伴随常染色体显性遗传多囊肾病的颅内动脉瘤发病特点及遗传因素分析

The pathogenesis of intracranial aneurysm (ICA) is still unclear, but several studies demonstrated that genetic factor is an important risk factor. The high incidence of ICA in patients with ADPKD has long been recognized. Subarachnoid haemorrhage (SAH) from a ruptured aneurysm is a frequent complication in patients with ADPKD and makes up a considerable proportion of the causes of death in this group of patients. However, the characteristics of ICA in patients with ADPKD is unclear, most information is derived from case reports and small studies, and many reported results were contradictive. Therefore, it is necessary to assess the characteristics which are based on large sample study. We have performed a largest sample study about it in the world which use the head 3T three-dimensional time of flight magnetic resonance angiography (3D TOF-MRA ) to screen for ICA in patients with ADPKD, so that its prevalence and characteristics feature are investigated. .It is known that almost all ADPKD are originated from mutations in PKD1 and PKD2, but the role is not clear that PKD1 and PKD2 play in the development of ICA. We intend to screen for mutations in PKD1 and PKD2 gene from ADPKD patients with ICA by means of high resolution melting curve analysis (HRM or HRMA) so that to get some hint for the pathogenesis of ADPKD complicated with ICA. This also will provide the basis for the development of gene diagnosis method, risk prediction, treatment strategy and prognosis assessment, even more, for the invention of new treatment methods. Apart from these, by analyzing the prevalence of ICA in the first-degree relatives of ADPKD with ICA patients, we want to investigate if there are other genetic factors involved in the pathogenesis. If other genes are involved, they could be found by linkage analysis with genome-wide scanning in the future.

颅内动脉瘤(ICA)的发生机制还不清楚，但是多项研究证明遗传因素是一个重要因素。常染色体显性遗传多囊肾病（ADPKD）的致病基因是PKD1和PKD2。ADPKD患者易伴发ICA，但是其特点还不清楚。本研究将在既往工作的基础上进一步深入研究，我们拟采用3T场强 三维时间飞跃法磁共振血管成像(3D TOF-MRA)继续筛查ADPKD患者的ICA，扩大样本量，研究其发病特点。通过高分辨率溶解曲线法筛查ADPKD伴发ICA患者PKD1和PKD2基因所发生的突变，分析突变特点及其与ICA发病的关系，探讨ADPKD并发ICA的分子机理，为ADPKD并发ICA的基因诊断、风险预测和预后评估提供依据。研究ADPKD并发ICA患者一级亲属和二级亲属中的ICA发病规律及特点，探讨除PKD1和PKD2基因外，是否有其它遗传因素参与ADPKD并发ICA的发病机制，为进一步用全基因组扫描寻找这些基因打下基础。

颅内动脉瘤（ICA）的发生机制还不清楚，但是多项研究证明遗传因素是一个重要因素。常染色体显性遗传多囊肾病(ADPKD)患者易伴发颅内动脉瘤，但是其发病率，影响因素等仍在探索中。我们用头颅3T 三维时间飞跃法磁共振血管成像(3D TOF-MRA)法在常染色体显性遗传多囊肾病患者筛查颅内动脉瘤，研究了其发病率和影响因素。PKD1和PKD2基因是导致ADPKD的两个基因，我们希望通过查找分析PKD1和PKD2基因中所发生的突变，分析颅内动脉瘤的形成机制。在355例ADPKD患者中发现了54例伴发颅内动脉瘤。ICAN在ADPKD患病率为12.4% (95%可信区间：8.95%-15.82%)。通过高分辨率溶解曲线法和直接测序法筛查ADPKD伴发ICA患者PKD1基因的部分区域所发生的突变，在32个病例中发现了22个突变，包括同义突变，无义突变和可疑致病突变。通过课ADPKD突变数据库中数据进行对比，确定突变的性质。这些突变和ADPKD及ICA的发病关系需要进一步分析总结。PKD1基因存在高度同源基因，使得其基因区域的特异扩增较困难。这些区域的突变筛查可能需要优化反应条件或者重新设计引物来进行。未发现PKD1基因突变的病例，推测突变将发生在PKD2基因中。需要进一步的研究来筛查。