高血压病易感基因FGF5和L3MBTL4的功能及其分子机制研究

Though recently they have fallen into some disrepute, genome-wide association studies have been formulated and applied to understanding essential hypertension. The principal goal here is to use data gathered in a GWAS to gauge the extent to which SNPs and their interactions with other features can be combined to predict arterial blood pressure in Han Chinese. More precisely, we want to quantify the extent to which data as described permit prediction of BP beyond what is possible from traditional risk factors. In all, there were 30 such single nucleotide polymorphisms (SNPs) have been genotyped in 2300 cases and 2300 controls. Data from stage 1 and stage 2 we studied are from first visit measurements taken as part of the Kailuan study. We will begin by assessing SNP features in their abilities to predict BP, employing a novel regression technique with two stages, first the discovery of main effects and next discovery of their interactions. The long list of SNPs genotyped is reduced to a manageable list for combining with SNP features in southern (11398 persons),middle(6972 persons) and northern (10513 persons). We selecte real associated SNP and investigate SNP biologic function and their molecular mechanisms. This study is important for an-hypertensive drug discovery.

高血压病是我国乃至全球最常见慢性病，也是心脑血管疾病最重要的危险因素。为阐明中国汉族人群高血压发病的分子遗传基础，我们已采用illumina全基因组SNP芯片和GoldenGate定制芯片分别在276高血压和252对照以及2300例高血压和2300例对照对高血压病易感基因或区域进行了定位和验证，筛选出30个潜在易感位点。本项目将对其中关联度最高的2个标签SNP rs1458038（位于FGF5启动子区）和rs403814（L3MBTL4）进行精细定位，并应用生物信息学分析SNP对基因功能和表达翻译等影响，另外在体外培养细胞-血管环-动物整体层面应用siRNA、质粒转染、体外磷酸化、EMSA和转基因/基因敲除动物探讨FGF5和L3MBTL4的功能及其参与调节血压的信号转导机制，从而为高血压分子病因学研究和抗高血压新药开发提供依据。

高血压是我国居民的重大疾病负担，我国高血压患病率估计达到25.2%，而控制率仅13.8%。然而，我们对于高血压发病机理的认知没有质的飞跃，近50年没有找到新的高血压干预靶点，30年没有真正意义的降压药问世，如何从根源上预防高血压以及如何更有效的治疗高血压病亟待解决。我们课题组在国自然基金资助下，从三个方面探讨了高血压的发病机制：课题组在超过2万名汉族人群中完成了GWAS研究，发现了数个中国汉族人群高血压的新易感基因（L3MBT4，LOC729251和TCEANC），并重复验证了数个欧美人群高血压易感基因位点，我们还通过构建转基因大鼠进一步研究了新易感基因L3MBT4及SNP rs16998073附近的基因ANTXR2与血压调节的关系和机制；此外，课题组通过芯片技术筛选了高血压患者血浆差异表达lncRNA和circRNA，通过验证试验确定关键分子，利用生物信息分析探索其潜在功能及信号通路，进一步功能和机制研究探讨其参与高血压发生发展的机理，奠定了未来新型降压药物治疗及基因治疗的理论基础；课题组还通过宏基因组技术分析高血压前期、高血压与健康人群肠道菌群的基因组成、菌群结构、分布、肠型和血清代谢产物，建立疾病分类器，并且通过无菌小鼠肠道菌群移植证实肠道菌群促进高血压发病，从而为下一步肠道菌群监测及调节作为新型诊治手段应用于高血压病提供理论依据。.研究共发表标注国家自然基金资助SCI论文14篇，培养博士生1名，硕士生2名。在资助期间，项目负责人成功获得国家杰出青年科学基金、国家自然科学基金优秀青年科学基金项目、973国家重大研究计划、国家自然科学基金重点项目资助，亦获得第十四届中国青年科技奖。