Genetic Modifiers of Iron Status in Hemochromatosis HFE C282Y Homozygotes

描述(由申请人提供)：在美国，大约有100万人面临铁超载的风险，主要原因是一种称为血色素沉着症(HH)的遗传疾病。HH一度被认为是一种罕见的疾病，现在被认为是最常见的常染色体隐性遗传病之一，在北欧血统的人群中每1000人中约有5人发生。大多数血色沉着症患者是HFE基因C282Y突变纯合子。这种与生俱来的铁代谢错误的特征是饮食中铁的过度吸收和体内铁的逐渐积累，通常在中年时达到中毒水平。这项种子拨款提案的目标是计划一项合作研究，以回答这样一个问题：“基因修饰物在确定HFE C282Y基因纯合子的铁积累方面发挥了什么作用？”一组调查人员将收集通过筛查研究或临床实践确定的参与者的现有数据。全项目R24协作研究的规划将包括在研究地点进行安全的、基于网络的数据捕获，从而能够开展以下主题的研究项目：(1)非表达基因与血色素沉着的患病率；(2)静脉采血治疗后低铁再积聚的机制；以及(3)铁超载的疾病表现和临床表现的谱。随着拟议规划项目的完成，预计该小组将能够通过NIDDK糖尿病、内分泌学和代谢性疾病跨学科合作研究计划(PAR-08-182)准备和提交完整项目R24赠款的申请。这项完整的项目研究将提供对铁超载易感性或抵抗力的可能遗传贡献的洞察，有助于了解不同患有这种疾病的人铁负荷的显著差异及其与临床表现的关系，并最终导致针对个人量身定做的创新预防和治疗策略的开发。 公共卫生相关性：拟议的规划项目预计将导致一项完整的项目研究，该研究将深入了解铁超载易感性或抵抗力的可能遗传因素。研究结果将有助于了解不同个体铁负荷的显著差异及其与临床表现的关系，并最终导致针对个人量身定做的创新预防和治疗策略的发展。

DESCRIPTION (provided by applicant): Approximately 1 million people in the United States are at risk for development of iron overload, attributable primarily to the genetic disorder known as hemochromatosis (HH). Once considered a rare disease, HH is now recognized as one of the most common autosomal recessive disorders, occurring in approximately 5 persons per 1,000 in populations of northern European descent. Most patients with hemochromatosis are homozygous for the C282Y mutation in the HFE gene. This inborn error of iron metabolism is characterized by excessive dietary iron absorption and progressive accumulation of iron in the body, typically reaching toxic levels by mid life. The goal of this seeding grant proposal is to plan a collaborative study that will answer the question, "What role do genetic modifiers play in determining iron accumulation in persons homozygous for the HFE C282Y genotype?" A team of investigators will assemble existing data from participants identified through screening studies or clinical practice. Planning for a full-project R24 collaborative study will include secure, web-enabled data capture at study sites, enabling conduct of research projects on the following topics: (1) The prevalence of non-expressors with hemochromatosis; (2) The mechanism underlying low iron re-accumulation after phlebotomy treatment; and (3) The spectrum of disease expression and clinical manifestations of iron overload. With completion of the proposed planning project, the group is expected to be well-positioned to prepare and submit an application for a full-project R24 grant through the NIDDK collaborative Interdisciplinary Research Program in Diabetes, Endocrinology and Metabolic Diseases solicitation (PAR-08-182). The full-project research will provide insight into possible genetic contributions to susceptibility or resistance to iron overload, help to understand the significant variation in iron loading in different individuals with this disorder and the relationship to clinical manifestations, and ultimately lead to development of innovative prevention and treatment strategies tailored to the individual. PUBLIC HEALTH RELEVANCE: The proposed planning project is expected to lead to a full-project research study that will provide insight into possible genetic contributions to susceptibility or resistance to iron overload. Results will help to understand the significant variation in iron loading in different individuals with this disorder and the relationship to clinical manifestations, and ultimately lead to development of innovative prevention and treatment strategies tailored to the individual.