Aggrecan和Aggrecanase的基因多态性对腰椎间盘突出症易感性的影响及其机制研究

Symptomatic Lumbar disc Herniation (LDH) is a familiar orthopaedics disease, and its incidence increased year by year. The majority of patients with symptomatic lumbar disc herniation (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. Aggrecanases and aggrecanase-generated aggrecan fragments have been found in human degenerated discs. However, the mechanism of the association between the gene polymorphism of aggrecan and aggrecanase(ADAMTS-4, ADAMTS-5) with susceptibility of symptomatic lumbar disc herniation 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 and ADAMTS4/5 gene polymorphism in a Large sample, through the determination of ADAMTS4/5 enzyme activity, the content of aggrecan, chondroitin sulfate (CS), ADAMTS4/5 and the profile of aggrecan fragmentation in the samples with the same repeats of Aggrecan gene VNTR, to ascertain the mechanism of the association between the gene polymorphism of aggrecan and aggrecanase(ADAMTS-4, ADAMTS-5) with susceptibility of symptomatic lumbar disc herniation.

腰椎间盘突出症（LDH）是骨科常见病之一，发病率逐年增高。基因多态性的研究是继人类基因组计划之后又一国际研究新热点。有报道称：在人类退行性变间盘组织发现了大量的Aggrecanase和Aggrecan酶解碎片。然而关于Aggrecan和Aggrecanase的基因多态性与腰椎间盘突出症易感性之间的相互关系还没有被很好的研究。因此本课题的开展具有十分重要的意义。本课题通过相对较大样本进一步筛查、检测、验证病例组和对照组中Aggrecan和ADAMTS4/5基因多态性；通过进一步测定相同Aggrecan基因串联重复序列样本中，ADAMTS4/5的酶活性、Aggrecan大分子和裂解片段含量、硫酸软骨素含量、ADAMTS4/5在间盘组织中的表达量，来研究Aggrecan和Aggrecanase的基因多态性对腰椎间盘突出症易感性的影响及其机制，对临床腰椎间盘突出症的防治开拓了有价值的新思路。

腰椎间盘突出症（LDH）是骨科常见病之一，发病率逐年增高。基因多态性的研究是继人类基因组计划之后又一国际研究新热点。有报道称：在人类退行性变间盘组织发现了大量的聚集蛋白聚糖酶（Aggrecanase）和聚集蛋白聚糖（Aggrecan）酶解碎片。然而关于Aggrecan基因多态性与腰椎间盘突出症易感性之间的相互关系还没有被很好的研究。本研究发现：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 基因串联重复多态性（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；Aggrecanase与Aggrecan VNTR在LDH发病过程中不存在直接交互作用；与既没有一个或两个小于等于Allele 25等位基因危险因素也没有肥胖危险因素的个体相比，仅有一个或两个小于等于Allele 25等位基因危险因素而没有肥胖危险因素的个体的LDH发病率为1.057倍（P=0.895；95% CI：0.463-2.412）；仅有肥胖危险因素而没有一个或两个小于等于Allele 25等位基因危险因素的个体的LDH发病率为1.061倍（P=0.885；95% CI：0.475-2.368）；既有一个或两个小于等于Allele 25等位基因危险因素也有肥胖危险因素的个体的LDH发病率为4.667倍（P=0.0003；95% CI：2.135-10.201）。本项目系统地阐明了：Aggrecan VNTR和Aggrecanase分别影响Aggrecan含量，进一步导致LDH发病，但二者之间无直接交互作用； Aggrecan VNTR与肥胖之间存在交互作用影响LDH的发病，但具体机制尚不明确。本项目有助于深入分析Aggrecan VNTR对Aggrecan结构及功能的影响，对LDH的早期筛查及精准诊断具有重要意义。