一项荟萃分析和一项功能研究支持 mtDNA 变体 m.16519C 对膝骨关节炎快速进展风险的影响。
A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritis.
机构信息
Grupo de Investigación en Reumatología (GIR), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), Instituto de Investigación Biomédica de A Coruña, A Coruna, Galicia, Spain.
Grupo de Avances en Telemedicina e Informática Sanitaria (ATIS), Plataforma de Bioinformática, Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), Instituto de Investigación Biomédica de A Coruña, A Coruna, Galicia, Spain.
出版信息
Ann Rheum Dis. 2023 Jul;82(7):974-984. doi: 10.1136/ard-2022-223570. Epub 2023 Apr 6.
OBJECTIVES
To identify mitochondrial DNA (mtDNA) genetic variants associated with the risk of rapid progression of knee osteoarthritis (OA) and to characterise their functional significance using a cellular model of transmitochondrial cybrids.
METHODS
Three prospective cohorts contributed participants. The osteoarthritis initiative (OAI) included 1095 subjects, the Cohort Hip and Cohort Knee included 373 and 326 came from the PROspective Cohort of Osteoarthritis from A Coruña. mtDNA variants were screened in an initial subset of 450 subjects from the OAI by in-depth sequencing of mtDNA. A meta-analysis of the three cohorts was performed. A model of cybrids was constructed to study the functional consequences of harbouring the risk mtDNA variant by assessing: mtDNA copy number, mitochondrial biosynthesis, mitochondrial fission and fusion, mitochondrial reactive oxygen species (ROS), oxidative stress, autophagy and a whole transcriptome analysis by RNA-sequencing.
RESULTS
mtDNA variant m.16519C is over-represented in rapid progressors (combined OR 1.546; 95% CI 1.163 to 2.054; p=0.0027). Cybrids with this variant show increased mtDNA copy number and decreased mitochondrial biosynthesis; they produce higher amounts of mitochondrial ROS, are less resistant to oxidative stress, show a lower expression of the mitochondrial fission-related gene fission mitochondrial 1 and an impairment of autophagic flux. In addition, its presence modulates the transcriptome of cybrids, especially in terms of inflammation, where interleukin 6 emerges as one of the most differentially expressed genes.
CONCLUSIONS
The presence of the mtDNA variant m.16519C increases the risk of rapid progression of knee OA. Among the most modulated biological processes associated with this variant, inflammation and negative regulation of cellular process stand out. The design of therapies based on the maintenance of mitochondrial function is recommended.
目的
鉴定与膝关节骨关节炎（OA）快速进展风险相关的线粒体 DNA（mtDNA）遗传变异，并通过线粒体传递细胞杂种的细胞模型来描述其功能意义。
方法
三个前瞻性队列为研究提供了参与者。骨关节炎倡议（OAI）纳入了 1095 名受试者，髋关节队列和膝关节队列分别纳入了 373 名和 326 名来自拉科鲁尼亚前瞻性骨关节炎队列的受试者。通过对 OAI 中 450 名受试者的 mtDNA 进行深度测序，筛选 mtDNA 变体。对三个队列进行了荟萃分析。通过构建细胞杂种模型，通过评估 mtDNA 拷贝数、线粒体生物合成、线粒体裂变和融合、线粒体活性氧（ROS）、氧化应激、自噬和通过 RNA 测序进行全转录组分析，研究携带风险 mtDNA 变体的功能后果。
结果
快速进展者中 mtDNA 变体 m.16519C 过度表达（合并 OR 1.546；95%CI 1.163 至 2.054；p=0.0027）。具有该变体的细胞杂种显示 mtDNA 拷贝数增加和线粒体生物合成减少；它们产生更多的线粒体 ROS，对氧化应激的抵抗力降低，显示出与线粒体裂变相关的基因分裂线粒体 1 的表达降低，并且自噬流受损。此外，其存在调节细胞杂种的转录组，尤其是在炎症方面，其中白细胞介素 6 作为差异表达基因之一出现。
结论
mtDNA 变体 m.16519C 的存在增加了膝关节 OA 快速进展的风险。与该变体相关的最受调节的生物学过程中，炎症和细胞过程的负调节尤为突出。建议基于维持线粒体功能的治疗设计。
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