Hemochromatosis -- Epidemiology and Molecular Mechanisms

描述(由申请人提供)：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，并识别可能改变表型的基因多态。来自Kaiser Permanente健康评估诊所的自愿患者提供了超过41,000个DNA样本，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。将继续收集所有继续在Kaiser Permanente系统中接受护理的患者的数据，并将对这一患者队列进行纵向研究，特别是关于C282Y和H63D基因多态对心血管疾病和癌症发病率的影响。候选基因方法将被用来识别可能在铁稳态中发挥作用的基因。当确定这些基因的多态时，将确定它们是否影响C282Y突变纯合子的表型，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。有希望被研究的候选药物包括结合珠蛋白和Nramp1。将尝试识别新的候选基因。这些基因包括位于染色体LQ上的幼年血色沉着症(JH)基因和可能的海普西丁受体。JH从其他家族定位到的区域在GenBank中没有准确表示，它的结构将被建立。然后对LQ连锁幼年血色沉着症家族成员和对照的基因序列进行比较。由于在这个区间内没有已知的参与铁代谢的基因，这应该可以识别出以前未知的铁稳态的调节器。这种调节剂可能不仅与幼年血色素沉着症有关，而且可能以较温和或杂合型的形式参与改变HFE血色沉着症的表型。通过制备针对海普西丁的抗体，将海普西丁与细胞结合，然后与抗体进行交联和沉淀，就可以分离出海普西丁受体。或者，通过将不与海普西丁结合的细胞系与由确实表达该受体的细胞制成的cdna文库相结合来实现分离。计划中的研究应该会提高我们对铁代谢控制的理解，并使那些可能受到临床影响的血色素沉着症病例的检测成为可能。

DESCRIPTION (provided by applicant): 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 Nramp1. 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.