Toll样受体基因多态性与EV71感染及严重程度的相关性研究

The increased size and frequency of Eneterovirus(EV71) outbreaks in China has greatly increased over the past 12 years. Similar with other infectious diseases, EV71 infection may also be the result of complex interactions between pathogen, environmental factors and host genes. It has been shown that TLR3, TLR4, TLR7 and TLR8 play an important role in the pathogenesis of EV71 infection. So we hypothesized that aforementioned four TLRs might be potential candidate susceptibility genes for EV71 infection. To our knowledge, the role between polymorphisms of TLRs and EV71 infection has never been specifically investigated. We have selected 22 tag SNPs on the basis of the HapMap Beijing Han population data obtained from the HapMap database using HaploView software. In this study, we will examine whether the 22 tag SNPs are related to the risk and severity of EV71 through case-control association study. Then, to clarify the biological sense of association results, functional studies will carriy out to explore the function of significantly associated SNPs. The identification of susceptibility genes and SNPs contributing to EV71 infection would assist in predicting individual and population risks of EV71 infection, as well as clarifying pathogenesis of this infectious disease.

近12年来，肠道病毒EV71在我国暴发的频率和幅度均显著增加。同其它传染病一样，EV71感染也是由病原体、环境因素和宿主的遗传因素共同决定的。已知Toll样受体（TLRs）中的TLR3、TLR4、TLR7和TLR8在EV71感染中发挥重要作用，是研究EV71感染遗传易感性很好的侯选基因。目前关于TLRs基因多态性与EV71感染及其严重程度易感性的研究尚未见报道。前期我们下载了HapMap数据库北京汉族人群TLR3、TLR4、TLR7和TLR8基因的数据，采用HaploView软件计算得到了22个标签SNPs。我们拟通过病例-对照关联研究，确定22个标签SNPs是否与EV71的发生风险和严重程度关联，然后采用功能实验进一步探索显著关联的SNPs的功能，揭示遗传学关联背后蕴含的生物学意义。希望通过此项研究，获得具有应用价值的易感基因和SNPs，为EV71感染高危人群的预警和预防提供新的指标。

按计划开展Toll样受体等基因多态性与EV71感染及严重程度的相关性研究。建立了最大的EV71感染病例-对照人群（441例病人和958例对照），采用基于侯选基因的研究策略，在收集到的病例-对照人群中对Toll样受体、MxA等基因的SNPs进行了分型，并对关联位点进行了中间表型的测定和功能研究。结果发现所选择Toll样受体基因的多态性与EV71相关手足口病的遗传易感性不相关，MxA基因的C-123A和G-88T多态性位点及其单体型与EV71感染相关。在群体水平和流行病学角度首次揭示了MxA基因多态性与EV71相关手足口病的遗传易感性相关。对手足口病患者和健康儿童所携带的EV71进行了VP1基因序列分析，结果发现本研究中手足口病患者和健康儿童所携带的EV71基因序列基本一致，都属于C4a亚型。此项研究获得具有易感基因和SNPs为EV71感染高危人群的预警和预防提供新的指标。项目执行期间共发表标注资助号的SCI论文2篇，影响因子总计7.4分，项目负责人均为第一作者。