Studies of the Natural History of Sickle Cell Disease

镰状细胞病（SCD）正在迅速成为全球公共卫生问题。它是一种遗传性血液疾病，主要发生在非洲裔个体中;它影响美国约10万人，其中每365名黑人儿童中就有一名出生时患有SCD。SCD的一个典型特征是疾病严重程度变化极大，这给临床管理带来了重大挑战。随着一般医疗护理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的变化越来越多。骨髓移植仍然是唯一的治疗方法，但它是一种高风险的手术，适合少数患者，并且在发生重大并发症（如中风）后往往进行得太迟。 很明显，遗传背景和其他基因的共同遗传对SCD的严重程度有很大的影响。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，中风风险较低。脑是SCD儿童发病的主要部位，10岁奥尔兹中约6%发生明显卒中，2奥尔兹卒中发病率最高。早期脑血管疾病可以通过经颅多普勒（TCD）扫描发现，显示大脑中动脉的血流速度增加，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，一些儿童不必要地输血，因为40%的儿童在TCD异常后10年内预计不会发生中风，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，尽管接受定期输血治疗二级预防中风，继续经历脑血管损伤。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，因为在那个阶段损害已经发生。除了显性卒中，无症状性脑梗死影响了20%的SCD儿童，这些儿童没有明确的卒中史，但脑MRI显示小梗死。这些无症状性梗死也开始发生在生命的最初几年，并与认知障碍和学习成绩差有关。如果没有脑部核磁共振成像，它们很难被发现，因为需要全身麻醉，所以很难在幼儿中常规进行。 SCD中未满足的医疗保健需求是预测疾病严重程度的能力，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，有两种已建立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中的所有变异性。其他遗传变异的鉴定也可以预测其他并发症，如骨坏死、肾和肺损伤，这些并发症在发生不可逆损伤之前通常在临床上是沉默的。 基因型-表型关联研究可用于鉴定新的遗传修饰剂。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剂的理解。本方案将允许开发来自在儿童国家卫生系统（CNHS）和美国国立卫生研究院（NIH）接受医疗护理的SCD患者的样本和临床数据的生物储存库。利用这个数据库，我们将确定在何种程度上目前的遗传标记（单核苷酸多态性，SNPs）可以预测镰状细胞SCD患者的临床表型和疾病严重程度。我们还建议使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获得新的遗传标记。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，从而开发新的治疗方法并改善SCD患者的预后。 该方案正在积极地从美国国立卫生研究院临床中心和位于华盛顿的儿童国立医院招募患者。迄今为止，共入组了990例（827例NIH，163例CNMC）患者。

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.