Department of Geriatrics and Gerontology, National Taiwan University Hospital College of Medicine, National Taiwan University, Taipei, Taiwan.
Renal Division, Department of Internal Medicine, National Taiwan University, College of Medicine, No. 1, Jen-Ai Road, Section 1, Taipei, 100, Taiwan.
Clin Epigenetics. 2024 Jun 15;16(1):80. doi: 10.1186/s13148-024-01694-y.
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.
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.
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.
老年患者存在急性肾损伤和慢性肾脏病的风险。CpG 岛的 DNA 甲基化随年龄的增长与癌症和心血管疾病等与衰老相关的疾病有关，但肾脏衰老与其他肾脏疾病之间甲基化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。我们使用来自台湾生物银行的人类全血基因组甲基化分析，纳入了既有全血基因组甲基化数据又有血清肌酐随访数据的参与者。我们比较了整体队列中肾小球滤过率（eGFR）下降率较高和较低的参与者，以及在 eGFR 下降率较高的参与者亚组中比较了老年人和年轻人，研究了高甲基化和低甲基化基因。在两个比较分析中确定了常见的基因和信号通路。
在分析的 1587 名参与者中，有 187 名参与者的 eGFR 下降率较高。根据不同 eGFR 下降和不同年龄的参与者的甲基化比较，我们分别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，这些基因在 eGFR 下降率较高的参与者和年龄较大的参与者中均存在。我们观察到信号通路的甲基化状态与衰老和肾功能下降之间存在关联。这些通路包括自噬、p38 丝裂原活化蛋白激酶和沉默调节蛋白，它们与自噬过程和细胞因子产生有关。
通过对 PBMC 的甲基化分析，我们确定了一些基因和信号通路，它们可能在肾脏衰老和肾功能下降的相互作用中发挥关键作用。这些发现有助于开发新的生物标志物来识别高危人群，甚至有助于发现治疗药物。
