Hemochromatosis -- Epidemiology and Molecular Mechanisms

血色素沉着症——流行病学和分子机制

• 批准号: 6841615
• 负责人: Ernest Beutler
• 金额: $ 91.6万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-28 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6841615
• 关键词: Hemochromatosis; Epidemiology; Molecular; Mechanisms

EXCEED THE SPACE PROVIDED. The overall purpose of this grant is to understand the phenotypic effect of mutations that cause hemochromatosis and to identify genetic polymorphisms that may modify the phenotype. More than 41,000 DNA samples are available from consenting patients who attended the Kaiser Permanente Health Appraisal Clinic and extensive health data including serum ferritin and transferrin saturation and HFE genotype have been obtained on virtually all of these subjects. Data collection will be continued on all of the patients who continue to receive their care in the Kaiser Permanente system and longitudinal studies will be conducted on this patient cohort, particularly with respect to the effect of the C282Y and H63D polymorphisms on the incidence of cardiovascular disease and of cancer. The candidate gene approach will be used to identify genes that may play a role in iron homeostasis. When polymorphisms are identified in such genes it will be determined whether they influence the phenotype of homozygotes for the C282Y mutation and whether they have any effect on serum transferrin saturation and ferritin levels. Promising candidates to be studied include haptoglobin and Nrampl. Attempts will be made to identify new candidate genes. These include the juvenile hemochromatosis (JH) gene located on chromosome lq and the putative hepcidin receptor. The region to which the JH has been localized positionally from other families is not accurately represented in GenBank, and its structure will be established. Then a comparison will be made of the sequence of genes within this interval from members of a family with lq linked juvenile hemochromatosis and controls. Since no genes known to be involved in iron metabolism are present in this interval, this should permit identification of a previously unknown modulator of iron homeostasis. Such a modulator might be involved not only in juvenile hemochromatosis but, presumably in the milder or heterozygous form, in modifying the phenotype of HFE hemochromatosis. The hepcidin receptor will be isolated by making antibody against hepcidin, binding hepcidin to cells, cross-linking and precipitating with antibody. Alternatively, isolation will be achieved by transfecting a cell line that does not bind hepcidin with a cDNA library made from cells that do express the receptor_ The projected studies should improve our understanding of control of iron metabolism and make possible detection of those cases of hemochromatosis who are likely to become clinically affected. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。这项资助的总体目的是了解导致血色素沉着症的突变的表型效应，并确定可能改变表型的遗传多态性。超过41，000份DNA样本来自参加Kaiser Permanente健康评估诊所的同意患者，并且几乎所有这些受试者都获得了广泛的健康数据，包括血清铁蛋白和转铁蛋白饱和度以及HFE基因型。将继续收集继续在Kaiser Permanente系统中接受治疗的所有患者的数据，并将对该患者队列进行纵向研究，特别是关于C282Y和H63D多态性对心血管疾病和癌症发病率的影响。候选基因的方法将被用来确定可能在铁稳态中发挥作用的基因。当在这些基因中鉴定出多态性时，将确定它们是否影响C282Y突变的纯合子的表型，以及它们是否对血清转铁蛋白饱和度和铁蛋白水平有任何影响。待研究的有希望的候选物包括触珠蛋白和Nrampl。将尝试鉴定新的候选基因。这些包括位于染色体lq上的青少年血色病（JH）基因和假定的铁调素受体。JH从其他科定位到的区域在GenBank中没有准确表示，其结构将被建立。然后，比较lq连锁青少年血色病家系成员和对照组在此区间内的基因序列。由于没有已知参与铁代谢的基因存在于这段时间内，这应该允许识别以前未知的铁稳态调节剂。这种调节剂可能不仅参与青少年血色病，而且可能以较温和或杂合的形式参与改变HFE血色病的表型。通过制备抗铁调素的抗体，将铁调素与细胞结合，与抗体交联和沉淀，分离铁调素受体。或者，通过用表达铁调素受体的细胞制成的cDNA文库分离不结合铁调素的细胞系来实现分离。预计的研究将提高我们对铁代谢控制的理解，并可能检测那些可能受到临床影响的血色素沉着症病例。性能现场=