PDF(Pubmed)
Abstract：
BACKGROUND: Older patients are at risk for acute kidney injury and chronic kidney disease. Age-related increases in DNA methylation at CpG islands have been linked to aging-related diseases like cancer and cardiovascular disease, but the exact causal relationship between methylation in renal aging and other kidney diseases remains unclear. This study aimed to elucidate the methylation status of peripheral blood mononuclear cells (PBMCs) in the Asian population. Using human whole blood DNA methylation analysis from the Taiwan Biobank, we included participants with both whole blood genome-wide methylation data and follow-up data on serum creatinine. We investigated hyper- and hypomethylated genes in comparison of participants with higher and lower estimated glomerular filtration (eGFR) decline rate in overall cohort as well as in comparison of old and young participants in subgroup of participants with higher eGFR decline rate. Common genes and signaling pathways in both comparative analyses were identified.
RESULTS: Among 1587 participants in the analysis, 187 participants had higher eGFR decline rate. According to the comparison of methylation in participants with different eGFR declines and at different ages, respectively, we identified common hypermethylated genes, including DNMT3A and GGACT, as well as hypomethylated genes such as ARL6IP5, CYB5D1, BCL6, RPRD2, ZNF451, and MIAT in both participants with higher eGFR decline and those of older age. We observed associations between the methylation status of signaling pathways and aging as well as renal function decline. These pathways notably included autophagy, p38 mitogen-activated protein kinases, and sirtuins, which were associated with autophagy process and cytokine production.
CONCLUSIONS: Through methylation analysis of PBMCs, we identified genes and signaling pathways which could play crucial roles in the interplay of renal aging and renal function decline. These findings contribute to the development of novel biomarkers for identifying at-risk groups and even for therapeutic agent discovery.
RESULTS: Among 1587 participants in the analysis, 187 participants had higher eGFR decline rate. According to the comparison of methylation in participants with different eGFR declines and at different ages, respectively, we identified common hypermethylated genes, including DNMT3A and GGACT, as well as hypomethylated genes such as ARL6IP5, CYB5D1, BCL6, RPRD2, ZNF451, and MIAT in both participants with higher eGFR decline and those of older age. We observed associations between the methylation status of signaling pathways and aging as well as renal function decline. These pathways notably included autophagy, p38 mitogen-activated protein kinases, and sirtuins, which were associated with autophagy process and cytokine production.
CONCLUSIONS: Through methylation analysis of PBMCs, we identified genes and signaling pathways which could play crucial roles in the interplay of renal aging and renal function decline. These findings contribute to the development of novel biomarkers for identifying at-risk groups and even for therapeutic agent discovery.
摘要：
背景：老年患者存在急性肾损伤和慢性肾病的风险。CpG岛DNA甲基化的年龄相关增加与癌症和心血管疾病等衰老相关疾病有关。但肾脏衰老中甲基化与其他肾脏疾病之间的确切因果关系尚不清楚.本研究旨在阐明亚洲人群外周血单个核细胞（PBMC）的甲基化状态。使用台湾生物库的人类全血DNA甲基化分析，我们纳入了同时具有全血基因组甲基化数据和血清肌酐随访数据的参与者.我们调查了高甲基化和低甲基化基因，比较了总体队列中肾小球滤过率（eGFR）下降率较高和较低的参与者，以及eGFR下降率较高的参与者亚组中老年和年轻参与者的比较。鉴定了两个比较分析中的常见基因和信号通路。
结果：在分析的1587名参与者中，187名参与者的eGFR下降率较高。根据不同eGFR下降和不同年龄参与者的甲基化比较，分别,我们确定了常见的高甲基化基因，包括DNMT3A和GGACT，以及低甲基化基因如ARL6IP5,CYB5D1,BCL6,RPRD2,ZNF451和MIAT在eGFR下降较高的参与者和年龄较大的参与者中.我们观察到信号通路的甲基化状态与衰老以及肾功能下降之间的关联。这些途径特别包括自噬，p38丝裂原活化蛋白激酶，和sirtuins，与自噬过程和细胞因子产生有关。
结论：通过PBMC的甲基化分析，我们确定了可能在肾脏衰老和肾功能下降的相互作用中起关键作用的基因和信号通路。这些发现有助于开发新的生物标志物，用于识别风险群体，甚至用于发现治疗剂。
结果：在分析的1587名参与者中，187名参与者的eGFR下降率较高。根据不同eGFR下降和不同年龄参与者的甲基化比较，分别,我们确定了常见的高甲基化基因，包括DNMT3A和GGACT，以及低甲基化基因如ARL6IP5,CYB5D1,BCL6,RPRD2,ZNF451和MIAT在eGFR下降较高的参与者和年龄较大的参与者中.我们观察到信号通路的甲基化状态与衰老以及肾功能下降之间的关联。这些途径特别包括自噬，p38丝裂原活化蛋白激酶，和sirtuins，与自噬过程和细胞因子产生有关。
结论：通过PBMC的甲基化分析，我们确定了可能在肾脏衰老和肾功能下降的相互作用中起关键作用的基因和信号通路。这些发现有助于开发新的生物标志物，用于识别风险群体，甚至用于发现治疗剂。
