Ge Yanzhi, Zhou Chenfen, Xiao Xiujuan, Jin Zhijiang, Zhou Li, Chen Zuxiang, Liu Fucun, Yuan Qiang, Zhang Guoqing, Shan Letian, Tong Peijian
The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China.
National Genomics Data Center, CAS Key Laboratory of Computational Biology, Bio-Med Big Data Center, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Front Genet. 2021 Nov 11;12:784176. doi: 10.3389/fgene.2021.784176. eCollection 2021.
To investigate the correlation between gene mutation and knee osteoarthritis (KOA), a whole-exome sequencing (WES) was applied to analyze blood samples of four KOA patients and two normal subjects in a family. Gene mutations were identified by gene-trapping and high-throughput sequencing analysis across the differences between the patients and normal subjects. The interactive gene network analysis on the retrieval of interacting genes (STRING) database and the KOA-related genes expression data sets was performed. A possibly detrimental and nonsynonymous mutation at the kallikrein-related peptidase 6 (KLK6) gene (rs201586262, c. C80A, P27H) was identified and attracted our attention. KLK6 belongs to the kallikrein family of serine proteases and its serum level is known as a prevalent biomarker in inflammatory and malignant diseases. KLK6 expresses in the extracellular compartment for matrix degradation, highlighting that KLK6 plays a role in the pathogenesis of KOA. By using the gene databases, the KOA-related genes were mined after de-duplication and IL6 was selected as the most relevant gene through interactive analysis of protein-protein interaction (PPI) network. The data suggested that KLK6 gene mutation and the related expression alteration of IL6 gene might determine the occurrence of hereditary KOA. The is the first study discovering the gene mutation of KLK6 as a factor of pathogenesis of KOA, especially the hereditary KOA.
为了研究基因突变与膝关节骨关节炎（KOA）之间的相关性，应用全外显子组测序（WES）分析了一个家族中4例KOA患者和2名正常对照者的血液样本。通过基因捕获和高通量测序分析患者与正常对照者之间的差异来鉴定基因突变。对检索到的相互作用基因（STRING）数据库和KOA相关基因表达数据集进行了交互式基因网络分析。在激肽释放酶相关肽酶6（KLK6）基因上鉴定出一个可能有害的非同义突变（rs201586262，c.C80A，P27H），这引起了我们的注意。KLK6属于丝氨酸蛋白酶的激肽释放酶家族，其血清水平是炎症和恶性疾病中一种常见的生物标志物。KLK6在细胞外区域表达以降解基质，这突出表明KLK6在KOA发病机制中起作用。通过使用基因数据库，对KOA相关基因进行去重挖掘，并通过蛋白质-蛋白质相互作用（PPI）网络的交互式分析选择IL6作为最相关的基因。数据表明，KLK6基因突变和IL6基因的相关表达改变可能决定遗传性KOA的发生。这是首次发现KLK6基因突变是KOA发病机制的一个因素，尤其是遗传性KOA。
