Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, Kursk, Russia.
Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russia.
J Mol Neurosci. 2021 Sep;71(9):1914-1932. doi: 10.1007/s12031-021-01840-8. Epub 2021 Apr 17.
Dysregulation of the oxidant-antioxidant system contributes to the pathogenesis of cerebral stroke (CS). Epigenetic changes of redox homeostasis genes, such as glutamate-cysteine ligase (GCLM), glutathione-S-transferase-P1 (GSTP1), thioredoxin reductase 1 (TXNRD1), and myeloperoxidase (MPO), may be biomarkers of CS. In this study, we assessed the association of DNA methylation levels of these genes with CS and clinical features of CS. We quantitatively analyzed DNA methylation patterns in the promoter or regulatory regions of 4 genes (GCLM, GSTP1, TXNRD1, and MPO) in peripheral blood leukocytes of 59 patients with CS in the acute phase and in 83 relatively healthy individuals (controls) without cardiovascular and cerebrovascular diseases. We found that in both groups, the methylation level of CpG sites in genes TXNRD1 and GSTP1 was ≤ 5%. Lower methylation levels were registered at a CpG site (chr1:94,374,293, GRCh37 [hg19]) in GCLM in patients with ischemic stroke compared with the control group (9% [7%; 11.6%] (median and interquartile range) versus 14.7% [10.4%; 23%], respectively, p < 0.05). In the leukocytes of patients with CS, the methylation level of CpG sites in the analyzed region of MPO (chr17:56,356,470, GRCh3 [hg19]) on average was significantly lower (23.5% [19.3%; 26.7%]) than that in the control group (35.6% [30.4%; 42.6%], p < 0.05). We also found increased methylation of MPO in smokers with CS (27.2% [23.5%; 31.1%]) compared with nonsmokers with CS (21.7% [18.1%; 24.8%]). Thus, hypomethylation of CpG sites in GCLM and MPO in blood leukocytes is associated with CS in the acute phase.
氧化还原系统的失调导致了中风（CS）的发病机制。氧化还原稳态基因（如谷氨酸-半胱氨酸连接酶（GCLM）、谷胱甘肽 S-转移酶 P1（GSTP1）、硫氧还蛋白还原酶 1（TXNRD1）和髓过氧化物酶（MPO））的表观遗传变化可能是 CS 的生物标志物。在这项研究中，我们评估了这些基因的 DNA 甲基化水平与 CS 及 CS 临床特征的相关性。我们定量分析了 59 名急性期 CS 患者和 83 名无心血管和脑血管疾病的相对健康个体（对照组）外周血白细胞中 4 个基因（GCLM、GSTP1、TXNRD1 和 MPO）启动子或调控区的 DNA 甲基化模式。我们发现，在两组中，TXNRD1 和 GSTP1 基因的 CpG 位点的甲基化水平均≤5%。与对照组相比，缺血性中风患者 GCLM 中一个 CpG 位点（chr1:94,374,293，GRCh37 [hg19]）的甲基化水平较低（9%[7%；11.6%]（中位数和四分位间距）比对照组（14.7%[10.4%；23%]），p<0.05）。在 CS 患者的白细胞中，分析区域 MPO（chr17:56,356,470，GRCh3[hg19]）的 CpG 位点的甲基化水平平均显著降低（23.5%[19.3%；26.7%]），低于对照组（35.6%[30.4%；42.6%]），p<0.05）。我们还发现，CS 吸烟者的 MPO 甲基化程度增加（27.2%[23.5%；31.1%]），高于 CS 非吸烟者（21.7%[18.1%；24.8%]）。因此，血液白细胞中 GCLM 和 MPO 的 CpG 位点的低甲基化与急性期 CS 有关。
