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）：该项目的目的是为代谢肌肉疾病开发一种大规模的基因分型工具，该工具可用于某些高风险组，以防止危及生命的症状，这些症状迅速成为公共卫生问题。环境因素（例如药物，病毒感染，极端劳累，麻醉，睡眠剥夺，暴露于温度极端温度和其他环境压力源）在环境因素中引发威胁生命的代谢肌肉疾病的触发。在可能有风险的人中，有近2000万美国人服用降低胆固醇的药物，称为他汀类药物。那些服从多个环境诱因，包括军事，警察和战斗新兵以及运动员；每年在全身麻醉下进行手术的1500万美国人进行。最近的新生儿筛查还负责检测出大量的新生儿，患有严重代谢疾病的风险，没有全面的突变筛查。需要一个全面的基因分型平台，该平台将为所有这些高风险群体提供引起疾病突变和风险相关的遗传变异的检测，最好在症状出现之前。考虑到数百万美国人可能处于风险的风险，预防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。在这一阶段的研究中，我们建议开发针对与10种肌肉疾病相关的384个突变和遗传变异的大规模基因分型测定法，从长远来看，这些肌肉疾病可以应用于筛查所有7个风险组。使用的平台将是Goldengate Genotyping Assay（Illumina），该测定法（Illumina）采用尖端技术来生产行业中最强大的基因分型系统之一。黄金分析允许在扩展和扩增步骤中高度多路复用，从而最大程度地减少了该过程所需的时间，试剂量和材料。该测定法将用于从患有严重汀类药物肌病和4个对照组的个体中筛选960个DNA样品。在初步研究中，评估了7种引起3种常见代谢肌肉疾病的突变，患有严重的他汀类肌病的患者。百分之十的患者患有疾病突变；这些疾病中的某些疾病中的某些疾病的状态仅增加了20倍。拟议的研究将增加通过55倍评估的突变和变体的数量，并增加研究的疾病数量的数量为2.75倍，以预测患有疾病危险因素的个体数量将增加到至少25％。预计该项目的结果将为开发II期市售测定法的开发奠定了基础，该测定法将扩展到包括各种遗传变异和疾病，并将应用于其他高风险组。目前，在本研究中提出的水平上，尚无对代谢肌肉疾病的全面基于遗传的测试。这些疾病的共同事实是，它们可能是由越来越普遍的一般人群中越来越普遍的环境暴露引起的。每年，成千上万的人每年都会遭受丧命的肌肉损害，这是由于意外引发的潜在疾病的意外触发，从不良药物反应（例如他汀类药物暴露）到暴露于非凡温度（例如，士兵部署到Iraq）的极端劳累。拟议的遗传性肌肉疾病全面基因分型的发展将长期导致具有成本效益的筛查，发病降低以及降低与至少7个代表3500万个人的高风险群体相关的医疗保健成本。