Li Hongdong, Guo Zheng, Guo You, Li Mengyao, Yan Haidan, Cheng Jun, Wang Chenguang, Hong Guini
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou, China.
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
Oncotarget. 2016 Apr 12;7(15):19089-98. doi: 10.18632/oncotarget.7862.
Alzheimer's disease (AD) is a common aging-related neurodegenerative illness. Recently, many studies have tried to identify AD- or aging-related DNA methylation (DNAm) biomarkers from peripheral whole blood (PWB). However, the origin of PWB biomarkers is still controversial. In this study, by analyzing 2565 DNAm profiles for PWB and brain tissue, we showed that aging-related DNAm CpGs (Age-CpGs) and AD-related DNAm CpGs (AD-CpGs) observable in PWB both mainly reflected DNAm alterations intrinsic in leukocyte subtypes rather than methylation differences introduced by the increased ratio of myeloid to lymphoid cells during aging or AD progression. The PWB Age-CpGs and AD-CpGs significantly overlapped 107 sites (P-value = 2.61×10-12) and 97 had significantly concordant methylation alterations in AD and aging (P-value < 2.2×10-16), which were significantly enriched in nervous system development, neuron differentiation and neurogenesis. More than 60.8% of these 97 concordant sites were found to be significantly correlated with age in normal peripheral CD4+ T cells and CD14+ monocytes as well as in four brain regions, and 44 sites were also significantly differentially methylated in different regions of AD brain tissue. Taken together, the PWB DNAm alterations related to both aging and AD could be exploited for identification of AD biomarkers.
阿尔茨海默病（AD）是一种常见的与衰老相关的神经退行性疾病。最近，许多研究试图从外周全血（PWB）中鉴定出与AD或衰老相关的DNA甲基化（DNAm）生物标志物。然而，PWB生物标志物的来源仍存在争议。在本研究中，通过分析2565个PWB和脑组织的DNAm图谱，我们发现PWB中可观察到的与衰老相关的DNAm CpG（年龄-CpG）和与AD相关的DNAm CpG（AD-CpG）主要反映了白细胞亚型内在的DNAm改变，而非衰老或AD进展过程中髓系与淋巴细胞比例增加所导致的甲基化差异。PWB年龄-CpG和AD-CpG在107个位点显著重叠（P值 = 2.61×10-12），97个位点在AD和衰老中具有显著一致的甲基化改变（P值 < 2.2×10-16），这些位点在神经系统发育、神经元分化和神经发生方面显著富集。在正常外周CD4+ T细胞和CD14+单核细胞以及四个脑区中，发现这97个一致位点中有超过60.8%与年龄显著相关，并且在AD脑组织的不同区域中，44个位点也存在显著的甲基化差异。综上所述，与衰老和AD相关的PWB DNAm改变可用于鉴定AD生物标志物。
