高度近视并发性白内障发病与预后精准医学基因预测模型的构建研究

High myopic cataract (HMC) is a blinding type of cataract featuring early onset, great operative difficulty, various complicating vitreoretinopathy and many postsurgical complications. Due to the complexity of pathogenesis of HMC, it is difficult to precisely assess its onset, predict the prognosis and implement corresponding risk prevention and control measures. Precision medicine is a medical model emphasizing the application of genetic technology to realize the precise treatment of a specific disease, which provides new ideas for the difficult problems of the prevention and optimal treatment of HMC. Previously, we have conducted exome sequencing in a small sampling of HMC and studies of HMC characteristics, on the basis of which, we preliminarily select genes related to its pathogenesis (CRYAA/GSTP1/TXNRD2), genes related to its vitreoretinopathy (MCP1/VEGFA/CFH), and genes related to its postoperative complications (TGFB2/CERS2). In this project, we plan to further consummate the clinical database of HMC, thoroughly analyze the polymorphism of all these HMC characteristics-related genes, select their functional sites and verify their effects on gene expression and function. Then the correlation analysis of genetic findings and clinical phenotypes will proceed, aiming at the ultimate establishment of genetic prediction model of HMC pathogenesis and prognosis in the light of precision medicine to ground the future precise prevention and treatment of HMC.

高度近视并发性白内障（HMC）是高致盲风险的白内障类型，具有发病早、手术难度大、合并眼底病变多、术后并发症常见等特点。由于其发病机制复杂，目前很难精确地判断其发病和预后并进行风险防控。精准医学强调通过遗传学等技术，对疾病实现精准诊疗，为解决HMC防治难题提供了新思路。项目组前期对HMC进行了小样本全外显子组测序，并结合其疾病特征研究，初步筛选了：HMC发病相关基因（CRYAA/GSTP1/TXNRD2）、其眼底病变相关基因（MCP1/VEGFA/CFH）及其术后并发症相关基因（TGFB2/CERS2）。本项目拟进一步完善HMC临床资料库，全面检测这些HMC疾病特征相关基因的多态性位点，筛选功能性位点并验证其对基因表达和功能的影响，结合临床表型关联分析其与HMC疾病特征的关系，最终建立HMC发病与预后的精准医学基因预测模型，为HMC的精准防治打下基础。

高度近视并发性白内障（HMC）是高致盲风险的复杂白内障，与年龄相关性白内障相比，具有发病早、手术难度大、合并眼底病变多、术后并发症常见等特点。由于其发病机制复杂，目前很难精确地判断其发病和预后并进行风险防控。精准医学强调通过遗传学等技术，对疾病实现精准诊疗，为解决HMC防治难题提供了新思路。在本研究中，我们通过基因Panel检测和全基因组测序的结果对目的基因进行初步筛选及验证，并通过神经网络构建HMC发病和预后的精准医学基因预测模型。首先，我们在Panel检测中发现存在4个罕见突变位点(CHRNG, TLR2, B3GLCT和CC2D2A)与高度近视并发性白内障患者的白内障严重程度、白内障术后眼压升高、术后最佳矫正视力相关并验证，同时通过神经网络初步实现多态性位点对于高度近视并发性白内障患者术后视力进行预测。其次，我们通过全基因组测序结果进行全基因组关联分析筛选出显著调控高度近视并发性白内障临床表型的多态性位点，并通过相关基因的GO功能富集和KEGG通路富集探索相关临床表型的病理机制：在HMC发病特征方面，我们发现蛋白降解通路在早发白内障患者中显著富集；炎症相关通路则在黑核性白内障中富集；在HMC眼轴延长特征方面，我们发现信号传导和细胞黏附功能发挥了重要作用，而催产素信号通路、生物节律相关通路也与眼轴的延长显著相关；针对HMC患者手术前后均易存在高眼压的现象，我们也发现肌动蛋白纤维等功能以及诸多经典的信号通路可能参与到该过程中。此外，根据我们的遗传学分析，HMC患者较高比例的眼底病变除了与眼轴延长这一临床表型有关外，还可能存在其他的发病机制。通过对高度近视并发性白内障患者临床表型的遗传学分析，并在此基础上建立高度近视并发性白内障发病和预后的精准医学基因预测模型，能够辅助判断其发病和预后并进行风险防控，从而实现高度近视白内障的精准防治。