IRON

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。人类基因组计划的成功为理解和改变人类疾病提供了一个新时代的希望。在下一代，我们将确定主要的宿主基因及其遗传变异，这些基因调节疾病的易感性和严重性以及对药物治疗的反应性，这似乎是可能和可行的。为了将这一承诺转化为现实，将需要对不同患者表型进行仔细的临床表征，并结合基因型（遗传变异）、基因表达信息（通过微阵列的mRNA等）、以及mRNA翻译成蛋白质的信息（蛋白质组学）。一些研究已经确定了基因型，大大提高了预测慢性血管或肿瘤性疾病的易感性和/或这些疾病的严重程度和结果的准确性。该项目将充分利用通过具有里程碑意义的HALT-C试验获得的样本和临床数据，以便为慢性丙型肝炎（CHC）开发类似的知识体系。 该计划的长期目标是确定使患者易患晚期CHC和/或对（干扰素）IFN治疗缺乏反应性的主要遗传变异。我们将集中我们的努力在选定的基因，在以前的较小的研究中，已被证明可以预测CHC的严重程度和/或IFN治疗的反应性的变化。具体来说，我们将描绘铁，HFE基因突变，和/或多态性在其他选定的基因或基因启动子的CHC的生产和发展的作用。我们的主要假设是，肝铁，与HLA连锁遗传性血色病（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进展为肝硬化，失代偿和肝细胞癌和/或CHC对基于IFN的治疗的反应的重要宿主因素。 该项目的具体目标是：确定慢性丙型肝炎的进展（即，HALT-C试验的主要终点）和肝脏或全身铁含量和/或HFE基因突变的存在（C282 Y，H63 D，S65 C）与HHC相关;确定慢性丙型肝炎进展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-10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）;探讨HFE突变、其他基因多态性和患者对治疗或长期结局的反应之间是否存在显著的相互作用;为了确定这些遗传变异的频率在HALT-C试验中的受试者与其他患有不太晚期CHC的受试者或没有CHC的对照受试者之间是否存在显著差异，年龄性别和种族都匹配

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.