Genetic Modifiers of Transfusional Iron Overload

输血铁超负荷的基因修饰

• 批准号: 9119096
• 负责人: Jonathan Michael Flanagan
• 金额: $ 12.91万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119096
• 关键词: Address; Affect; Biochemical; Biopsy Specimen; Blood; Catabolism; Chronic; Clinical; Clinical Research; Clinical Trials; Code; Copy Number Polymorphism; DNA Sequence Alteration; Data; Data Set; Deposition; Development; Dysmyelopoietic Syndromes; Endocrine; Enrollment; Erythrocyte Transfusion; Erythrocytes; Event; Excision; Fibrosis; GSTM1 gene; Gene Deletion; Gene Expression; Gene Mutation; General Population; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Germ-Line Mutation; Goals; Health; Heart; Heme Iron; Hemochromatosis; Hepatic; Hereditary hemochromatosis; Homeostasis; Individual; Iron; Iron Overload; Laboratories; Lead; Literature; Liver; Liver Fibrosis; Measurement; Medical; Metabolism; Morbidity - disease rate; Mutation Analysis; National Heart, Lung, and Blood Institute; Pathway interactions; Patients; Phenotype; Physiological; Process; Public Health; Recycling; Research; Research Personnel; Risk; Sickle Cell Anemia; Single Nucleotide Polymorphism; Site; Spleen; Systems Biology; Thalassemia; Tissue-Specific Gene Expression; Tissues; Toxic effect; Transfusion; Variant; Venous blood sampling; Work; base; chelation; cohort; differential expression; exome sequencing; genetic variant; innovation; inter-individual variation; interest; interpatient variability; iron metabolism; liver biopsy; liver inflammation; liver injury; macrophage; novel therapeutics; prevent; research study; response; routine therapy; senescence; theories; uptake

 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.

 描述（由适用提供）：慢性红细胞翻译是一种常规治疗方法，用于预防镰状细胞贫血（SCA）的临床并发症。尽管有好处，但反复输血会导致不可避免的铁负荷，因为没有特定的物理机制可以去除每个血液中包含的大量铁。 SCA患者的交叉铁超负荷是众所周知的发病率的原因。肝脏是接受慢性输血的SCA患者铁沉积的主要部位。在输血的SCA患者中，已经观察到了实力累积率和对活铁伯嫩的反应，已经观察到了个体间的差异。肝脏IRN超负荷通常会引起肝脏注射和纤维化，但是尽管有高铁伯氏铁，但有些SCA患者并未产生任何肝脏损伤。目前，几乎没有了解哪些调节肝脏的输血摄取，或者是什么因响应单个铁伯嫩而引发的副群损害。在正在进行的实验中，我们已经确定了特定的基因，这些基因在交叉SCA患者的生活中以不同的方式表达，并且与输血铁负荷相关。这表明肝脏中的基因表达差异可能会影响SCA患者的铁负荷率。从其他研究中知道，参与铁稳态的基因的种系突变会改变普通人群和遗传性血色素沉着病患者的总体铁水平。有问题的是，影响一般人群或血色素沉着病患者铁稳态的遗传突变也会影响SCA患者的铁代谢，遇到慢性输血中铁的挑战。从这些数据中，我们假设遗传修饰剂会影响SCA患者的交叉铁超载和毒性。我们建议使用现有数据集来确定遗传修饰符控制输血过载的发展。我们将以我们的两个具体目的解决我们的假设：1）我们将使用肝活检样品中的基因表达数据来识别各种水平的铁超载或肝损害患者的生活中的基因表达差异； 2）我们将使用整个表达序列和单个核苷酸多态性阵列数据来识别编码变体以及与铁超载相关的任何遗传拷贝数变体。为了对输血过载和基因组因素进行全面分析，我们还将整合我们的两个目标，以解释铁超载中遗传变异和差异基因表达网络的结果。我们预计这项研究将为所有与输血铁超载相关的基因提供全面的表型，转录和功能分析。这项工作将与所有对输血累积机制感兴趣的研究人员有关，以及其他具有输血铁超负荷的医疗状况，例如丘脑症或骨髓增生综合征的患者。