Genetic Modifiers of Transfusional Iron Overload

 描述(申请人提供)：慢性红细胞输注是用于预防镰状细胞性贫血(SCA)临床并发症的常规治疗方法。尽管有这样的好处，但重复输血不可避免地会导致铁负荷，因为没有特定的生理机制来去除每单位血液中包含的大量铁。输血铁超载是SCA患者发病的一个公认的原因。在接受慢性输血的SCA患者中，肝脏是铁沉积的主要部位。在输血SCA患者中，他们的肝铁蓄积率和对肝铁负荷的反应有很大的个体差异。肝脏IRN超载通常会导致肝脏炎症和纤维化，但一些SCA患者尽管铁负荷很高，但不会发展成任何肝脏损害。目前对是什么调节了肝脏对铁的摄取，或者是什么引发了对个体铁负荷的实质损害，目前还知之甚少。在正在进行的实验中，我们已经确定了在输血SCA患者的肝脏中差异表达的特定基因，这些基因与输血铁负荷有关。这提示肝脏中基因表达的差异可能影响SCA患者输血铁负荷率。从其他研究中得知，铁稳态相关基因的胚系突变可以改变普通人群和遗传性血色素沉着症患者的全身铁水平。在普通人群或血色素沉着症患者中，影响铁稳态的基因突变很可能也会影响面临慢性输血铁挑战的SCA患者的铁代谢。根据这些数据，我们假设遗传修饰物影响SCA患者的输血铁超载和毒性。我们建议使用现有的数据集来确定遗传修饰物控制输血铁超载发展的程度。我们将以两个具体目标来解决我们的假设：1)我们将使用来自肝活检样本的基因表达数据来确定不同水平的铁超载或肝损害患者肝脏中的基因表达差异；2)我们将使用全外显子组序列和单核苷酸多态阵列数据来确定与铁超载相关的编码变种和任何遗传拷贝数变异体。为了提供输血铁超载和基因组因素的综合分析，我们还将结合我们的两个目标来解释遗传变异和差异基因表达网络对铁超载的影响。我们期望这项研究将对所有与输血铁超载相关的基因进行全面的表型、转录和功能分析。这项工作将与对输血铁积累机制感兴趣的研究人员相关，并对其他有输血铁超载的疾病，如地中海贫血或骨髓增生异常综合征的患者。

 DESCRIPTION (provided by applicant): Chronic erythrocyte transfusions are a routine treatment used to prevent clinical complications of sickle cell anemia (SCA). Despite the benefits, repeated transfusions lead to inevitable iron loading as there are no specific physiological mechanisms for removal of the large amount of iron contained in each unit of blood. Transfusional iron overload is a well-recognized cause of morbidity among patients with SCA. The liver is the major site of iron deposition in SCA patients receiving chronic transfusions. Substantial inter-individual variation has been observed among transfused SCA patients in their rate of liver iron accumulation and their response to liver iron burden. Liver irn overload typically causes liver inflammation and fibrosis but some SCA patients do not develop any liver damage despite having high iron burdens. There is currently little understanding of what regulates transfusional iron uptake by the liver or what initiates parenchymal damage in response to individual iron burden. In ongoing experiments, we have identified specific genes which are differentially expressed in the livers of transfused SCA patients and are associated with transfusional iron loading. This suggests that gene expression differences in the liver may affect the rate of transfusional iron loading in SCA patients. It is known from other studies that germline mutations in genes involved in iron homeostasis can alter total body iron levels in the general population and in patients with hereditary hemochromatosis. It is probable that genetic mutations that affect iron homeostasis in the general population or hemochromatosis patients will also affect iron metabolism in SCA patients confronted with the challenge of iron from chronic transfusions. From these data, we hypothesize that genetic modifiers affect transfusional iron overload and toxicity in SCA patients. We propose to use existing datasets to determine the extent genetic modifiers control development of transfusional iron overload. We will address our hypothesis with our two specific aims: 1) We will use gene expression data from liver biopsy samples to identify gene expression differences in the livers of patients with variabl levels of iron overload or liver damage; 2) We will use whole exome sequence and single nucleotide polymorphism array data to identify coding variants and any genetic copy number variants associated with iron overload. To provide a comprehensive analysis of transfusional iron overload and genomic factors, we will also integrate our two aims to interpret the consequence of genetic variant and differential gene expression networks on iron overload. We expect this study will provide a comprehensive phenotypic, transcriptional and functional analysis of all genes associated with transfusional iron overload. This work will be relevant to al researchers interested in the mechanisms of transfusional iron accumulation, and for other medical conditions with transfusional iron overload, such as patients with thalassemia or myelodysplastic syndromes.