Li Hong-Dong, Hong Gui-Ni, Guo Zheng
School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.
1.School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.
Yi Chuan. 2015 Feb;37(2):165-173. doi: 10.16288/j.yczz.14-394.
Aging is associated with many complex diseases such as cancer and neurodegenerative diseases. Recently, many age-related DNA methylation biomarkers in peripheral whole blood have been identified. These biomarkers may reflect DNA methylation changes derived from changes in the number of a specific leukocyte cell type during aging. To clarify the source of these age-related DNA methylation changes, we analysed DNA methylation profile of peripheral whole blood from three independent cohorts of healthy subjects and identified age-related DNA methylation CpG sites (arCpGs) using the Spearman's rank test with high reproducibility (Hypergeometric test, P=1.65 × 10⁻¹¹). Using a deconvolution algorithm, we found that the proportion of myeloid lineage cells was increased while that of lymphoid lineage cells was decreased in the peripheral whole blood with age (Spearman's rank correlation test, P<0.05, r ≤ 0.22). The CpG sites, whose methylation levels were significantly different in myeloid cells and lymphoid cells, were preferentially recognized as arCpGs in peripheral whole blood. Moreover, the arCpGs in CD4+ T cells significantly overlapped with that in peripheral whole blood (Hypergeometric test, P=6.14 × 10⁻¹²) and 99.1% of the overlapping arCpGs had consistent positive or negative correlations with age. Though the arCpGs in CD14+ monocytes did not significantly overlap with that in peripheral whole blood (Hypergeometric test, P=0.232), 90.1% of 51 overlapping arCpGs were correlated with age in CD14+ monocytes, peripheral whole blood, and CD4+ T cells consistently. In summary, most of the methylation changes in arCpGs identified in peripheral whole blood come from common or specific DNA methylation changes in leukocyte subtypes, while part of them reflect alterations in the number of specific cell types of leukocytes.
衰老与许多复杂疾病相关，如癌症和神经退行性疾病。最近，在外周全血中已鉴定出许多与年龄相关的DNA甲基化生物标志物。这些生物标志物可能反映了衰老过程中特定白细胞类型数量变化所导致的DNA甲基化变化。为了阐明这些与年龄相关的DNA甲基化变化的来源，我们分析了来自三个独立健康受试者队列的外周全血的DNA甲基化谱，并使用具有高重现性的Spearman秩检验（超几何检验，P = 1.65×10⁻¹¹）鉴定了与年龄相关的DNA甲基化CpG位点（arCpGs）。使用反卷积算法，我们发现随着年龄增长，外周全血中髓系谱系细胞的比例增加，而淋巴系谱系细胞的比例降低（Spearman秩相关检验，P<0.05，r≤0.22）。在髓系细胞和淋巴系细胞中甲基化水平有显著差异的CpG位点在外周全血中被优先识别为arCpGs。此外，CD4⁺T细胞中的arCpGs与外周全血中的arCpGs显著重叠（超几何检验，P = 6.14×10⁻¹²），并且99.1%的重叠arCpGs与年龄具有一致的正相关或负相关。虽然CD14⁺单核细胞中的arCpGs与外周全血中的arCpGs没有显著重叠（超几何检验，P = 0.232），但在CD14⁺单核细胞、外周全血和CD4⁺T细胞中，51个重叠arCpGs中的90.1%与年龄始终相关。总之，外周全血中鉴定出的arCpGs中的大多数甲基化变化来自白细胞亚型中常见或特定的DNA甲基化变化，而其中一部分反映了特定白细胞类型数量的改变。
