1,25-二羟维生素D3及其受体基因多态性在新疆维吾尔族糖尿病视网膜病变患者发病中作用及机制的研究

Diabetic retinopathy (DR) is one of the most common and severe microvascular complications of diabetes and is a leading cause of blindness in people of the working age all over the world. Type 2 diabetic patients may already have background retinopathy at the time of diagnosis, and over 60% will development some form of retinopathy after 20 years. According to the International Diabetes Federation, diabetes currently affects nearly 285 million people worldwide, and this number is expected to reach 438 million by 2030.It is expected that DR will have a growing impact on large populationa. Multiple mechanisms are involved in DR, Hyperglycemia is admitted to be the main risk factor in the development of DR. But the clear and detailed pathogenesis of DR is not elucidated. There is increasing evidence that an ongoing cytokine-induced acute-phase response (sometimes called low-grade inflammation, but part of a widespread activation of the innate immune system) is closely involved in the pathogenesis of type 2 diabetes and associated complications such as DR .1,25(OH)2D3, the biologically active metabolite of Vitamin D3, has recently been shown to have immunomodulation property. Recent studies showed that 1,25(OH)2D3 was able to skew the T cell compartment into a more anti-inflammatory and regulated state, as evidenced by inhibition of Th1 and Th17 cells and promotion of Th2 and T reg cells. In Vitro experiments showed that 1,25(OH)2D3 could promote both innate and adaptive immune responses. Studies revealed that the development of DR depend on not only duration of diabetes and level of blood glucose but also positive family history and individual diversities. This phenomenon may be related to various genetic polymorphisms and individuals. DR is a disease of the role of multi-gene, and therefore there is different polymorphisms in each gene. It is very important for us to accurately understand the mechanism of the difference expression of gene during the occurrence and development of DR in the early diagnosis and prevention of DR. Whether 1,25(OH)2D3 and VDR polymorphisms is involved in the pathogenesis in DR in Uyghur population has not been determined. This study is, therefore, designed to investigate the alteration and the possible function of 1,25(OH)2D3 and VDR in Uyghur DR population.

糖尿病视网膜病变（DR）是糖尿病最常见和最严重的微血管并发症, 也是最常见的致盲性眼病之一。DR发病原因复杂，越来越多的研究表明DR的发病与免疫和低度炎性反应有关。活性维生素D （1,25(OH)2D3）具有免疫调节的作用， 可通过细胞表面的受体 （VDR）对免疫细胞发挥复杂的调控作用，如抑制T细胞增殖，抑制炎症因子的表达，从而减轻或抑制免疫或炎症反应的发生。本项目以DR为研究对象，以1,25(OH)2D3及VDR为切入点，探讨患者血清中1,25(OH)2D3表达水平的差异；探讨1,25(OH)2D3对DR患者单个核细胞和CD4+T细胞增殖及细胞因子分泌的影响， 阐明1,25(OH)2D3在DR发病过程中的免疫调节作用；探讨VDR基因多态性与DR的相关性，从基因易感性层面揭示其作用。本研究将可能回答免疫反应在DR发病过程中是否起作用及可能的作用机制，可能为DR的防治提供新的靶点和切入点。

糖尿病视网膜病变（DR）是糖尿病最常见和最严重的微血管并发症，也是导致工作人群失明的首要原因。新疆是中国的一个多民族聚居的地区，维吾尔族是其主要的民族，高脂高盐的饮食习惯导致维吾尔族成为DM的高发人群。DR发病与多种机制作用相关，高血糖和DM 病程是DR 的主要危险因素，但是DR明确的发病机制尚不清楚。越来越多的研究表明DR 的发病与免疫和低度炎性反应有关，炎症因子和炎症介质的过度分泌以及微血管中白细胞大量渗出直接损伤视网膜微血管，诱导新生血管的形成。1,25(OH)2D3 是维生素D的活性形式，最近的研究发现1,25(OH)2D3 具有免疫调节的作用。1,25(OH)2D3 可通过细胞表面的受体（VDR）对免疫细胞发挥抗免疫炎症反应的作用，如抑制T细胞增殖，抑制炎症因子的表达，从而减轻或抑制免疫或炎症反应的发生。研究显示，DR 的发展不仅与糖尿病的血糖水平和糖尿病病程有关，而且还与于家族病史和个体差异性有关，这种现象可能与多种基因多态性和个体差异有关。DR是一种多基因的作用的疾病，因此准确了解在DR发病过程中基因表达的差异对早期预防和诊断DR 有重要意义。本以DR为研究对象，以1,25(OH)2D3 及VDR为切入点，证实了DR的发展与细胞因子的变化有关。在新疆维、汉族DR患者血清中低水平IFN-γ是DR患者视网膜病变的危险因素，血清中1,25(OH)2D3 浓度与DR的严重程度呈负相关，提示临床医生可以早期检测1,25(OH)2D3 含量。同时研究证实了1,25(OH)2D3作为一种免疫调节剂，可以抑制PBMCs细胞的增殖，并显著抑制PBMCs合成和分泌的IL-17A、IFN-γ及IL-6等细胞因子，为探究1,25(OH)2D3 在DR发病机制中的作用提供了体外研究的证据。此外，研究提示rs1544410的CC基因型和C等位基因、rs731236位点的AA基因型和A等位基因可能是新疆维吾尔DR 患者的易感因素；rs7975232位点的AA 基因型和A 等位基因可能是新疆维吾尔族DR患者的保护因素。