Endothelial Dysfunction in Children With Obstructive Sleep Apnea Is Associated With Epigenetic Changes in the eNOS Gene
Endothelial Dysfunction in Children With Obstructive Sleep Apnea Is Associated With Epigenetic Changes in the eNOS Gene
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DOI：
10.1378/chest.12-2026
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发表时间：
2013-04-01
期刊：
影响因子：
9.6
通讯作者：
Wang, Yang
中科院分区：
文献类型：
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作者：
Kheirandish-Gozal, Leila;Khalyfa, Abdelnaby;Wang, Yang
背景：阻塞性睡眠呼吸暂停（OSA）是一种非常普遍的疾病，与心血管发病风险增加有关，即使在儿童中也是如此。然而，并非所有患有 OSA 的儿童都表现出内皮闭塞后充血的改变，这是一种内皮一氧化氮合酶 (eNOS) 依赖性反应。由于 eNOS 基因的表达受到表观遗传机制的调节，而 OSA 可能会导致表观遗传修饰，例如 DNA 高甲基化，因此我们假设 eNOS 基因的表观遗传修饰可能是儿科 OSA 血管表型差异的基础。 方法：评估年龄、性别、种族和 BMI 匹配的青春期前儿童，患有多导睡眠图证实的 OSA 以及正常 (OSAn) 或异常 (OSAab) 闭塞后充血反应作为通过激光多普勒血流计达到峰值再灌注流量（Tmax）的时间，被招募。使用焦磷酸测序评估血液基因组 DNA 中 eNOS 基因的表观遗传修饰。无 OSA 或内皮功能障碍证据的儿童作为对照组。结果：该研究包括 36 名 OSA 儿童（11 名 OSAab 儿童，25 名 OSAn 儿童）和 35 名对照组儿童。总体而言，平均年龄为 7.5 +/- 2.4 岁，其中 65% 为男孩，30% 为肥胖；患有 OSA 的儿童的平均呼吸暂停低通气指数为 18 +/- 8.6/小时睡眠。 OSAab 组的 Tmax 为 66.7 +/- 8.8 秒，OSAn 组为 30.1 +/- 8.3 秒 (P < .001)。 eNOS 基因近端启动子区域的焦磷酸测序显示七个 CpG 位点中的六个没有显着差异。然而，与 OSAn 或对照组相比，位于 -171 位（相对于转录起始位点）的 CpG 位点接近重要的转录元件，在 OSAab 组中显示出显着更高的甲基化水平（分别为 81.5% +/- 3.5%、74.8% +/- 1.4% 和 74.5% +/- 1.7%；P < .001）。在另一组儿童中评估了 eNOS mRNA 表达水平，与 OSAn 组相比，OSAab 组的 eNOS mRNA 表达水平显着降低。结论：OSA 儿童中异常 eNOS 依赖性血管反应的存在与 eNOS 基因的表观遗传修饰有关。胸部 2013； 143(4):971-977
Background: Obstructive sleep apnea (OSA) is a highly prevalent disorder that has been associated with an increased risk for cardiovascular morbidity, even in children. However, not all children with OSA manifest alterations in endothelial postocclusive hyperemia, an endothelial nitric oxide synthase (eNOS)-dependent response. Since expression of the eNOS gene is regulated by epigenetic mechanisms and OSA may cause epigenetic modifications such as DNA hypermethylalion, we hypothesized that epigenetic modifications in the eNOS gene may underlie the differential vascular phenotypes in pediatric OSA.Methods: Age-, sex-, ethnicity-, and BMI-matched prepubertal children with polysomnographically confirmed OSA and either normal (OSAn) or abnormal (OSAab) postocclusive hyperemic responses, assessed as the time to attain peak reperfusion flow (Tmax) by laser Doppler flowmetry, were recruited. Blood genomic DNA was assessed for epigenetic modifications in the eNOS gene using pyrosequencing. Children with no evidence of OSA or endothelial dysfunction served as a control group.Results: The study comprised 36 children with OSA (11 with OSAab and 25 with OSAn) and 35 children in the control group. Overall, the mean age was 7.5 +/- 2.4 years, 65% were boys, and 30% were obese; mean apnea-hypopnea index was 18 +/- 8.6/h of sleep for the children with OSA. Tmax Was 66.7 +/- 8.8 s in the OSAab group and 30.1 +/- 8.3 s in the OSAn group (P < .001). Pyrosequencing of the proximal promoter region of the eNOS gene revealed no significant differences in six of the seven CpG sites. However, a CpG site located at position -171 (relative to transcription start site), approximating important transcriptional elements, displayed significantly higher methylation levels in the OSAab group as compared with the OSAn or control groups (81.5% +/- 3.5%, 74.8% +/- 1.4%, and 74.5% +/- 1.7%, respectively; P < .001). eNOS mRNA expression levels were assessed in a separate group of children and were significantly reduced in the OSAab group in comparison with the OSAn group.Conclusions: The presence of abnormal eNOS-dependent vascular responses in children with OSA is associated with epigenetic modifications in the eNOS gene. CHEST 2013; 143(4):971-977