Outcome Modifying Genes in Sickle Cell Disease

描述（由申请人提供）： 镰状细胞病（SCD）是由一个单一的突变纯合性引起的， β血红蛋白基因尽管这种遗传异常是恒定的， SCD患者的临床过程是显著可变的。SCD可以 影响功能，导致多器官系统衰竭， 血管闭塞的过程。然而，我们还不明白为什么 SCD的临床过程和受影响的器官在患者中是如此可变。 血管闭塞的过程本身似乎既复杂，涉及多个 病理生理过程，以及可能从一个器官变量 系统到另一个。因此，这项研究旨在确定遗传 使SCD患者易发生特定终末器官的因素 并发症和经历或多或少严重的临床过程。我们会0 入组1000例Hb SS和Hb S-β地中海贫血患者，随访时间为 三个区域机构（杜克大学医学中心， 北卡罗来纳州医学中心和埃默里大学医学中心）。医疗 获得的信息将确定是否存在特定的 目标结果（总体疾病严重程度以及特定类型的终点） 器官损伤）。所有临床数据将在PEDIGENE上进行管理和存储 系统，并将包括医疗状况（病史，体检， 实验室结果）和关于潜在混杂因素的信息 环境因素我们还将采集血液进行DNA分析， 可能用于后续相关研究的样本（例如细胞因子 水平或凝血激活）也将被存储。样品信息 质量和数量将存储在PEDIGENE系统中，并与 获得的临床数据。用于基因突变的SNP的鉴定和开发 候选靶基因将被执行，并且DNA样品将被分析 将结果输入PEDIGENE系统。State-of-the-art 将使用统计方法来检查特定 SNP的临床结果，以确定哪些遗传特征 使SCD患者倾向于或多或少严重的总体临床病程 以及个体器官特异性并发症。查明这类 遗传因素将揭示新的治疗靶点 针对SCD的特定并发症进行个体化，从而最终导致 改善SCD患者的预后并延长预期寿命。

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is caused by homozygosity for a single mutation of the beta hemoglobin gene. Despite the constancy of this genetic abnormality, the clinical course of patients with SCD is remarkably variable. SCD can affect the function and cause the failure of multiple organ systems through the process of vaso-occlusion. However, we as yet do not understand why the clinical course of SCD and the organs affected are so variable among patients. The process of vaso-occlusion itself appears both complex, involving multiple pathophysiological processes, as well as possibly variable from one organ system to another. This study, therefore, is designed to identify genetic factors that predispose SCD patients to develop specific end-organ complications and to experience more or less severe clinical courses. We will0 enroll 1000 patients with Hb SS and Hb S-beta thalassemia being followed at three regional institutions (Duke University Medical Center, University of North Carolina Medical Center, and Emory University Medical Center). Medical information obtained will identify the presence or absence of specific targeted outcomes (overall disease severity as well as specific types of end organ damage). All clinical data will be managed and stored on the PEDIGENE system and will include medical status (history, physical examination, and laboratory results) and information regarding potentially confounding environmental factors. We will also obtain blood for DNA analysis, and plasma samples potentially useful for later correlative studies (e.g. of cytokine levels or coagulation activation) will also be stored. Information on sample quality and quantity will be stored in the PEDIGENE system and linked to the clinical data obtained. Identification and development of SNPs for the candidate target genes will be performed, and the DNA samples will be analyzed for these, with results entered into the PEDIGENE system. State-of-the-art statistical methods will be used to examine the relationship between specific clinical outcomes with the SNPs, to determine which genetic characteristics predispose patients with SCD to a more or less severe overall clinical course as well as to individual organ-specific complications. Identification of such genetic factors will reveal new targets for development of therapy individualized to specific complications of SCD, thus leading eventually to improved outcomes and increased life expectancy for patients with SCD.