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，主要归因于遗传性疾病血色素沉着症（HH）。HH曾经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，在北欧血统人群中每1000人中约有5人发生。大多数血色素沉着症患者是HFE基因C282Y突变的纯合子。这种天生的铁代谢错误的特征是过量的饮食铁吸收和体内铁的逐渐积累，通常在中年达到有毒水平。这个种子基金提案的目标是计划一项合作研究，以回答这个问题，“遗传修饰因子在决定HFE C282Y基因型纯合人的铁积累中起什么作用？”一组调查人员将收集通过筛选研究或临床实践确定的参与者的现有数据。完整项目R24合作研究的规划将包括在研究地点进行安全的、支持网络的数据采集，从而能够开展以下主题的研究项目：(1)血色素沉着症非表达者的患病率；(2)放血后低铁再积累的机制；(3)铁超载的疾病表达谱及临床表现。随着拟议计划项目的完成，该小组有望通过NIDDK糖尿病、内分泌和代谢疾病跨学科合作研究项目征集（PAR-08-182）准备并提交一份完整项目R24资助申请。整个项目的研究将深入了解可能的遗传因素对铁超载的易感性或抗性的影响，有助于了解不同患者铁负荷的显著差异及其与临床表现的关系，并最终导致针对个体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.