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。这项研究的总体目标是回答这样一个问题，“遗传修饰物在决定HFE C282Y纯合子人群铁蓄积方面扮演了什么角色？”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，开发和验证了表型鉴定方案，并进行了初步研究。这个完整的R24项目将利用目前的外显子组测序能力，然后有针对性地对铁相关基因组区域和单核苷酸变异进行测序，以确定与血色素沉着症患者严重或轻度铁表达相关的罕见和常见的因果变异。将采用有效的选择性基因分型研究设计，对三个对照组进行鉴定，即首次诊断时铁储存正常或轻度升高(低表达)的HFE C282Y纯合子，确诊时铁储存显著增加(高表达)的HFE C282Y纯合子，以及铁储存正常但没有HFE突变的第三组非血色素沉着症受试者。将进行后续验证研究，并将开发预测高表达风险的模型。这项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，有助于理解 不同患者铁负荷的显著差异及其与临床表现的关系，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。PHS 398/2590(06/09版)页面续格式页面

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