HEMOCHROMATOSIS--EPIDEMIOLOGY AND MOLECULAR MECHANISMS

血色病--流行病学和分子机制

• 批准号: 6381082
• 负责人: Ernest Beutler
• 金额: $ 117.52万
• 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 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381082
• 关键词: age difference; antibody receptor; biological signal transduction; clinical research; epidemiology; family genetics; ferritin; gender difference; gene frequency; gene mutation; genotype; hereditary hemochromatosis; heterozygote; histocompatibility gene; homeostasis; human subject; intermolecular interaction; iron metabolism; longitudinal human study; mass screening; membrane transport proteins; microcytic /hypochromic anemia; phenotype; protein structure function; racial /ethnic difference

Hereditary hemochromatosis, a disease characterized by excess iron absorption leading to diabetes, cardiomyopathy, cirrhosis, and arthropathies, is arguably the most common clinically important genetic disorder of Europeans. Recently an HLA Class 1 gene, HLA-H was implicated in the etiology of this disease. Over 80 percent of hemochromatosis patients are homozygous for a C282Y mutation. Compound heterozygotes for C282Y and H62D appear to have an increased incidence of the disease. Sixty-thousand adults undergoing health care screening in the Kaiser-Permanente system will be screened, determining serum iron, iron binding capacity, ferritin, and mutations in HLA-H. Patients classified as having hemochromatosis will be phlebotomized to remove excess iron and to measure iron stores. This will establish the relationship between genotype, age, sex and clinical state, and size of iron stores, and provide data that can be used to guide programs screening for hemochromatosis. The hypotheses that heterozygotes are more susceptible to cardiovascular disease and other disorders and that they are benefited by being less susceptible to iron deficiency anemia will be tested using the extensive Kaiser-Permanente database. Hemochromatosis mutations, other than those known, will be sought. The HLA-H gene product may function like other HLA class 1 genes, binding peptides and associating with proteins such as beta2 microglobulin, calreticulin, transporter associated with antigen processing (TAP) and tapascin. Alternatively, it may function as a signaling molecule, like the Fc receptor. Determining how the HLA-H gene product functions should provide insight into its role in maintaining iron homeostasis. This will be done by using immunoprecipitating HLA-H containing complexes, determining HLA-H Fc receptor signaling properties and measuring the binding of peptides and other small molecules by HLA-H.

遗传性血色沉着症，一种以过量铁为特征的疾病 吸收导致糖尿病、心肌病、肝硬变和 关节病，可以说是临床上最常见的重要基因 欧洲人的混乱。最近发现了一种人类白细胞抗原1类基因，即人类白细胞抗原H。 与这种疾病的病因学有关。超过80%的 血色沉着症患者为C282Y突变纯合子。化合物 C282Y和H62D杂合子的发病率似乎有所增加 这种疾病的危害。6万名接受健康检查的成年人 在Kaiser-Permanente系统中将进行筛查，测定血清 铁、铁结合力、铁蛋白和人类白细胞抗原-H的突变。病人 被归类为血色素沉着症的患者将接受抽血以移除 过量的铁和测量铁的储存量。这将确立 基因分型、年龄、性别与临床状态及肿瘤大小的关系 铁存储，并提供可用于指导节目的数据 血色素沉着症筛查。关于杂合子是 更容易患心血管疾病和其他疾病，而且 他们的好处是不太容易患缺铁性贫血 将使用广泛的Kaiser-Permanente数据库进行测试。 将寻找血色素沉着症突变，而不是那些已知的突变。 人类白细胞抗原-H基因产物可能具有与其他人类白细胞抗原1类基因相同的功能， 结合多肽并与Beta2等蛋白质结合 微球蛋白、钙网蛋白、抗原相关转运蛋白 加工(攻丝)和攻丝。或者，它也可以用作 信号分子，比如Fc受体。确定人类白细胞抗原-H如何 基因产物的功能应该让我们深入了解它在 维持铁的稳态。这将通过使用 免疫沉淀法测定人类白细胞抗原-H的Fc 受体信号转导特性及多肽与受体结合的测定 其他小分子由人类白细胞抗原H。