青少年2型糖尿病者视网膜病变的人群及分子流行病学研究

Nowadays, the type 2 diabetes mellitus (T2DM) patients in youth with diabetic retinopathy (DR) are expanding rapidly due to living habits change and increasing obesity. The key strategy for prevention and control of DR is screening and treatment in early-stage among patients with high risks. However, in our previous population-based study, we found the high risk factors of DR in adults cannot be applied to youth, and we are still unsure about the related factors of DR incidence in T2DM in youth. Persistent oxidative stress is believed to be the main cause of DR occurrence and progression in young T2DM patients with proper low blood glucose level. In our previous study, peroxisome proliferator-activated receptors (PPARs) were found to be involved in oxidative stress of DR. What’s more, in previous studies, since PPARs gene polymorphisms were found relevant to T2DM in youth and DR in the adults, based on our previous small scale study in genes, we infer that gene polymorphisms also correlate with DR in T2DM in youth. However, up till now, there was neither population-based epidemiology report nor association study of specific gene polymorphisms on DR in young T2DM patients. In the present study, we plan to conduct a 4-year perspective cohort observation of 1977 Chinese young T2DM residents. Through the study, we try to find out related physical and biochemical risk factors of DR, and the specific PPARs gene polymorphism relevant to DR. The results of study will facilitate discrimination of DR high risk groups in young T2DM patients, and provide important theoretical basis for DR blocking agents which target on gene polymorphism. The present grant application is in line with the guideline of National Science Foundation of China (NSFC) which now supports cohort epidemiology study on eye diseases.

在日益肥胖化的青少年人群中，2型糖尿病(T2DM)及并发糖尿病视网膜病变(DR)的患者正迅速增加。DR防盲的关键是发现高危人群并早期干预，但我们前期研究证实，成人DR防盲方案并不适用于青少年，该人群DR高危因素仍属未知。持续的氧化应激是青少年T2DM者在血糖下降后DR仍高发的主要机制。我们前期研究已证实PPARs直接参与了DR眼氧化应激，另由于PPARs基因多态性与青少年患T2DM、成人DR发病均相关，综合我们前期小规模基因研究结果，推测青少年T2DM者DR发病的个体差异也与PPARs基因多态性相关，但尚无研究证实。鉴于国家自然科学基金现支持眼科流行病学队列研究，本研究拟对已建档的1977名青少年T2DM者进行连续4年的前瞻性队列研究，得到DR发病相关的个体特征、生化等预测指标和PPARs基因型，从而为实现该人群中DR高危者早期发现和干预，以及以特定基因型为靶点的DR早期阻断提供理论依据。

在日益肥胖化的青少年人群中，糖尿病（DM）及并发糖尿病视网膜病变(DR)的患者正迅速增加。DR防盲的关键是发现高危人群并早期干预，但我们前期研究证实，成人DR防盲方案并不适用于青少年，该人群DR高危因素仍属未知。持续的氧化应激是青少年DM者在血糖下降后DR仍高发的主要机制。我们前期研究已证实PPARs直接参与了DR眼氧化应激，另由于PPARs基因多态性与青少年患DM、成人DR发病均相关，综合我们前期小规模基因研究结果，推测青少年DM者DR发病的个体差异也与PPARs基因多态性相关，但尚无研究证实。本项目在纳入研究的青少年糖尿病人群中发现，4年后DR人群的年发病率为16.39%（年平均发病率为5.46%），高血糖化血红蛋白值、高血肌酐值是DR发病的影响因素。在分子流行病学学研究部分，发现研究组和对照组之间，PPARα和PPARγrs3856806、rs1801282、rs709158和rs10865710的等位基因频率无显著差异。进一步甲基化分析发现，相对于正常组，视网膜异常组以低甲基化为主，视网膜异常的相关通路包括Notch信号通路、AMPK信号通路、Oxytocin信号通路、cGMP-PKG信号通路、Calcium信号通路、Axion guidance、insulin secretion、endocytosis，chemokine信号通路、protein processing in endoplasmic reticulum、ubiquitin mediated proteolysis、神经递质的吸收和转运，氨基酸的转运等。本项目是国内首个关于青少年人群糖尿病者中DR发病率和基因型相关性的研究。随着生活习惯改变和日益肥胖化，我国青少年人群中糖尿病患者数量正迅速上升，DR是高发的，且将危害他们一生健康的严重眼部并发症。本研究探查了上海社区青少年糖尿病人群中DR的发病率和相关因素，明确了严格控制血糖，血肌酐、血胆固醇等对于青少年儿童DR防控的重要意义，探讨了PPARα和PPARγ基因多态性，以及j基因甲基化与青少年儿童DR发病的相关性，为筛查高危人群提供了理论依据。因此，具有良好的科学价值。本项目研究成果在IOVS等期刊发表论文12篇，获得科技奖励4项。培养已毕业研究生7名。