miR155HG基因及其遗传多态在心源性猝死发生中的分子机制研究

Sudden cardiac death (SCD) is often defined as a natural death of an apparently healthy individual, which takes place generally in the margin of an hour from the start of symptoms. SCD is a very traumatic event that occurs without an explainable cause of death after a comprehensive medico-legal investigation. Plenty of studies have indicated that genetic factors are important contributors to the risk of SCD which inferred by the positive family history. Our preliminary studies discovered that a 4-bp insertion/deletion polymorphism (rs72014506) within miR-155 host gene (MIR155HG) was significantly associated with SCD risk. Luciferase reporter assay showed that rs72014506 was a functional polymorphism. Further studies demonstrated that there was a significant correlation between rs72014506 genotype and MIR155HG/miR-155 expression in vivo and in vitro. However, the molecular mechanisms underling these associations were still not fully elucidated. Using bioinformatics prediction, we found that the region harboring rs72014506 may influence MIR155HG/miR-155 expression as an intronic enhancer which could interact with the promoter of MIR155HG, which in turn regulating MIR155HG/miR-155 expression, thereby involving in the development of SCD. On the basis of above results, our present proposal plans to clarify the roles of MIR155HG/miR-155 mediated by rs72014506 in SCD progression with multiple methods, such as multiple-center large sample analysis, mechanisms exploring and phenotype-function investigations, to provide scientific basis and effective approachs for SCD diagnosis in forensic practice, as well as prevention of high-risk SCD populations.

心源性猝死（SCD）指由心脏原因引起的突发性非预料死亡。因其具有发病出人意料和死亡急骤等特点，一直是法医学面临的重大课题。以往大量研究表明，SCD具有明显遗传倾向，遗传因素是SCD发生的重要决定因素之一。我们的前期研究发现位于miR-155宿主基因（MIR155HG）中一个四碱基插入缺失多态与SCD易感性显著相关。报告基因方法证明该多态具有功能性。基因型-表型关联研究发现该多态与MIR155HG及miR-155表达量相关，但其中的具体机制不明。生物信息学预测结果提示该多态所在区域可能作为一个内含增强子与MIR155HG基因启动子协同作用，共同调节该基因表达，进而参与SCD发生。本项目拟在此基础上，通过多中心大样本分析、机制研究及功能表型实验等方法系统阐明该多态通过调控MIR155HG/miR-155及其下游通路，参与SCD发生的具体分子机制，为SCD法医学诊断及高危人群的筛查提供理论依。

心源性猝死（SCD）是指由心脏原因引起的突发性非预料死亡。因其具有发病出人意料和死亡急骤等特点，一直是法医学面临的重大课题。以往大量研究表明，SCD具有明显遗传倾向，遗传因素是SCD发生的重要决定因素之一。本研究利用多中心大样本分析、机制研究及功能表型实验等方法筛查了数个与SCD患病风险显著相关的遗传多态，并对其参与调控SCD发生的具体分子机制进行了初步探讨。具体如下：（1）发现位于miR-155宿主基因（MIR155HG）中一个四碱基插入缺失多态（rs72014506）与SCD易感性显著相关。rs72014506缺失型等位基因通过与转录因子POU2F1结合发挥抑制转录作用，调控MIR155HG及mir-155成熟体的表达，进而参与到SCD的发生；（2）发现位于COX10基因3’UTR的遗传多态rs397763766与SCD易感性显著相关。rs397763766多态可能通过影响COX10 mRNA与hsa-miR-15b的结合而调控COX10基因表达，进而参与SCD的发生；（3）发现位于HSPA1B基因3’UTR的遗传多态rs3036297与SCD易感性显著相关。rs3036297多态可能一方面通过影响HSPA1B mRNA与hsa-miR-134-5p的结合调控HSPA1B基因表达；另一方面作为顺式调控元件通过与HLA-DRB5基因启动子区域发生交互，远距离调控该基因的表达，进而共同参与SCD的发生；（4）位于STAT5A基因3’UTR的遗传多态rs3833144与SCD易感性显著相关。该多态可通过改变局部3D构象影响STAT5A表达，同时可作为顺式调控元件通过与RARA、PTGES3L-AARSD1基因启动子区域发生交互，远距离调控该基因的表达，进而共同参与SCD的发生。上述研究发现的阳性遗传多态为SCD法医学诊断及高危人群的筛查提供了候选遗传标记，为最终阐明SCD发生的分子遗传学基础提供了理论依据。