Biochemical and Molecular Newborn Screening for Familial Hypercholesterolemia

项目总结 动脉粥样硬化性心血管疾病仍然是人类死亡的主要原因，尽管 诊断和治疗进展。家族性高胆固醇血症是一种遗传性疾病，可导致 从出生起血液中低密度脂蛋白胆固醇(LDL-C)水平显著增加 并使受影响的人更容易患上早期心血管疾病。FH影响每200-250人中就有1人，使 FH是人类最常见的潜在致命遗传病。所有未经治疗的FH患者中有一半死于 心血管疾病按55岁计算，未经治疗的FH妇女中有15%在60岁之前死亡。在美国 在美国，大多数FH患者仅根据他们的血液低密度脂蛋白-C水平就被诊断出来，尽管遗传 检测表明，已知的导致FH的基因之一存在致病突变，这是另一种使 诊断。尽管广泛使用胆固醇测试，但FH的诊断仍然严重不足 包括美国在内的大多数国家都有10%的FH患者。 开发一种检测新生儿FH的工具代表着一个前所未有的机会，可以在早期启动 治疗。FH的早期诊断和治疗是预防早产和死亡率的有效方法。 此外，确认患有FH的幼儿通常会导致父母和其他一级患者的诊断。 亲属处于危险之中，产生了积极的级联效应。出于这些原因，多种不同的筛查策略 已经被设计用来识别患有FH的儿童和成人，但它们取得的成功有限。 筛查新生儿FH为全人群检测提供了一个潜在的机会，但尚未实现 迄今为止进行了系统的研究。 本研究的目的是设计一种能够在新生儿群体中检测FH的测试算法。vbl.使用 威斯康星州废弃新生儿的生化和分子遗传学检测及现存的干血斑点 筛选样本，这项研究将评估一大组(10,000)新生儿的FH生化标记物和 导致FH的基因突变。生化标记、遗传数据和新生儿人口统计信息 将被用来创建一个多因素模型来预测给定个体的FH。FH的有效诊断 新生儿时期，使用现有的、高效的人口筛查工具，具有真正的潜力 戏剧性地改变一种疾病的自然历史，这种疾病目前正在给我们的人口造成毁灭性的损失。

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.