基因、环境及其交互作用与肌萎缩侧索硬化发病、临床表型及预后相关性研究

Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease, affecting upper and/or lower motor neurons in motor cortex and spinal cord. It is suggested by epidemiology that genetic, environmental and aging are important risk factors. Although the major progresses have been made in the past decades for this devastating disease, the etiology and pathogenesis of ALS is still largely unknown. Moreover, our team has identified two new susceptibility loci for amyotrophic lateral sclerosis in Han Chinese by Genome-wide association analyses (GWAS), suggesting genetic heterogeneity and different epidemiological characteristics for ALS between Chinese and European populations. Our project intends to integrate and analyze environmental risk factors associated with the pathogenesis of ALS on the basis of the existing 2000 cases of ALS biological samples, clinical phenotype and epidemiological database, identify the gene mutation spectrum of TDP43, FUS and C9ORF72 in Chinese populations. Furthermore, our team proposes to screen new disease genes using exome sequencing in ALS pedigrees excluding those with known mutant genes and study the epidemiological associations between gene, environment and their interaction with ALS onset, clinical phenotype and severity of disease on the basis of previous GWAS results. This project would provide experimental basis for the early diagnosis, prognosis and future individualized gene therapy for ALS disease.

肌萎缩侧索硬化(ALS)是一类上、下运动神经元损害并存的致死性神经变性病，ALS认知功能的改变颠覆了传统上对该病的认识。流行病学发现遗传、环境与衰老是发病重要因素，但已有的研究不足以解释ALS的病因及机制。本课题组新近应用全基因组关联研究首次在中国人群ALS患者中发现两个新的易感基因 (Deng, et al. Nature Genetics 2013)，表明ALS在中国人群与欧美人群有着不同的易感基因谱和流行病学特征。本项目拟在已有的ALS生物样本、临床表型和流行病学数据库基础上整合和分析环境致ALS发病的相关危险因素；认知相关的TDP43、FUS、CORF72基因在中国人群的突变图谱；用外显子组测序方法在排除已知基因的家系患者筛选新致病基因；结合前期GWS结果进行基因、环境及其交互作用与ALS起病、临床表型和疾病严重程度的分子流行病学研究，为疾病早期诊断、预后和治疗提供实验依据

肌萎缩侧索硬化(ALS)是一类上、下运动神经元损害并存的致死性神经变性病，ALS认知功能的改变颠覆了传统上对该病的认识。流行病学发现遗传、环境与衰老是发病重要因素， 但已有的研究不足以解释ALS的病因及机制。本项目结合最新研究进展及已有的工作基础，按照原计划内容，系统地整合了已收集的2000例A LS生物样本、临床表型和流行病学数据库，并分析了吸烟、饮酒及环境因素与ALS发病的相关性;系统地筛查并绘制了认知相关的TDP43、FUS、CORF72基因在中国人群的突变图谱。结合前期GWS结果分享了基因、环境及其交互作用与ALS起病、临床表型和疾病严重程度的相关性；并在排除已知基因的家系患者进行了全外显子组测序，为ALS疾病的遗传病因诊断、预防及预后分析提供了有力的实验依据及可靠的遗传学数据库资源。总之，本项目已较好的完成了原计划研究内容，已发表SCI论文3篇，其中一篇IF>5，中华医学杂志1篇，已投稿在审理中的SCI论文4篇，国际大会报告3次，壁报交流2次；骨干人员晋升高级职称2人, 培养硕士研究生3名。

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