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用于代谢性肌肉疾病的大规模基因分型工具，可应用于某些高危人群，以防止迅速成为公共卫生问题的危及生命的症状。环境因素如药物、病毒感染、极度劳累、麻醉、睡眠剥夺、暴露于极端温度和其他环境压力源引发危及生命的代谢性肌肉疾病在一般人群中正在增加。在这些潜在的风险中，有近2000万美国人服用降胆固醇药物，称为他汀类药物;那些受到多种环境触发的人，包括军队，警察和消防新兵以及运动员;以及超过1500万美国人每年在全身麻醉下进行手术。最近扩大新生儿筛查也是检测出大量新生儿有可能患上严重代谢紊乱的原因，而目前还没有全面的突变筛查。需要一种综合的基因分型平台，该平台将为所有这些高风险群体提供致病突变和风险相关遗传变异的检测，优选地在症状出现之前。考虑到数百万美国人可能面临的风险，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，我们建议开发一种大规模的基因分型检测方法，用于检测与10种肌肉疾病相关的384种突变和遗传变异，从长远来看，可以应用于筛查所有7个风险组。所使用的平台将是GoldenGate基因分型检测（Illumina），该检测采用尖端技术，生产出业内最强大的基因分型系统之一。GoldenGate检测试剂盒允许在延伸和扩增步骤中进行高度的多重检测，从而最大限度地减少过程所需的时间、试剂体积和材料。该试验将用于筛选来自严重他汀类肌病患者和4个对照组的960份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种突变。10%的患者有疾病突变;对于某些疾病，仅携带者状态就增加了20倍。拟议的研究将使评估的突变和变异数量增加55倍，使研究的疾病数量增加2. 75倍，预测具有致病风险因素的个体数量将上升到至少25%。预计该项目的结果将为II期的市售检测方法的开发奠定基础，该检测方法将扩展至包括各种遗传变异和疾病，并将应用于其他高风险人群。目前，在本研究中提出的水平上，还没有针对代谢性肌肉疾病的全面的基于遗传的测试。这些疾病有一个共同点，即它们可以由在普通人群中日益普遍的环境暴露引发。每年有数千人因意外触发潜在疾病而遭受危及生命的失能性肌肉损伤发作，所述潜在疾病包括药物不良反应（例如，他汀类暴露）在暴露于异常温度（例如，派往伊拉克的士兵）。拟议的遗传性肌肉疾病综合基因分型的发展将导致长期的成本效益筛查，降低发病率，并降低与至少7个高风险群体（代表> 3500万人）的不良结局相关的医疗保健成本。