支气管上皮的基因和环境相互作用对哮喘表型的影响:哮喘发病机制的探讨

项目名称： 支气管上皮的基因和环境相互作用对哮喘表型的影响:哮喘发病机制的探讨

项目编号： No.81470229

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 高金明

作者单位： 中国医学科学院北京协和医院

项目金额： 70万元

中文摘要： 哮喘是异质性疾病包括很多表型，受到不同基因调节。我们一直进行哮喘基础和临床研究，报道了（1）我国哮喘及表型相关的易感基因SNP；（2）哮喘患者维生素D明显低下与肺通气功能损害显著相关，饮食中抗氧化物对患者肺功能的有益作用。全基因组关联研究定位了哮喘或表型相关的基因座位，但这些结果在我国哮喘中没有得到复制，并且这些哮喘易感基因缺乏功能研究。支气管上皮的基因与环境因素相互作用通过表观遗传机制介导了哮喘的发病，哮喘气道上皮缺欠性疾病。此次申请，我们将在已经建立了表型特征完整的哮喘研究队列（1000名患者和500名对照者）中，采用定制SNP芯片的方法系统研究支气管上皮基因以及哮喘气道炎症基因SNP，通过遗传学分析，以期发现新的调节哮喘及表型的SNP或单倍型，并深入研究这些易感基因SNP与特定环境因素相互作用在哮喘发病及进展中的特点。主要目的是探索新的影响哮喘自然过程的治疗靶位如补充维生素D。

中文关键词： 过敏性哮喘；单核苷酸多态性；气道上皮细胞；发病机制；气道炎症

英文摘要： Asthma is a heterogeneous disease involving several phenotypes, which are affected by different genetic pathways. In 15 years, we have been focused on studying the basic and clinical aspects of asthma and reported several important novel findings in Chinese patients: (1) asthma or asthma phenotypes associated single nucleotide polymorphisms (SNPs) of susceptible loci identified by positional cloning approach including HLA-DR-DQ polymorphism regulating specific respone,beta 2 adrenoceptor polymorphisms association with nocturnal asthma, genetic variant in TNF alpha promoter for severe asthma, DPP10 and PHF11 SNPs in allergy status and lung function, and genes encoding vitamin D metabolism pathway for asthma overall risk; (2) predominance of lower circulating vitamin D levels in asthmatics, its significant association with lung function impairment in patients, and the beneficial effect of dietary antioxidants on lung function. Genome-wide association studies have located gene SNPs associated with asthma or asthmatic phenotypes. However, these gene SNPs have not been replicated in Chinese individuals with asthma, particularly, there lack the functional investigation clarifying the importance of these SNPs in asthmatic pathobiology. Asthma is a complex disorder made up of interacting local airway genetic and environmental factors through epigenetic mechanism, thus, asthma is more recognized as an airway epithelial defective disease. We will take this unique opportunity to systemically explore SNPs of genes expressing in airway epithelium and regulating asthmatic airway inflammation by adopting high-throughout DNA chips in a well-phenotyped asthma cohort (including 1000 asthma patients and 500 healthy controls) that has established and described elsewhere by us. With the pivotal aid of updated biostatistical software, we will aim at identifying new gene SNPs or haplotypes in airway mediating asthma susceptibility or asthma phenotypes, as listed in this proposal. Furthermore, we will define the functional characterizations of these gene SNPs under the specific environmental context in influencing the chronicity and persistence of asthma. The ultimate goal of this proposal is hopefully expecting to find the novel therapeutic targets that could influence the natural course of asthma (for example, supplementing with vitamin D).

英文关键词： allergic asthma;single nucleotide polymorphism;airway epithelium;mechanism;airway inflammation