Peng Hao, Fan Yiming, Li Jing, Zheng Xiaowei, Zhong Chongke, Zhu Zhengbao, He Yan, Zhang Mingzhi, Zhang Yonghong
Department of Epidemiology (H.P., J.L., X.Z., C.Z., Z.Z., Y.H., M.Z., Y.Z.), School of Public Health, Medical College of Soochow University; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (H.P.); and Medical College of Soochow University (Y.F.), Suzhou, China.
Neurol Genet. 2022 May 11;8(3):e679. doi: 10.1212/NXG.0000000000000679. eCollection 2022 Jun.
The natriuretic peptide (NP) system has been considered an important regulator for ischemic stroke (IS) with a limited clinical implication. A better understanding of the underlying molecular mechanisms is urgent. Here, we aimed to examine the role of DNA methylation of NP system genes in IS.
DNA methylation at promoter regions of 4 core NP system genes, e.g., , , , and , was measured by targeted bisulfite sequencing in 853 patients with IS and 918 controls. We first examined the association between DNA methylation at each single CpG and IS, followed by gene-based and gene set analyses to examine the joint associations of DNA methylation at multiple CpGs in a gene or all 4 genes as a pathway with IS.
After control of covariates and multiple testing, DNA methylation at 19 of the 36 assayed CpGs was individually associated with IS at < 0.05. Higher average methylation levels at the targeted regions of (odds ratio [OR] = 0.64, 95% confidence interval [CI]: 0.56-0.73), (OR = 0.78, 95% CI: 0.69-0.88), and (OR = 0.78, 95% CI: 0.69-0.88) were associated with a lower odds of IS (all < 0.05). The truncated product method revealed the same gene-based associations (all < 0.05) and found that DNA methylation at all 4 NP system genes together was jointly associated with IS ( = 0.0001).
DNA methylation at NP system genes was downregulated in patients with IS. Our results may unravel a molecular mechanism underlying the regulating effect of the NP system on IS and highlight the relevance of testing the joint effect of multiple CpGs in the epigenetic analysis.
利钠肽（NP）系统被认为是缺血性脑卒中（IS）的重要调节因子，但其临床意义有限。迫切需要更好地了解其潜在的分子机制。在此，我们旨在研究NP系统基因的DNA甲基化在IS中的作用。
采用靶向亚硫酸氢盐测序法，对853例IS患者和918例对照者的4个核心NP系统基因（即 、 、 、 ）启动子区域的DNA甲基化进行检测。我们首先研究每个单个CpG位点的DNA甲基化与IS之间的关联，随后进行基于基因和基因集的分析，以研究一个基因中多个CpG位点或作为一个通路的所有4个基因的DNA甲基化与IS的联合关联。
在控制协变量和多重检验后，36个检测的CpG位点中有19个位点的DNA甲基化与IS单独相关，P<0.05。 （优势比[OR]=0.64，95%置信区间[CI]：0.56-0.73）、 （OR=0.78，95%CI：0.69-0.88）和 （OR=0.78，95%CI：0.69-0.88）靶向区域较高的平均甲基化水平与较低的IS发病几率相关（均P<0.05）。截短乘积法揭示了相同的基于基因的关联（均P<0.05），并发现所有4个NP系统基因的DNA甲基化共同与IS相关（P=0.0001）。
IS患者NP系统基因的DNA甲基化下调。我们的结果可能揭示了NP系统对IS调节作用的分子机制，并强调了在表观遗传分析中检测多个CpG联合效应的相关性。
