Comprehensive Genotyping for Susceptibility to Metabolic Muscle Disease

代谢性肌肉疾病易感性的综合基因分型

• 批准号: 7539777
• 负责人: KENNETH M KAUFMAN
• 金额: $ 11万
• 依托单位: JK AUTOIMMUNITY, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2010-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7539777
• 关键词: American; Anesthesia procedures; Biological Assay; Categories; Cholesterol; Clinical; Control Groups; DNA; Data; Detection; Development; Diagnostic; Diagnostic tests; Disease; Early Diagnosis; Environmental Exposure; Environmental Risk Factor; Evaluation; Exertion; Exposure to; Fire - disasters; General Anesthesia; General Population; Generations; Genetic; Genomics; Genotype; Goals; Health Care Costs; Hereditary Disease; Individual; Industry; Inherited; Iraq; Laboratories; Lead; Life; Manufacturer Name; Measures; Medical; Metabolic; Metabolic Diseases; Military Personnel; Monitor; Morbidity - disease rate; Muscle; Mutation; Myopathy; Neonatal Screening; Newborn Infant; Numbers; Operative Surgical Procedures; Outcome; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Police; Predisposition; Process; Production; Public Health; Quality of life; Range; Reaction; Reagent; Recruitment Activity; Reproduction; Risk; Risk Factors; Sampling; Screening procedure; Sequence Analysis; Severities; Sleep Deprivation; Societies; Soldier; Staging; Symptoms; System; Technology; Temperature; Testing; Time; Variant; Virus Diseases; base; cost; cost effectiveness; design; disease-causing mutation; disorder prevention; environmental stressor; extreme temperature; fighting; genetic variant; genotyping technology; improved; mortality; mutation carrier; new technology; prevent; success; tool

DESCRIPTION (provided by applicant): The goal of this project is to develop a large-scale genotyping tool for metabolic muscle disease that can be applied to certain high risk groups in order to prevent life-threatening symptoms that are fast becoming a public health problem. The triggering of life-threatening metabolic muscle diseases by environmental factors such as drugs, viral infections, extreme exertion, anesthesia, sleep deprivation, exposure to temperature extremes, and other environmental stressors is increasing in the general population. Among those potentially at risk are nearly 20 million Americans taking cholesterol-lowering drugs, known as statins; those submitted to multiple environmental triggers including military, police and fire-fighting recruits, as well as athletes; and more than 15 million Americans who have surgery performed annually under general anesthesia. The recent expansion of newborn screening is also responsible for detecting larger numbers of newborns at risk for developing serious metabolic disorders for which no comprehensive mutation screen is available. There is a need for a comprehensive genotyping platform that will provide detection of disease-causing mutations and risk-associated genetic variants for all of these high risk groups preferably before symptoms arise. The extent of disease prevention from this screening tool will have a large impact on reducing both mortality and morbidity considering the millions of Americans potentially at risk. For this Phase I study, we propose to develop a large-scale genotyping assay for 384 mutations and genetic variants associated with 10 muscle diseases that, in the long-term, can be applied to screening all 7 risk groups. The platform used will be the GoldenGate Genotyping Assay (Illumina) which employs cutting edge technology for producing one of the most robust systems for genotyping in the industry. The GoldenGate assay allows for a high degree of multiplexing during extension and amplification steps, thus minimizing time, reagent volumes, and materials required for the process. The assay will be used to screen 960 DNA samples from individuals with severe statin myopathy and 4 control groups. In preliminary studies, 7 mutations causing 3 common metabolic muscle diseases were evaluated in patients with severe statin myopathy. Ten percent of patients had disease mutations; carrier status alone was increased for certain of these disorders as much as 20-fold. The proposed study will increase the number of mutations and variants evaluated by 55-fold and increase the number of disorders studied by 2.75-fold, predicting that the number of individuals with disease- causing risk factors will rise to at least 25%. The results of this project are expected to set the stage for the development of a commercially available assay in Phase II that will be expanded to include a wide variety of genetic variants and disorders and will be applied to additional high risk groups. At the present time, there is no comprehensive genetic-based testing for metabolic muscle diseases at the level proposed in this study. The disorders have in common the fact that they can be triggered by environmental exposures that are increasingly prevalent in the general population. Thousands of individuals suffer life-threatening episodes of incapacitating muscle damage every year from unexpected triggering of underlying disease ranging from adverse drug reactions (e.g., statin exposure) to extreme exertion during exposure to extraordinary temperatures (e.g., soldiers deployed to Iraq). The proposed development of comprehensive genotyping for hereditary muscle diseases will lead in the long-term to cost-effective screening, reduced morbidity, and lower healthcare costs relevant to adverse outcomes for at least 7 high risk groups representing >35 million individuals.

描述（由申请人提供）：该项目的目标是开发一种针对代谢性肌肉疾病的大规模基因分型工具，该工具可应用于某些高危人群，以预防迅速成为公共卫生问题的危及生命的症状。在普通人群中，药物、病毒感染、过度劳累、麻醉、睡眠不足、暴露于极端温度和其他环境压力等环境因素引发危及生命的代谢性肌肉疾病的情况正在增加。近 2000 万美国人服用降胆固醇药物（即他汀类药物），可能面临风险。那些受到多种环境触发因素影响的人，包括军队、警察和消防新兵以及运动员；每年有超过 1500 万美国人在全身麻醉下接受手术。最近新生儿筛查的扩大还有助于检测出大量有可能患上严重代谢紊乱的新生儿，而目前还没有全面的突变筛查。需要一个全面的基因分型平台，最好是在症状出现之前，为所有这些高危人群提供致病突变和风险相关遗传变异的检测。考虑到数百万美国人可能面临风险，这种筛查工具的疾病预防程度将对降低死亡率和发病率产生重大影响。对于这项 I 期研究，我们建议针对与 10 种肌肉疾病相关的 384 个突变和遗传变异开发大规模基因分型测定，从长远来看，可用于筛查所有 7 个风险群体。所使用的平台将是 GoldenGate 基因分型测定 (Illumina)，该平台采用尖端技术来生产业内最强大的基因分型系统之一。 GoldenGate 测定允许在延伸和扩增步骤中进行高度多重分析，从而最大限度地减少该过程所需的时间、试剂体积和材料。该检测将用于筛选来自患有严重他汀类肌病的个体和 4 个对照组的 960 个 DNA 样本。在初步研究中，在严重他汀类肌病患者中评估了导致 3 种常见代谢性肌肉疾病的 7 个突变。百分之十的患者患有疾病突变；其中某些疾病仅携带者状态就增加了 20 倍。拟议的研究将把评估的突变和变异数量增加 55 倍，将研究的疾病数量增加 2.75 倍，预测具有致病危险因素的个体数量将上升到至少 25%。该项目的结果预计将为第二阶段商业化检测的开发奠定基础，该检测将扩大到包括多种遗传变异和疾病，并将应用于其他高风险人群。目前，还没有达到本研究提出的水平的针对代谢性肌肉疾病的全面的基于基因的检测。这些疾病的共同点是，它们可能是由普通人群中日益普遍的环境暴露引发的。每年都有成千上万的人因意外引发潜在疾病而遭受危及生命的肌肉损伤，这些疾病包括不良药物反应（例如，他汀类药物暴露）到暴露在异常温度下的过度劳累（例如，部署到伊拉克的士兵）。拟议的遗传性肌肉疾病综合基因分型开发将从长远来看，为代表超过 3500 万人的至少 7 个高风险群体带来具有成本效益的筛查、降低发病率并降低与不良结果相关的医疗费用。