增殖期糖尿病视网膜病变16q24.3致病位点定位及功能研究

Proliferative diabetic retinopathy (PDR), which is one of the leading causes of blindness, is a complex disease of genetic and environmental factors. While the clinical characters of PDR are complex. Research of contribution of gene-gene interaction to PDR genetic is less. Currently known PDR susceptible loci are limited. So it is imperative to position the causal variants of PDR through extreme clinical phenotype and functional analysis. Previously, we found five PDR susceptibility loci by exome sequencing in "extreme samples" of PDR and controls. Among them, two loci (rs1800337 rs7195906) are located in the region of chromosome 16q24.3, and suggesting that some casual variants may exist in the region. Based on this, we plan to explore the fine mapping in the region of 16q24.3, combined with large sample validation population, bioinformatics analysis and cell biology. Moreover, we will elucidate the exact genetic mechanism and explore the prediction effect of causal loci. This study will supply theoretical basis for the prediction and personalized therapy of PDR.

增殖期糖尿病视网膜病变（PDR）是遗传和环境因素共同作用的复杂疾病，是致盲的主要原因之一。但PDR临床表型复杂，研究样本混杂程度高，且基因间交互作用对PDR遗传度贡献的研究较少，故已发现PDR易感位点有限，且缺乏功能解析。本研究拟通过“极端”临床表型，定位PDR致病位点并进行功能解析。课题组前期通过极端PDR病例-对照样本进行外显子组测序发现5个PDR易感位点，其中两个位点均位于染色体16q24.3区域，分别为rs7195906及rs1800337，提示该区域可能存在多个致病位点。在此基础上，本课题拟通过极端病例-对照样本对16q24.3区域精细作图、结合大样本病例-对照人群验证、生物信息学分析，明确该区域致病位点；通过细胞生物学功能研究，明确致病基因突变导致PDR发生的信号通路与机制；通过队列研究，明确致病位点在PDR易感人群筛查和预警中的作用。本课题将为PDR早期基因诊断提供理论依据。

将信号通路分析与候选基因法结合，利用目标序列捕获测序，将有助于加深对糖尿病视网膜病变遗传结构的理解。基于本研究团队前期工作及最新研究进展，在“极端”样本中对染色体16q24.3区域进行精细作图，筛选出位于基因ZNF276与基因FANCA之间的潜在致病多态位点，rs17227064、rs1800337，rs11644967，rs7195906, 其中rs1800337（P=2.97*10-7）具有最大统计效力，随后对上述位点进行验证，发现rs1800337增加PDR发病风险7%，rs17227064位点可增加PDR发病风险9%；Fanconi信号通路与PDR关联具有统计学意义；上述两位点危险等位基因的组合对PDR发生风险预测的曲线下面积为0.68，本文将为PDR基因诊断提供一定的理论依据。