中国组织工程研究

中国组织工程研究 ›› 2020, Vol. 24 ›› Issue (32): 5128-5132.doi: 10.3969/j.issn.2095-4344.2860

• 脊柱组织构建 spinal tissue construction • 上一篇    下一篇

椎间盘退行性变与HTRA1和HAPLN1基因多态性的相关性

杨金丰，马三辉   

  1. 定州市人民医院骨科，河北省定州市  073000
  • 收稿日期:2019-09-10 修回日期:2019-09-12 接受日期:2019-12-05 出版日期:2020-11-18 发布日期:2020-09-24
  • 作者简介:杨金丰，男，1981年生，河北省定州市人，汉族，主治医师，主要从事骨科方面的研究。
  • 基金资助:
    河北省卫生厅科研基金项目(20181772)

Association of HTRA1 and HAPLN1 gene polymorphism with intervertebral disc degeneration

Yang Jinfeng, Ma Sanhui   

  1. Department of Orthopedics, People’s Hospital of Dingzhou, Dingzhou 073000, Hebei Province, China
  • Received:2019-09-10 Revised:2019-09-12 Accepted:2019-12-05 Online:2020-11-18 Published:2020-09-24
  • About author:Yang Jinfeng, Attending physician, Department of Orthopedics, People’s Hospital of Dingzhou, Dingzhou 073000, Hebei Province, China
  • Supported by:

    the Scientific Research Foundation of Hebei Provincial Health Department, No. 20181772

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摘要：

文题释义：

HTRA1：在Duchenne型肌营养不良骨骼肌及骨关节炎和和类风湿性关节炎软骨中HTRA1表达上调， HTRA1的上调可能有助于此类疾病的进展。对HTRA1单核苷酸多态性基因型的等位基因频率与高椎间隙狭窄评分之间的关联性进行分析，HTRA1基因启动子区域的单核苷酸多态性基因型与椎间盘退变相关，在携带G等位基因组(GG+GA)和未携带组(AA)的患者中均观察到椎间隙狭窄程度显著增加，因此HTRA1可能在椎间盘病理学中起作用。  

HAPLN1：是软骨细胞外基质的关键组分，通过透明质酸链结合蛋白多糖，从而稳定蛋白多糖与透明质酸的聚合体，有助于关节的抗压和减震。试验中HAPLN1基因仅在rs179851单核苷酸多态性受试者中观察到骨赘形成和椎间隙狭窄的显著组间差异，而其余3个单核苷酸多态性(5’侧翼 rs975563、内含子1 rs10942332和内含子4 rs4703570)则未见。因此，HAPLN1可能是软骨稳态的重要调节因子，并有助于椎间盘退变引起的骨关节炎发病机制。

背景：研究发现，HTRA1基因启动子区域的单核苷酸多态性基因型与椎间盘退变相关，而HAPLN1基因与椎间盘退变引起的骨关节炎相关。

目的：探讨分泌型丝氨酸蛋白酶HTRA1和骨细胞外基质的关键组分HAPLN1变异在椎间盘退变发病机制中的作用。

方法：选择2015年4月至2018年12月在定州市人民医院接受体检的498名绝经后女性受试者，利用TaqMan PCR方法检测受试者HTRA1基因启动子rs11200638单核苷酸多态性和HAPLN1基因5’侧翼rs975563、内含子1 rs10942332、内含子2 rs179851和内含子4 rs4703570的单核苷酸多态性，分析HTRA1和HAPLN1基因多态性与椎间盘退变影像学特征之间的相关性。试验已通过定州市人民医院伦理道德委员会批准。

结果与结论：①在498名受试者HTRA1基因rs11200638单核苷酸多态性中，178名为GG纯合子，222名为GA杂合子，98名为AA纯合子，将具有至少一个G等位基因(GG+GA，n=400)和没有G等位基因(AA，n=98)受试者间的椎间盘退变参数进行比较；②在HTRA1基因rs11200638单核苷酸多态性中，GG+GA等位基因组的椎间隙狭窄评分低于AA等位基因组(P < 0.001)；随着椎间隙狭窄评分的升高，受试者中AA等位基因型发生风险增高(P ≤ 0.001)；③在498名受试者HAPLN1基因单核苷酸多态性中，137名为TT纯合子，230名为CT杂合子，131名为CC纯合子，将CC+TT等位基因(n=361)、TT等位基因(n=137)的椎间盘退变参数进行比较；④在HAPLN1基因中，仅rs179851单核苷酸多态性的CC+TT等位基因组与TT等位基因组骨赘形成、椎间隙狭窄存在显著差异(P < 0.01)；⑤在HAPLN1基因rs179851单核苷酸多态性中，椎间隙狭窄≥6分受试者的TT等位基因型发生风险显著增高(P < 0.05)；随着骨赘形成评分的升高，受试者TT等位基因TT等位基因型发生风险显著增高(P < 0.001)；⑥结果表明，HTRA1和HAPLN1特定基因位点的遗传变异与椎间盘退变相关。

ORCID: 0000-0002-4567-2930(杨金丰)

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 单核苷酸多态性, HTRA1基因, HAPLN1基因, 椎间盘退变, 遗传变异, 等位基因, 骨赘形成, 椎间隙狭窄

Abstract:

BACKGROUND: Studies have found that single nucleotide polymorphism genotypes in the HTRA1 gene promoter region are associated with intervertebral disc degeneration, while HAPLN1 is associated with osteoarthritis caused by intervertebral disc degeneration.

OBJECTIVE: To explore the role of human secretory serine protease HTRA1 and the key group of extracellular matrix HAPLN1 in the pathogenesis of intervertebral disc degeneration.

METHODS: This study included 498 postmenopausal female subjects who underwent a physical examination at Dingzhou People’s Hospital from April 2015 to December 2018. TaqMan PCR was used to detect HTRA1 gene promoter rs11200638 single nucleotide polymorphism and HAPLN1 gene 5' flanking rs975563, intron 1 rs10942332, intron 2 rs179851 and intron 4 rs4703570 single nucleotide polymorphism in 498 postmenopausal Chinese women. The correlation between the HTRA1orHAPLN1 gene polymorphisms and the radiographic features of spinal disc degeneration was analyzed. The trial has been approved by the Ethics Committee of Dingzhou People’s Hospital.

RESULTS AND CONCLUSION: Among the 498 subjects with the HTRA1 gene rs11200638 single nucleotide polymorphism, 178 were GG homozygotes, 222 were GA heterozygotes, and 98 were AA homozygotes. We compared the parameters of intervertebral disc degeneration in subjects with at least one G allele (GG+GA, n=400) and without G allele (AA, n=98). In HTRA1 gene rs11200638 single nucleotide polymorphism, the score on intervertebral space stenosis in the subjects with GG+GA allele genome was lower than that in the subjects with AA allele (P < 0.001). With the increase of the score on intervertebral space stenosis, the proportion of the subjects with AA alleles increased (P ≤ 0.001). Among the 498 subjects with single nucleotide polymorphisms of the HAPLN1 gene, 137 were homozygous for TT, 230 were heterozygous for CT, and 131 were homozygous for CC. Intervertebral disc degeneration parameters of CC+TT allele (n=361) and TT allele (n=137) were compared. In the HAPLN1 gene, there was a significant difference between the CC+TT and TT alleles of the rs179851 single nucleotide polymorphism in osteophyte formation and intervertebral space stenosis (P < 0.01). Among the HAPLN1 gene rs179851 single nucleotide polymorphisms, the proportion of subjects with TT alleles and intervertebral space stenosis ≥ 6 points increased (P < 0.05). With an increase in osteophyte formation score, the proportion of subjects with TT allele increased (P < 0.001). These results reveal that HTRA1 and HAPLN1 genetic variations at specific genetic loci are associated with intervertebral disc degeneration.

Key words: ">single nucleotide polymorphism, high temperature requirement serine protease A1 (HTRA1), hyaluronan and proteoglycan link protein 1 (HAPLN1), intervertebral disc degeneration, genetic variation, allele, osteophyte formation, intervertebral space stenosis

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