液输血疗法，但一些儿童仍会继续遭受脑血管损伤。理想情况下，人们想在TCD异常之前鉴定出患有脑血管疾病的高风险的儿童，因为在那个阶段已经发生了损害。除了明显的中风外，无声的大脑梗塞影响了多达20％的SCD儿童，其中尚无中风病史，但脑部MRI显示出小小的梗塞。这些无声的梗死也开始发生在生命的头几年，并且与认知障碍和学校表现不佳有关。没有大脑MRI，他们无法轻易检测到，由于需要全身麻醉，因此在幼儿中很难进行常规执行。 SCD中未获得的医疗保健需求是预测疾病严重程度以促进早期干预的能力，从而最大程度地减少器官损害并改善患者的生活质量。目前，有两个已建立的遗传修饰剂胎儿血红蛋白（HBF）水平和αthalassyalassya的共同疗法，但这两个遗传变异并不能解释疾病谱的所有可变性。对其他遗传变异的鉴定也可能允许预测其他并发症，例如骨坏死，肾脏和肺损伤，这些并发症通常在临床上保持沉默，直到发生不可逆的损害。基因型 - 表型关联研究可用于鉴定新的遗传修饰剂。此外，整个基因组和外显子组测序可以鉴定出新的变体，并增加我们对该疾病遗传修饰剂的理解。该方案将允许从儿童国家卫生系统（CNHS）和国立卫生研究院（NIH）的SCD接受医疗服务的患者的样品和临床数据生物验证。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）可以预测镰状细胞SCD受试者的临床表型和疾病严重程度。我们还建议使用全基因组扫描，整个基因组测序（WGS）和整个外显子组测序的整个基因组关联研究（GWAS）得出新的遗传标记。收集的信息将有助于评估该人群的临床需求，并开发研究项目，以更好地了解该疾病，这可能导致新疗法的发展并改善SCD患者的结果。该方案是从华盛顿特区的NIH临床中心和儿童国家医院积极收取患者。迄今为止，总共招募了990名（827 NIH，163名CNMC）患者。