Using Next Generation Sequencing to Unravel the Pathogenesis of Sporadic Inclusion Body Myositis - The International IBM Consortium Genetic Study

最常见的肌肉疾病发生在45岁以上的患者，是一种肌肉萎缩的疾病，称为包涵体肌炎(IBM)。患者通常会出现进行性肌肉萎缩和虚弱，进展并导致明显的残疾，最终在大约10年的过程中死于行动不便。目前还没有针对IBM患者的有效治疗方法。这种肌肉疾病的确切原因尚不清楚。然而，在患者的肌肉活组织检查中，似乎既有肌肉中的一些轻微炎症，也有异常蛋白质的积累，类似于阿尔茨海默氏症、额颞叶痴呆和运动神经元疾病等神经退行性疾病患者大脑中积累的蛋白质。以前的研究表明，可能有遗传因素使人们容易患上IBM，但之前的研究规模很小，并不是决定性的。在这项研究中，我们汇集了来自欧洲、美国和澳大利亚等世界各地的IBM专家，以提高对IBM的认识，定义诊断标准，收集临床信息和DNA。在过去的三年里，我们已经能够收集到有史以来最大的IBM患者和DNA样本-大约950例，一旦这项研究开始，这个数字将超过1000例。为了这项工作，患者的DNA和肌肉组织已经被仔细地储存起来。这一庞大的DNA收集使我们处于非常有利的地位，可以进行比以往任何时候都详细的遗传学研究，试图找出使人们容易患这种毁灭性疾病的遗传风险因素和基因。我们计划使用最新的下一代测序技术来揭开200名IBM患者DNA样本中存在的所有编码变异(那些改变蛋白质的变异)，与200名肌肉正常的患者相比。我们将分析我们已经从患者肌肉组织中提取的DNA，因为这是最好的诊断小组。我们将复制在另外700个IBM病例和2200多个其他对照中发现的变体。我们在下一代测序技术方面经验丰富，最近惠康信托设备公司授予我们购买最新的下一代测序仪的奖励，这一点得到了加强。最近，我们使用这些技术来确定其他神经肌肉疾病的遗传原因。与阿尔茨海默病等其他疾病相比，在疾病基因和遗传风险因素的识别方面取得了最大进展。阿尔茨海默病是指蛋白质聚集在大脑中，而不是IBM的肌肉。如果我们能够弄清楚关键基因是什么，以及这些致病途径是如何发挥作用的，我们将为帮助患者的新疗法和治疗方法铺平道路。

The commonest muscle disease that occurs in patients over the age of 45 years is a muscle wasting disease called inclusion body myositis (IBM). Patients typically develop progressive muscle wasting and weakness that progresses and causes marked disability and ultimately death from immobility over the course of around 10 years. There are no effective treatment for patients with IBM. The precise cause of this muscle disease is not known. However, on muscle biopsies from patients there seems to be a combination of some mild inflammation in the muscle and also an accumulation of abnormal proteins, similar to the accumulated proteins that are seen in the brains of patients with neurodegenerative diseases such as Alzheimer's, fronto-temporal dementia and motor neurone disease. Previous research has indicated that there may be genetic factors that predispose people to getting IBM but the previous studies have been quite small and not conclusive. In this research we have brought together experts in IBM from all over the world including Europe, USA and Australia to generate increased awareness of IBM, define diagnostic criteria, collect clinical information and DNA. Over the last three years we have been able to collect the largest group ever of IBM patients and DNA samples - approximately 950 cases and this number will be over 1000 once this study begins. The patient DNA and muscle tissue has been carefully stored for this work. This very large collection of DNA has put us in a very good position to undertake much more detailed genetic studies than have ever been done before to try and work out what the genetic risks factors and genes are that predispose people to this devastating disease.We plan to use the latest next generation sequencing techniques to unravel all the coding variants (those that alter proteins) that are present in 200 IBM patients DNA samples in comparison with 200 patients that are controls with normal muscles. We will analyze the DNA that we have already extracted from patients muscle tissue as this is the best diagnostic group. We will replicate the variants found in a further 700 IBM cases and over 2200 other controls. We are highly experienced in next generation sequencing technology and this has been strengthened by the recent award of a Wellcome Trust equipment grant to purchase the latest next generation sequencer. Recently we have used these techniques to identify the genetic causes of other neuromuscular disorders.In comparison with other disorders like Alzheimer's disease, where proteins are aggregated in the brain as opposed to the muscle as in IBM, the greatest advancement have been made with the identification of disease genes and genetic risk factors. If we can work out what the key genes are and how these disease causing pathways function, we will pave the way for new therapies and treatments to help patients.