Validation of clinical assessment tools for population genetic studies of epileps

描述（由申请人提供）：越来越多的人认识到遗传变异在一系列常见疾病的发展以及个体对药物的反应中起着重要作用。确定癫痫发生的遗传危险因素和对抗癫痫药物治疗的反应可以使我们对癫痫发病机制和耐药性的理解取得重大进展，从而产生新的治疗靶点和策略。然而，由于缺乏专业知识和先进的调查技术，在发展中国家（如中国农村）癫痫遗传学研究的进展以及研究结果的应用受到了缺乏准确诊断和表型的阻碍。为了克服这一关键的研究和临床障碍，本研究旨在通过开发和验证准确表型的临床评估工具和建立遗传学研究能力来开发必要的基础设施，包括研究后勤、网络和人员培训。开发的研究模式有可能应用于其他低收入和中等收入国家，世界5000万癫痫患者中有80%生活在这些国家。将开发用于癫痫表型的临床评估工具（问卷），重点是对各种癫痫发作类型和癫痫综合征的分类，这对药物选择和预后有影响。为了验证这些评估工具的有效性，经过培训的乡村医生将对从中国政府的国家癫痫治疗项目中选出的600名患者进行应用。表型临床评估工具的有效性将通过与金标准进行比较来确定，金标准包括专家评估、脑电图记录和大脑磁共振成像。为了获得初步数据，确定预测癫痫易感性增加的遗传标记位点，将从每位患者获得口腔涂片/唾液样本，进行DNA提取和随后的基因分型。将比较患者和对照组之间多态性的频率。候选多态性将从一项在中国癫痫患者独立队列中进行的全基因组关联研究中发现的显著变异中选择。

DESCRIPTION (provided by applicant): It is increasingly recognized that genetic variants play a significant role in the development of a range of common diseases as well as in the individual response to medications. Identifying genetic risk factors for the development of epilepsy and response to antiepileptic drug therapy can lead to major advances in our understanding of the pathogenesis of epilepsy and of drug resistance, leading to new treatment targets and strategies. However, progress in the research as well as application of findings in epilepsy genetics in developing countries, such as rural China, is hampered by deficiency in accurate diagnosis and phenotyping because of lack of specialist expertise and sophisticated investigation techologies. To overcome this critical research and clinical barrier, this research aims to develop the necessary infrastructure through the development and validation of clinical assessment tools for accurate phenotyping and building genetics research capacity, including research logistics, network and personnel training. The research model developed has the potential to be applied in other low- and middle-income countries, where 80% of the world's 50 million epilepsy patients live. Clinical assessment tools (questionnaires) will be developed for phenotyping of epilepsy, focusing on the classification of various seizure types and epilepsy syndromes which have implications for drug choice and prognosis. To validate the assessment tools, they will be applied by village doctors after training to 600 patients selected from the Chinese government's national epilepsy treatment programs. The validity of the clinical assessment tools in phenotyping will be determined by comparing with the gold standard, comprising of specialist evaluation, electroencephalography recording and magnetic resonance imaging of the brain. To obtain preliminary data in identifying genetic marker loci predictive of increased susceptibility to epilepsy, a buccal smear/saliva sample will be obtained from each patient for DNA extraction and subsequent genotyping. Frequencies of the polymorphisms will be compared between patients and controls. Candidate polymorphisms will be selected from significant variants identified in a genome wide association study being carried out in an independent cohort of Chinese epilepsy patients. PUBLIC HEALTH RELEVANCE: Affecting 50 million people worldwide with 80% living in resource poor countries, epilepsy is the most common neurological disorder and a major global public health issue. Understanding the genetic risk factors predisposing to epilepsy and drug resistance can help doctors find better treatment and potentially preventive therapy, but patients in developing countries are often excluded from such research because of lack of expertise and sophisticated investigation technologies to classify the different types of epilepsy. This research aims to develop the necessary infrastructure for conducting large scale genetics research in rural China through the development and validation of clinical assessment tools for accurate phenotyping and building genetics research capacity, including research logistics, network and personnel training.