Genetic Modifiers of Transfusional Iron Overload

输血铁超负荷的基因修饰

基本信息

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
项目类别：
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

项目摘要

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，尽管有好处，但重复输血会导致不可避免的铁负荷，因为没有特定的生理机制可以去除大的铁。每单位血液中含有的铁量输血铁超负荷是 SCA 患者发病的一个公认原因。肝脏是 SCA 患者铁沉积的主要部位。长期输血的 SCA 患者的肝脏铁积累率及其对肝脏铁负荷的反应存在显着的个体差异，但肝脏铁超负荷通常会导致肝脏炎症和纤维化，但一些 SCA 患者尽管如此，却不会出现任何肝脏损伤。目前，人们对于调节肝脏输血铁吸收的机制或响应个体铁负荷引发实质损伤的机制知之甚少。在输血的 SCA 患者的肝脏中表达，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 患者的输血铁负荷率。从其他研究中得知，涉及基因的种系突变。铁稳态可以改变一般人群和遗传性血色素沉着症患者的总体铁水平。影响一般人群或血色素沉着症患者铁稳态的基因突变很可能也会影响遗传性血色素沉着症患者的铁代谢。 SCA 患者面临着长期输血带来的铁影响挑战，我们从这些数据中探究了 SCA 患者的输血铁超负荷和毒性的遗传修饰因素。我们建议使用现有数据集来确定遗传修饰因素控制输血铁超负荷发展的程度。我们将通过两个具体目标来解决我们的假设：1）我们将使用肝活检样本的基因表达数据来识别铁过载或肝损伤水平不同的患者肝脏中的基因表达差异；2）我们将使用整个外显子组序列和单核苷酸多态性阵列数据来识别与铁超载相关的编码变异和任何遗传拷贝数变异。为了提供输血铁超载和基因组因素的全面分析，我们还将整合我们的两个目标来解释铁超载的后果。我们期望这项研究将对与输血铁超载相关的所有基因进行全面的表型、转录和功能分析。这项工作将与所有对遗传输血铁机制感兴趣的研究人员相关。蓄积，以及其他伴有输血铁超负荷的医疗状况，例如地中海贫血或骨髓增生异常综合征患者。