Genetic Modifiers of Iron Status in Hemochromatosis HFE C282Y Homozygotes

描述（由申请人提供）：在美国，大约有100万人处于铁过载的风险中，主要归因于称为血色病（HH）的遗传性疾病。HH曾被认为是一种罕见疾病，现在被认为是最常见的常染色体隐性遗传疾病之一，在北方欧洲血统人群中约每1，000人中有5人发生。大多数血色素沉着症患者的HFE基因C282 Y突变是纯合子。这种先天性铁代谢缺陷的特征是过量的膳食铁吸收和铁在体内的渐进积累，通常在中年达到有毒水平。这项研究的总体目标是回答这个问题，“遗传修饰剂在决定HFE C282 Y基因型纯合子患者铁积累方面起什么作用？”“在R24种子基金的帮助下，我们建立了一个国际合作研究团队，开发和验证了表型分析方案，并进行了初步研究。这个完整的R24项目将利用目前外显子组测序的能力，然后对铁相关基因组区域和单核苷酸变异进行靶向测序，以确定与血色病患者严重或轻度铁表达相关的罕见和常见致病变异。将使用有效的选择性基因分型研究设计，其中已确定了三个比较组，即首次诊断时铁储存正常或极轻微升高（低表达）的HFE C282 Y纯合子、诊断时铁储存显著增加（高表达）的HFE C282 Y纯合子和铁储存正常且无HFE突变的第三组非血色病受试者。将进行后续验证研究，并开发预测高表达风险的模型。这项研究将提供深入了解可能的遗传贡献的易感性或抵抗铁超载，有助于了解 铁负荷在不同个体与这种疾病的显着变化和临床表现的关系，并最终导致开发创新的预防和治疗策略，为个人量身定制。PHS 398/2590（Rev.06/09）

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 overall goal of this research is to answer te question, "What role do genetic modifiers play in determining iron accumulation in persons homozygous for the HFE C282Y genotype?" With assistance from a R24 seeding grant, we have established an international collaborative research team, developed and validated a phenotyping protocol and performed preliminary studies. This full R24 project will utilize current capabilities of exome sequencing followed by targeted sequencing of iron-related genome regions and single nucleotide variants to identify rare and common causal variants associated with severe or mild iron expression in hemochromatosis patients. An efficient selective genotyping study design will be used for which three comparison groups have been identified, HFE C282Y homozygotes with normal or minimally elevated iron stores (low expression) at the time of first diagnosis, HFE C282Y homozygotes with markedly increased iron stores (high expression) at diagnosis, and a third group of non-hemochromatosis subjects who have normal iron stores and no HFE mutations. A follow-up validation study will be preformed and a model will be developed for predicting risk of high expression. This 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. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page