Genetic Modifiers of Iron Status in Hemochromatosis HFE C282Y Homozygotes

血色病 HFE C282Y 纯合子铁状态的遗传修饰

• 批准号: 8771261
• 负责人: Paul Clifford Adams
• 金额: $ 59.52万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8771261
• 关键词: Affect; Age; Alcohol consumption; Alleles; Architecture; Clinical; Code; Control Groups; Cysteine; DNA; DNA Sequence Analysis; Data; Development; Diagnosis; Dietary Iron; Disease; Equilibrium; European; Exons; Family member; Ferritin; First Degree Relative; Frequencies; Gender; Genes; Genetic; Genetic Research; Genome; Genomics; Genotype; Goals; Gold; Grant; Health; Hemochromatosis; Hepatic; Hereditary Disease; Homozygote; Inborn Genetic Diseases; Individual; Informed Consent; Institutional Review Boards; International; Iron; Iron Overload; Knowledge; Lead; Modeling; Monoclonal Antibody R24; Mutation; Nucleotides; Outcome; Participant; Patients; Penetrance; Persons; Phase; Phenotype; Play; Population; Positioning Attribute; Predisposition; Prevention strategy; Proteins; Protocols documentation; Rare Diseases; Recording of previous events; Research; Research Design; Resistance; Risk; Role; Sample Size; Sampling; Serum; Severities; Severity of illness; Testing; Therapeutic Intervention; Time; Tyrosine; United States; Validation; Variant; Venous blood sampling; absorption; clinical practice; comparison group; design; exome sequencing; follow-up; genetic variant; high risk; innovation; insertion/deletion mutation; insight; iron metabolism; middle age; prevent; repository; research study; screening; treatment strategy; validation studies

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

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，这主要归因于称为血色素沉着病 (HH) 的遗传性疾病。 HH 曾经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，北欧血统人群中每 1,000 人中大约有 5 人患有 HH。大多数血色素沉着症患者的 HFE 基因 C282Y 突变是纯合的。这种铁代谢的先天性错误的特点是膳食铁吸收过多，铁在体内逐渐积累，通常在中年时达到有毒水平。这项研究的总体目标是回答以下问题：“遗传修饰剂在决定 HFE C282Y 基因型纯合子的铁积累方面发挥什么作用？”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 项目将利用当前的外显子组测序功能，然后对与铁相关的基因组区域和单核苷酸变异进行靶向测序，以识别与血色素沉着症患者中严重或轻度铁表达相关的罕见和常见的因果变异。将使用有效的选择性基因分型研究设计，确定三个比较组：首次诊断时铁储备正常或轻度升高（低表达）的 HFE C282Y 纯合子、诊断时铁储备显着增加（高表达）的 HFE C282Y 纯合子以及第三组铁储备正常且无 HFE 突变的非血色素沉着症受试者。将进行后续验证研究，并开发一个模型来预测高表达的风险。这项研究将深入了解遗传对铁超负荷的易感性或抵抗力的可能贡献，有助于了解 患有这种疾病的不同个体的铁负荷存在显着差异，以及与临床表现的关系，最终导致针对个体的创新预防和治疗策略的开发。 PHS 398/2590（修订版 06/09） 页面延续 格式页面