BDNF-SH2B1-MAPK通路基因与饮食行为在儿童肥胖发病中的作用与机制研究

The prevalence of childhood obesity has been increasing both in developed and developing countries. Childhood obesity is associated with a series of severe health problems. However, the pathogenesis of obesity has not been clarified so that no specific intervention. The pathogenesis of obesity has become a major problem for child and adolescent health. Based on biological function studies, population association studies, pathway analyses in KEGG and DAVID database, the proposed study will focus on the BDNF-SH2B1-MAPK pathway genes having central regulation on food intake and body weight. Firstly we selected 4200 children from the samples which have been collected in our previous studies, to perform case-control study. We will use exon sequencing to screen variants of the genes, detect SNPs in all samples, and study gene-gene interaction, relationship between gene and dietary behaviors, in order to identify the related gene variants and dietary behaviors. Secondly, we will recruit samples of 520 child-parent trios, make in-depth investigation on dietary behavior problems, perform validation study for the gene variants which were identified in case-control study. Subsequently, we will perform studies in cells to clarify functional mechanism of the gene variants found in the previous steps. This study is different from the previous studies which focus on single genes. It is a pathway study and will be helpful for identifying the network of multiple genes, relationship between gene and dietary behavior, target gene variants susceptible to specific diet. The study results will be important for clarifying the pathogenesis of childhood obesity and develop drugs, and provide evidences for improving intervention strategies for childhood obesity.

儿童肥胖率持续上升，对健康危害严重，然而肥胖的发病机制尚不明确，影响干预效果，已成为儿少卫生领域急待解决的问题之一。根据生物学功能研究、人群关联研究、生物信息数据库通路分析，本研究选择对食物摄入和体重有中枢调控的BDNF-SH2B1-MAPK通路基因进行系统研究。首先从既往研究样本库中选择4200名儿童进行病例对照研究，用外显子测序筛查基因变异，高通量检测SNPs，研究基因-基因交互、基因与饮食行为的中介和交互作用，筛选与儿童肥胖相关的基因变异和饮食行为；然后收集520个肥胖核心家系，深入调查儿童饮食行为，研究筛选的基因与饮食行为对肥胖的作用；最后通过细胞实验分析基因变异的作用机制。本研究不同于既往把基因作为单点研究，而基于通路研究多基因的网络关系以及与饮食行为的作用路径，找到在特定饮食下敏感的靶基因位点，从而对阐明儿童肥胖发病机制及药物研发有重要意义，为优化儿童肥胖干预策略提供依据。

儿童肥胖率持续上升，对健康危害严重，然而肥胖的发病机制尚不明确，影响干预效果，已成为儿少卫生领域急待解决的问题之一。前期研究提示BDNF-SH2B1-MAPK通路基因对食物摄入和体重有中枢调控有关。本研究基于既往研究建立的样本库进行病例-对照研究并收集肥胖核心家系，用外显子组测序筛查基因变异，高通量检测基因分型，筛选与儿童肥胖相关的基因变异和饮食行为，分析基因-基因交互、基因与饮食行为的中介和交互作用，并研究基因变异的功能。主要研究结果：（1）外显子测序研究发现5个基因多态性与儿童肥胖存在相关性，其中SKOR1基因多态性rs7170185与BDNF-SH2B1-MAPK通路中的MAP2K5基因存在强连锁不平衡；研究发现BDNF-SH2B1-MAPK通路5个基因多态性与儿童肥胖存在相关性（P<0.05）；该通路相关的PACS1、SKOR1、MYO9A等基因多态性与肥胖表型存在相关性（P<0.05）；（2）用可穿戴式相机评估儿童的饮食摄入量和行为，发现3天24小时膳食回顾调查问卷有低估，8%和1%的膳食调查条目会出现漏报和错报的情况，以零食形式摄入的食物比正餐更容易被漏报；调查发现北京超市售卖的含糖碳酸饮料和非含糖碳酸饮料中的含糖量和能量均较高；（3）部分BDNF-SH2B1-MAPK通路基因及其它相关基因多态性与饮食行为或生活方式对肥胖相关表型存在交互作用；家系研究发现MC4R基因多态性在儿童的食物响应和饮料摄入之间具有中介效应(P<0.05)；（4）细胞实验发现MAP2K5基因内含子rs7175517多态性A等位基因的转录活性低于野生型G等位基因，未发现SKOR1基因启动子区rs7170185多态性对转录活性的影响。因此，本研究发现BDNF-SH2B1-MAPK通路基因及相关基因在儿童肥胖发生中的作用，以及基因-基因、基因-饮食行为之间的交互和中介效应，通过细胞实验证实基因变异的作用机制，研究结果对阐明儿童肥胖发病机制有重要意义，为优化儿童肥胖筛查和干预策略提供依据。