Biochemical and Molecular Newborn Screening for Familial Hypercholesterolemia

新生儿家族性高胆固醇血症的生化和分子筛查

• 批准号: 10218453
• 负责人: Amy LH Peterson
• 金额: $ 15.54万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218453
• 关键词: 11 year old; 8 year old; Adult; Affect; Age; Age-Years; Algorithms; Apolipoproteins B; Atherosclerosis; Biochemical; Biochemical Genetics; Biochemical Markers; Biological Assay; Birth; Birth Weight; Blood; Cardiovascular Diagnostic Techniques; Cardiovascular Diseases; Cause of Death; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Childhood; Cholesterol; Country; DNA Sequence Alteration; Data; Detection; Development; Diagnosis; Disease; Early Diagnosis; Early treatment; Ethnic Origin; Familial Hypercholesterolemia; First Degree Relative; Genes; Genetic; Genetic Diseases; Genomics; Gestational Age; Goals; Gold; Guidelines; Health Benefit; Heart Diseases; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Individual; Inherited; LDL Cholesterol Lipoproteins; Low Density Lipoprotein Receptor; Mendelian disorder; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Mutation; Natural History; Neonatal; Neonatal Screening; Newborn Infant; Parents; Pathogenicity; Patients; Phenotype; Population; Prevention; Preventive care; Proprotein Convertases; Public Health; Publishing; Race; Recording of previous events; Reference Values; Reporting; Residual state; Risk; Sampling; Screening procedure; Societies; Specimen; Spottings; Subtilisins; Test Result; Testing; Umbilical Cord Blood; United States; Variant; Wisconsin; Woman; base; cost; cost effective; demographics; design; disease-causing mutation; early onset; genetic analysis; genetic testing; indexing; innovation; men; mortality; premature; prevent; screening; sex; success; tool; young adult

PROJECT SUMMARY Atherosclerotic cardiovascular disease remains the leading cause of death in humans despite significant advances in diagnosis and treatment. Familial hypercholesterolemia (FH) is a genetic disorder that leads to markedly increased levels of low-density lipoprotein cholesterol (LDL-C) in the blood that are present from birth and predispose affected individuals to early cardiovascular disease. FH affects 1 in 200-250 individuals, making FH the most common potentially fatal genetic disease in humans. Half of all untreated men with FH die of cardiovascular disease by age 55 and 15% of untreated women with FH die before 60 years of age. In the United States, most individuals with FH are diagnosed based on their blood levels of LDL-C alone, although genetic testing showing a disease-causing mutation in one of the genes known to cause FH is another way to make the diagnosis. Despite widespread use of cholesterol testing, FH remains profoundly underdiagnosed with less than 10% of individuals with FH identified in most countries, including the United States. The development of a tool to detect FH in the newborn represents an unprecedented opportunity to initiate early treatment. Early diagnosis and treatment of FH is effective at preventing premature morbidity and mortality. Additionally, identification of a young child with FH often leads to diagnosis of parents and other first-degree relatives at risk, creating a positive cascade effect. For these reasons, multiple different screening strategies have been designed to identify both children and adults with FH, but they have been of limited success. Screening newborns for FH presents a potential opportunity for population-wide detection but has not been systematically studied to date. The aim of this study is to design a testing algorithm that can detect FH in the newborn population. Using biochemical and molecular genetic tests and existing dried blood spots from discarded Wisconsin newborn screening specimens, this study will assess a large group (10,000) of newborns for FH biochemical markers and genetic mutations that cause FH. The biochemical markers, genetic data, and newborn demographic information will be used to create a multifactorial model to predict FH in a given individual. Effective diagnosis of FH in the newborn period, using an already existing and highly effective population screening tool, has the real potential to dramatically change the natural history of a disease that currently exerts a devastating toll on our population.

项目摘要 动脉粥样硬化心血管疾病仍然是人类死亡的主要原因 诊断和治疗的进展。家族性高胆固醇血症（FH）是一种遗传疾病，导致 从出生开始就存在的血液中低密度脂蛋白胆固醇（LDL-C）的水平明显增加 易患患者患有早期的心血管疾病。 FH影响200-250个人中的1个，使 FH是人类最常见的致命遗传疾病。所有未经处理的男人中有一半死于 55岁和15％的未经治疗的FH妇女在60岁之前死亡的心血管疾病。在曼联 州，大多数FH患者仅根据其血液水平的LDL-C诊断，尽管遗传 测试显示在已知引起FH的一个基因之一中发生疾病突变是使该突变的另一种方法是使 诊断。尽管广泛使用胆固醇测试，但FH仍被低于小于 在包括美国在内的大多数国家 /地区，有10％的FH患者确定。 在新生儿中检测FH的工具的开发代表了早期启动的前所未有的机会 治疗。 FH的早期诊断和治疗可有效预防过早的发病率和死亡率。 此外，鉴定有FH的幼儿通常会导致父母和其他一级的诊断 处于危险中的亲戚，产生积极的级联效应。由于这些原因，多种不同的筛选策略 旨在识别FH的儿童和成人，但成功的成功。 筛选新生儿的FH为范围内检测提供了潜在的机会，但尚未 迄今为止正在系统地研究。 这项研究的目的是设计一种可以检测到新生儿中FH的测试算法。使用 威斯康星州新生儿的生化和分子基因检测以及现有的干血点 筛选标本，本研究将评估一大群（10,000）新生儿的FH生化标记和 引起FH的基因突变。生化标记，遗传数据和新生儿人口统计信息 将用于创建一个多因素模型，以预测给定个体中的FH。有效诊断FH 使用已经存在且高效的人口筛查工具的新生儿时期具有真正的潜力 急剧改变目前对我们人口造成破坏性损失的疾病的自然历史。