IRON

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。人类基因组计划的成功为理解和改造人类疾病提供了一个新时代的希望。在下一代中，我们将确定主要宿主基因及其遗传变异，这些基因调节对疾病的易感性和严重程度以及对药物治疗的反应，这似乎既可能又可行。要将这一前景转化为现实，需要对不同患者表型进行仔细的临床表征，同时确定基因型（遗传变异）、基因表达信息（通过微阵列等）以及mRNA转化为蛋白质的信息（蛋白质组学）。一些研究已经确定了基因型，可以大大提高预测慢性血管或肿瘤疾病的易感性和/或这些疾病的严重程度和结局的准确性。该项目将充分利用具有里程碑意义的HALT-C试验获得的样本和临床数据，以开发类似的慢性丙型肝炎（CHC）知识体系。该项目的长期目标是确定易使患者发展为晚期CHC和/或对（干扰素）ifn治疗缺乏反应性的主要遗传变异。我们将集中精力研究选定基因的变异，在之前的小型研究中，这些变异已被证明可以预测CHC的严重程度和/或对IFN治疗的反应性。具体来说，我们将描述铁、HFE基因突变和/或其他选定基因或基因启动子多态性在CHC产生和发展中的作用。我们的主要假设是，肝铁、与hla相关的遗传性血色素沉着症（HHC）相关的HFE基因突变和/或其他基因的选择性多态性是影响慢性丙型肝炎向肝硬化、代偿失代偿和肝细胞癌进展和/或CHC对基于ifn的治疗反应的重要宿主因素。该项目的具体目的是：确定慢性丙型肝炎的进展（即HALT-C试验的主要终点）与肝脏或全身铁含量和/或与HHC相关的HFE基因突变（C282Y, H63D, S65C）的存在之间是否存在直接相关性；确定慢性丙型肝炎的进展是否与血管紧张素原启动子（Ang-P）、载脂蛋白E （apo-E）基因型、白细胞介素i0启动子（IL-10-P）、微粒体环氧化物水解酶（mEH）、转化生长因子- β (TGF)或肿瘤坏死因子- α启动子（TNF-P）多态性相关；探讨HFE突变、其他基因多态性与患者对治疗的反应或长期预后之间是否存在显著的相互作用；并确定这些遗传变异的频率在HALT-C试验中与其他不太晚期CHC的受试者或没有CHC的对照受试者之间是否有显著差异，这些受试者的年龄、性别和种族匹配。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The success of the human genome project provides the promise of a new era in understanding and modifying human disease. It seems both likely and feasible that, during the next generation, we will identify the major host genes and their genetic variations, which modulate susceptibility to and severity of disease and responsiveness to medical therapies. To translate this promise into reality will require careful clinical characterizations of different patient phenotypes, coupled with determination of genotypes (genetic variations), gene expression information (mRNA's by microarrays, etc.), and information about translation of mRNA's into proteins (proteomics). A few studies have already identified genotypes that predict with greatly improved accuracy susceptibility to chronic vascular or neoplastic diseases and/or severity and outcome of these diseases. This project will take full advantage of the samples and clinical data obtained through the landmark HALT-C Trial, in order to develop a similar body of knowledge for chronic hepatitis C (CHC). The long-term goal of this program is to ascertain the major genetic variations that predispose patients to develop advanced CHC and/or lack of responsiveness to (Interferon) IFN-based treatment. We will concentrate our efforts on variations in selected genes, which in previous smaller studies, have been shown to predict severity of CHC and/or responsiveness to IFN treatment. Specifically, we will delineate the role of iron, HFE gene mutations, and/or polymorphisms in other selected genes or gene promoters on the production and progression of CHC. Our major hypotheses are that hepatic iron, mutations of the HFE gene associated with HLA-linked hereditary hemochromatosis (HHC), and/or selected polymorphisms in other genes, are important host factors that influence the progression of chronic hepatitis C to cirrhosis, decompensation, and hepatocellular carcinoma and/or the response of CHC to IFN-based therapies. The specific aims of this project are: To determine whether there is a direct correlation between progression of chronic hepatitis C (i.e., the major endpoints of the HALT-C Trial) and hepatic or total body iron content and/or the presence of the HFE gene mutations (C282Y, H63D, S65C) associated with HHC; To determine whether there are correlations between progression of chronic hepatitis C and polymorphisms of the angiotensinogen promoter (Ang-P), apolipoprotein E (apo-E) genotype, the interleukin-I0 promoter (IL-10-P), microsomal epoxide hydrolase (mEH), transforming growth factor-beta (TGF), or the tumor necrosis factor-alpha promoter (TNF-P); To explore whether there are significant interactions among mutations of HFE, polymorphisms of other genes, and patients' responses to therapy or long-term outcomes; and To determine whether the frequencies of these genetic variations differ significantly among subjects in the HALT-C Trial vs other subjects with less advanced CHC, or control subjects without CHC, matched for age, sex, and ethnicity.