IRON

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。人类基因组计划的成功为理解和修改人类疾病提供了一个新时代的希望。在下一代中，我们将确定主要的宿主基因及其遗传变异，这似乎既有可能也是可行的，这些基因调控着对疾病的易感性和严重程度以及对药物治疗的反应。要将这一承诺转化为现实，需要仔细研究不同患者表型的临床特征，并确定基因类型(遗传变异)、基因表达信息(通过微阵列等获得的信使核糖核酸)以及将信使核糖核酸转化为蛋白质的信息(蛋白质组学)。一些研究已经确定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基因型别，其准确性大大提高。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，以开发类似的慢性丙型肝炎(CHC)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)干扰素治疗缺乏反应性的主要基因变异。我们将集中精力研究选定基因的变异，在以前的较小规模研究中，这些变异已被证明可以预测慢性丙型肝炎的严重程度和/或对干扰素治疗的应答。具体地说，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的多态在CHC的产生和进展中的作用。我们的主要假设是，肝铁、与人类白细胞抗原连锁遗传性血色沉着症(HHC)相关的HFE基因突变和/或其他基因的选择性多态，是影响慢性丙型肝炎进展为肝硬变、失代偿和肝细胞癌和/或慢性丙型肝炎对干扰素治疗的应答的重要宿主因素。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)与肝脏或全身铁含量和/或与HHC相关的HFE基因突变(C282Y、H63D、S65C)之间是否存在直接关联；探讨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)、白细胞介素I0(IL-10-P)、微体环氧化物水解酶(Meh)、转化生长因子-β(TGF-β)或肿瘤坏死因子-α(TNF-P)基因多态性之间是否存在显著的交互作用，以及HFE基因突变和其他基因多态性与患者对治疗或长期疗效的反应之间是否存在显著的交互作用；并确定HALT-C试验中这些基因变异的频率是否在年龄、性别和种族匹配的HALT-C试验受试者与其他进展较慢的CHC受试者或没有CHC的对照受试者之间存在显著差异。

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.