Aggrecan VNTR与瘦素/脂联素等肥胖因子交互作用对腰椎间盘突出症易感性影响及其机制研究

Symptomatic lumbar disc herniation (LDH) is a familiar orthopaedics disease, and its incidence increased year by year. The majority of patients with Symptomatic LDH presented with leg and back pain. Despite numerous studies of its etiology and pathogenesis, it is not clear why susceptivity of symptomatic LDH is low in some individuals while high in others. Gene polymorphism has become the new research subject in the orthopaedics field of the world. There have been reported that Aggrecan Variable number of tandem repeats polymorphism (VNTR) and obesity correlated with lumbar disc herniation respectively. We found the interaction between aggrecan gene VNTR polymorphism and obesity in predicting incident symptomatic lumbar disc herniation. However, the mechanism of the interaction between the aggrecan VNTR and obesity with susceptibility of symptomatic lumbar intervertebral disc degeneration disease has not been well studied. Therefore, the development of this study has the very vital significance. This study aims to screen, detect and verify the distribution of aggrecan gene polymorphism in a Large sample, through the determination of the content of aggrecan，chondroitin sulfate (CS), the profile of aggrecan fragmentation, aggrecanase, MMPs, leptin, adiponectin in the samples with the same repeats of Aggrecan gene VNTR, to ascertain the mechanism of the association between the aggrecan gene VNTR and obesity with susceptibility of symptomatic LDH.

腰椎间盘突出症(LDH)发病率高及年轻化趋势增加了世界医疗消耗，业已成为严重的社会问题。基因多态性的研究是目前国际研究热点，聚集蛋白聚糖(Aggrecan)是椎间盘基质中的重要成分。国外报道显示Aggrecan基因串联重复多态性(VNTR)与肥胖分别参与LDH的发病。我们的前期研究首次报道Aggrecan VNTR与肥胖存在交互作用，协同影响LDH发病，然而其具体机制尚不明确，前期研究成果发表于Spine、中华外科杂志等期刊。本课题旨在应用较大样本深入研究Aggrecan VNTR与瘦素/脂联素交互作用对LDH易感性的影响机制。本研究有望为认识和防治LDH提供新线索，并进一步建立LDH易感人群筛查识别系统，对该病的早期筛查及精准诊疗具有重要意义。

腰椎间盘突出症（LDH）是目前全球发病率及保健费用消耗较大的疾病之一。聚集蛋白聚糖(Aggrecan)作为基质中的重要成分，其含量减少将引起椎间盘退变。LDH的发生常常是由于髓核从发生退变而有缺陷的椎间盘中突出。近年来有研究发现：Aggrecan基因串联重复多态性 (Variable number of tandem repeats polymorphism, VNTR) 与肥胖分别参与LDH的发病。本项目针对Aggrecan VNTR与肥胖因素进行综合性研究，探索他们之间的交互作用影响LDH的发病机制。.本项目发现：Aggrecan含量与LDH有相关性；LDH患者中Aggrecan短串联重复序列片段出现频率较高，具有小于等于25次重复的等位基因与Aggrecan的低表达有很强的相关性；拥有较短的Aggrecan VNTR等位基因的个体的Aggrecan分子结构，将结合较低数目的CS链或具有特殊结构的G3区域，进一步促进Aggrecan的降解和损失；椎间盘基质降解酶（如ADAMTS家族和MMPs家族）含量在BMI较高的人群中高表达；与既没Aggrecan VNTR基因危险因素也没有肥胖危险因素的个体相比，既有Aggrecan VNTR基因危险因素也有肥胖危险因素的个体LDH发病率显著增高。.通过本项目我们得出结论：在肥胖人群中，髓核降解酶含量明显增加，蛋白多糖含量明显减少，肥胖因子可以增强髓核基质的降解作用。Aggrecan短串联重复序列片段与Aggrecan低表达相关，拥有较短的Aggrecan 基因串联重复多态性（VNTR）等位基因个体的Aggrecan分子结构，将结合较低数目的CS链或具有特殊结构的G3区域。Aggrecan VNTR与肥胖之间存在交互作用引起Aggrecan合成减少及降解增加，进一步影响LDH的发病。本项目有助于为临床LDH的发病机制研究提供新思路以及有价值的科学依据。