Alwehaidah Materah Salem, Alsabbagh Manhel, Al-Kafaji Ghada
Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Kuwait University, City of Kuwait 31470, State of Kuwait.
Department of Molecular Medicine and Al-Jawhara Centre for Molecular Medicine, Genetics, and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 26671, Kingdom of Bahrain.
Biomed Rep. 2023 Sep 26;19(5):85. doi: 10.3892/br.2023.1667. eCollection 2023 Nov.
Growing evidence suggests that abnormalities in mitochondrial DNA (mtDNA) are involved in the pathogenesis of various inflammatory and immuno-mediated diseases. The present study analysed the entire mitochondrial genome by next-generation sequencing (NGS) in 23 patients with psoriatic arthritis (PsA) and 20 healthy controls to identify PsA-related variants. Changes in mtDNA copy number (mtDNAcn) were also evaluated by quantitative polymerase chain reaction (qPCR) and mtDNA oxidative damage was measured using an 8-hydroxy-2'-deoxyguanosine assay. NGS analysis revealed a total of 435 variants including 187 in patients with PsA only and 122 in controls only. Additionally, 126 common variants were found, of which 2 variants differed significantly in their frequencies among patients and controls (P<0.05), and may be associated with susceptibility to PsA. A total of 33 missense variants in mtDNA-encoded genes for complexes I, III, IV and V were identified only in patients with PsA. Of them, 25 variants were predicted to be deleterious by affecting the functions and structures of encoded proteins, and 13 variants were predicted to affect protein's stability. mtDNAcn analysis revealed decreased mtDNA content in patients with PsA compared with controls (P=0.0001) but the decrease in mtDNAcn was not correlated with patients' age or inflammatory biomarkers (P>0.05). Moreover, a higher level of oxidative damage was observed in patients with PsA compared with controls (P=0.03). The results of the present comprehensive analysis of mtDNA in PsA revealed that certain mtDNA variants may be implicated in the predisposition/pathogenesis of PsA, highlighting the importance of NGS in the identification of mtDNA variants in PsA. The current results also demonstrated that decreased mtDNAcn in PsA may be a consequence of increased oxidative stress. These data provide valuable insights into the contribution of mtDNA defects to the pathogenesis of PsA. Additional studies in larger cohorts are needed to elucidate the role of mtDNA defects in PsA.
越来越多的证据表明，线粒体DNA（mtDNA）异常与各种炎症和免疫介导疾病的发病机制有关。本研究通过下一代测序（NGS）分析了23例银屑病关节炎（PsA）患者和20名健康对照者的整个线粒体基因组，以鉴定与PsA相关的变异。还通过定量聚合酶链反应（qPCR）评估了mtDNA拷贝数（mtDNAcn）的变化，并使用8-羟基-2'-脱氧鸟苷测定法测量了mtDNA氧化损伤。NGS分析共发现435个变异，其中仅PsA患者中有187个，仅对照者中有122个。此外，还发现了126个常见变异，其中2个变异在患者和对照者中的频率差异显著（P<0.05），可能与PsA易感性相关。仅在PsA患者中鉴定出mtDNA编码的复合体I、III、IV和V基因中的33个错义变异。其中，25个变异预计会通过影响编码蛋白的功能和结构而有害，13个变异预计会影响蛋白的稳定性。mtDNAcn分析显示，与对照者相比，PsA患者的mtDNA含量降低（P=0.0001），但mtDNAcn的降低与患者年龄或炎症生物标志物无关（P>0.05）。此外，与对照者相比，PsA患者的氧化损伤水平更高（P=0.03）。本研究对PsA中mtDNA的综合分析结果表明，某些mtDNA变异可能与PsA的易感性/发病机制有关，突出了NGS在鉴定PsA中mtDNA变异方面的重要性。目前的结果还表明，PsA中mtDNAcn降低可能是氧化应激增加的结果。这些数据为mtDNA缺陷对PsA发病机制的贡献提供了有价值的见解。需要在更大的队列中进行进一步研究，以阐明mtDNA缺陷在PsA中的作用。
