Outcome Modifying Genes in Sickle Cell Disease

描述（由申请人提供）： 镰状细胞病（SCD）是由单一突变的纯合性引起的 β血红蛋白基因。尽管这种遗传异常持续存在， SCD 患者的临床病程差异很大。 SCD可以 影响功能并导致多个器官系统衰竭 血管闭塞的过程。然而，我们至今还不明白为什么 SCD 的临床病程和受影响的器官在患者之间差异很大。 血管闭塞的过程本身看起来很复杂，涉及多个 病理生理过程，以及可能来自一个器官的变量 系统到另一个。因此，本研究旨在确定遗传 导致 SCD 患者出现特定终末器官的因素 并发症并经历或多或少严重的临床过程。我们将0 招募 1000 名 Hb SS 和 Hb S-β 地中海贫血患者进行随访 三个地区机构（杜克大学医学中心、杜克大学 北卡罗莱纳州医学中心和埃默里大学医学中心）。医疗 获得的信息将确定特定的存在或不存在 目标结果（总体疾病严重程度以及特定类型的最终结果） 器官损伤）。所有临床数据将在PEDIGENE上管理和存储 系统，并将包括医疗状况（病史、体检和 实验室结果）和有关潜在混淆的信息 环境因素。我们还将获取血液进行 DNA 分析，以及血浆 样本可能对以后的相关研究有用（例如细胞因子的样本） 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系统中并链接到 获得的临床数据。 SNP 的鉴定和开发 将执行候选目标基因，并对DNA样本进行分析 对于这些，结果输入 PEDIGENE 系统。最先进的 将使用统计方法来检查特定之间的关系 SNP 的临床结果，以确定哪些遗传特征 使 SCD 患者有或多或少严重的总体临床病程的倾向 以及个别器官特异性并发症。识别此类 遗传因素将揭示治疗开发的新目标 针对 SCD 的特定并发症进行个体化治疗，从而最终导致 改善 SCD 患者的预后并延长其预期寿命。

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.