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.
These exploratory studies are relevant to public health for two reasons. First, they provide the first combined gene expression and mutation analysis to determine the regulators of transfusional iron overload. Secondly, identifying the genetic modifiers involved in these processes should provide a better understanding of the pathways that regulate transfusional iron loading, and possibly drive the development of new therapies for any patient with transfusional iron overload.
