Studies of the Natural History of Sickle Cell Disease

镰状细胞病自然史的研究

• 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
• 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

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)正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；在美国，它影响着大约10万人，在美国，每365名黑人儿童中就有一人出生时患有SCD。SCD的一个特征是疾病严重程度极不稳定，这给临床治疗带来了重大挑战。随着普通医疗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、脑、肝、心和肺的新出现的并发症将越来越不稳定。骨髓移植仍然是唯一的治愈方法，但它是一种高风险的手术，适合少数患者，而且通常在中风等重大并发症发生后进行得太晚。 可见，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)的患者疾病较轻，中风风险较低。大脑是儿童SCD的主要发病部位，约6%的10岁儿童有明显的卒中，其中2岁儿童的卒中发病率最高。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，一些儿童被不必要地输血，因为预计40%的儿童在TCD异常后10年内不会发生中风，而另一些儿童尽管TCD扫描正常，但仍会发生中风。此外，最近的一项研究表明，一些儿童尽管接受了定期输血治疗以二级预防中风，但仍继续遭受脑血管损伤。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的高危儿童，因为在那个阶段损害已经发生。除了明显的中风外，患有SCD的儿童中高达20%的人会受到无症状脑梗塞的影响，这些儿童没有明确的中风病史，但大脑核磁共振显示小梗塞。这些静止性脑梗塞也开始出现在生命的最初几年，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，他们很难被发现，而在幼儿中，由于需要全身麻醉，这是很难常规操作的。 SCD中一个尚未满足的医疗需求是预测疾病严重程度的能力，以便于早期干预，从而将器官损伤降至最低，并提高患者的生活质量。目前，有两个已确定的遗传修饰因素胎儿血红蛋白(HBF)水平和阿尔法地中海贫血的共同遗传，但这两个基因变异不能解释疾病谱中的所有变异。识别其他基因变异也可以预测其他并发症，如骨坏死、肾和肺损害，这些并发症在临床上通常是沉默的，直到发生不可逆转的损害。 基因-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了解。这项协议将允许开发SCD患者的样本和临床数据的生物储存库，这些患者在儿童国家卫生系统(CNHS)和国家卫生研究院(NIH)接受医疗护理。利用这个数据库，我们将确定目前的遗传标记(单核苷酸多态，SNPs)在多大程度上可以预测镰状细胞SCD患者的临床表型和疾病严重程度。我们还建议利用全基因组扫描、全基因组测序(WGS)和全外显子组测序，利用全基因组关联研究(GWAS)来获得新的遗传标记。合作收集的信息将有助于评估这一人群的临床需求，以及制定研究项目，以更好地了解这种疾病，这可能导致开发新的治疗方法，并改善SCD患者的结果。 该方案正在积极地从美国国立卫生研究院临床中心和华盛顿特区的儿童国家医院招募患者。到目前为止，共有990名患者入选(827名NIH，163名CNMC)。