{"title":"综合单细胞转录组和eQTL分析揭示PZP在衰老和慢性肾脏疾病中的作用","authors":"Xinhui Huang, Cheng Zhu, Shiqi Lv, Yulin Wang, Jiayi Wang, Shuangxin Yuan, Yue Yang, Xiaoqiang Ding, Xiaoyan Zhang","doi":"10.1002/jgm.70015","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Aging is a known driver of chronic kidney disease (CKD), yet the genetic mechanisms linking these two conditions remain unclear. This study aims to explore the role of CD8+ central memory T (T<sub>CM</sub>) cells and their associated gene expression in the interaction between aging and CKD.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Peripheral blood samples from young controls, elderly individuals, and CKD patients were analyzed using single-cell RNA sequencing to investigate immune cell populations. Expression quantitative trait loci (eQTL) and Mendelian randomization analyses were performed using data from genomic cohorts, including the UK Biobank and FinnGen, to assess causal relationships. Experimental validation evaluated correlations between pregnancy zone protein (PZP) expression and clinical indicators such as age, glomerular filtration rate (GFR), serum creatinine, and proteinuria.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Increased proportions of CD8+ T<sub>CM</sub> cells were observed in elderly individuals and CKD patients. PZP was identified as a key genetic factor in CKD progression and aging, linked to metabolic reprogramming and impaired intercellular communication. PZP expression correlated significantly with aging (<i>r</i> = 0.818, <i>p</i> = 0.047), reduced GFR (<i>r</i> = −0.557, <i>p</i> = 0.011), elevated serum creatinine (<i>r</i> = 0.507, <i>p</i> = 0.019), and proteinuria (<i>r</i> = 0.761, <i>p</i> = 0.047).</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Shared genetic and immunological mechanisms link CKD and aging, with CD8+ T<sub>CM</sub> cells contributing to immune dysregulation and chronic inflammation. The dual role of PZP, involving its upregulation, disrupted immune communication, and metabolic reprogramming, highlights its potential as a biomarker and therapeutic target for aging-associated kidney diseases.</p>\n </section>\n </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"27 3","pages":""},"PeriodicalIF":3.2000,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Integrated Single-Cell Transcriptome and eQTL Analyses Reveal the Role of PZP in Aging and Chronic Kidney Disease\",\"authors\":\"Xinhui Huang, Cheng Zhu, Shiqi Lv, Yulin Wang, Jiayi Wang, Shuangxin Yuan, Yue Yang, Xiaoqiang Ding, Xiaoyan Zhang\",\"doi\":\"10.1002/jgm.70015\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Aging is a known driver of chronic kidney disease (CKD), yet the genetic mechanisms linking these two conditions remain unclear. This study aims to explore the role of CD8+ central memory T (T<sub>CM</sub>) cells and their associated gene expression in the interaction between aging and CKD.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>Peripheral blood samples from young controls, elderly individuals, and CKD patients were analyzed using single-cell RNA sequencing to investigate immune cell populations. Expression quantitative trait loci (eQTL) and Mendelian randomization analyses were performed using data from genomic cohorts, including the UK Biobank and FinnGen, to assess causal relationships. Experimental validation evaluated correlations between pregnancy zone protein (PZP) expression and clinical indicators such as age, glomerular filtration rate (GFR), serum creatinine, and proteinuria.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Increased proportions of CD8+ T<sub>CM</sub> cells were observed in elderly individuals and CKD patients. PZP was identified as a key genetic factor in CKD progression and aging, linked to metabolic reprogramming and impaired intercellular communication. PZP expression correlated significantly with aging (<i>r</i> = 0.818, <i>p</i> = 0.047), reduced GFR (<i>r</i> = −0.557, <i>p</i> = 0.011), elevated serum creatinine (<i>r</i> = 0.507, <i>p</i> = 0.019), and proteinuria (<i>r</i> = 0.761, <i>p</i> = 0.047).</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>Shared genetic and immunological mechanisms link CKD and aging, with CD8+ T<sub>CM</sub> cells contributing to immune dysregulation and chronic inflammation. The dual role of PZP, involving its upregulation, disrupted immune communication, and metabolic reprogramming, highlights its potential as a biomarker and therapeutic target for aging-associated kidney diseases.</p>\\n </section>\\n </div>\",\"PeriodicalId\":56122,\"journal\":{\"name\":\"Journal of Gene Medicine\",\"volume\":\"27 3\",\"pages\":\"\"},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2025-03-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Gene Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/jgm.70015\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Gene Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jgm.70015","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
衰老是慢性肾脏疾病（CKD）的一个已知驱动因素，但将这两种疾病联系起来的遗传机制尚不清楚。本研究旨在探讨CD8+中枢记忆T （central memory T， TCM）细胞及其相关基因表达在衰老与CKD相互作用中的作用。方法采用单细胞RNA测序技术对年轻对照、老年人和CKD患者外周血样本进行免疫细胞群分析。使用来自基因组队列（包括UK Biobank和FinnGen）的数据进行表达数量性状位点（eQTL）和孟德尔随机化分析，以评估因果关系。实验验证评估妊娠带蛋白（PZP）表达与临床指标（如年龄、肾小球滤过率（GFR）、血清肌酐和蛋白尿）的相关性。结果老年人和CKD患者CD8+ TCM细胞比例升高。PZP被认为是CKD进展和衰老的关键遗传因素，与代谢重编程和细胞间通讯受损有关。PZP表达与衰老（r = 0.818, p = 0.047）、GFR降低（r = - 0.557, p = 0.011）、血清肌酐升高（r = 0.507, p = 0.019）、蛋白尿（r = 0.761, p = 0.047）相关。结论CKD与衰老有共同的遗传和免疫机制，CD8+ TCM细胞参与免疫失调和慢性炎症。PZP的双重作用，包括其上调、破坏免疫通讯和代谢重编程，突出了其作为衰老相关肾脏疾病的生物标志物和治疗靶点的潜力。
Integrated Single-Cell Transcriptome and eQTL Analyses Reveal the Role of PZP in Aging and Chronic Kidney Disease
Background
Aging is a known driver of chronic kidney disease (CKD), yet the genetic mechanisms linking these two conditions remain unclear. This study aims to explore the role of CD8+ central memory T (TCM) cells and their associated gene expression in the interaction between aging and CKD.
Methods
Peripheral blood samples from young controls, elderly individuals, and CKD patients were analyzed using single-cell RNA sequencing to investigate immune cell populations. Expression quantitative trait loci (eQTL) and Mendelian randomization analyses were performed using data from genomic cohorts, including the UK Biobank and FinnGen, to assess causal relationships. Experimental validation evaluated correlations between pregnancy zone protein (PZP) expression and clinical indicators such as age, glomerular filtration rate (GFR), serum creatinine, and proteinuria.
Results
Increased proportions of CD8+ TCM cells were observed in elderly individuals and CKD patients. PZP was identified as a key genetic factor in CKD progression and aging, linked to metabolic reprogramming and impaired intercellular communication. PZP expression correlated significantly with aging (r = 0.818, p = 0.047), reduced GFR (r = −0.557, p = 0.011), elevated serum creatinine (r = 0.507, p = 0.019), and proteinuria (r = 0.761, p = 0.047).
Conclusions
Shared genetic and immunological mechanisms link CKD and aging, with CD8+ TCM cells contributing to immune dysregulation and chronic inflammation. The dual role of PZP, involving its upregulation, disrupted immune communication, and metabolic reprogramming, highlights its potential as a biomarker and therapeutic target for aging-associated kidney diseases.
期刊介绍：
The aims and scope of The Journal of Gene Medicine include cutting-edge science of gene transfer and its applications in gene and cell therapy, genome editing with precision nucleases, epigenetic modifications of host genome by small molecules, siRNA, microRNA and other noncoding RNAs as therapeutic gene-modulating agents or targets, biomarkers for precision medicine, and gene-based prognostic/diagnostic studies.
Key areas of interest are the design of novel synthetic and viral vectors, novel therapeutic nucleic acids such as mRNA, modified microRNAs and siRNAs, antagomirs, aptamers, antisense and exon-skipping agents, refined genome editing tools using nucleic acid /protein combinations, physically or biologically targeted delivery and gene modulation, ex vivo or in vivo pharmacological studies including animal models, and human clinical trials.
Papers presenting research into the mechanisms underlying transfer and action of gene medicines, the application of the new technologies for stem cell modification or nucleic acid based vaccines, the identification of new genetic or epigenetic variations as biomarkers to direct precision medicine, and the preclinical/clinical development of gene/expression signatures indicative of diagnosis or predictive of prognosis are also encouraged.
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