儿童阻塞性睡眠呼吸暂停中内皮功能障碍与 eNOS 基因的表观遗传改变有关。
Endothelial dysfunction in children with obstructive sleep apnea is associated with epigenetic changes in the eNOS gene.
机构信息
Section of Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
Section of Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
出版信息
Chest. 2013 Apr;143(4):971-977. doi: 10.1378/chest.12-2026.
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 hypermethylation, 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.
背景
阻塞性睡眠呼吸暂停（OSA）是一种高发疾病，其与心血管发病率增加相关，即使在儿童中也是如此。然而，并非所有 OSA 患儿都会出现内皮后阻塞性充血的改变，这是一种内皮一氧化氮合酶（eNOS）依赖性反应。由于 eNOS 基因的表达受表观遗传机制调控，而 OSA 可能导致表观遗传改变，如 DNA 超甲基化，因此我们假设 eNOS 基因的表观遗传修饰可能是小儿 OSA 不同血管表型的基础。
方法
我们招募了年龄、性别、种族和 BMI 匹配的、经多导睡眠图证实的 OSA 患儿，他们的后阻塞性充血反应正常（OSAn）或异常（OSAab），通过激光多普勒流量测定评估达到峰值再灌注流量（Tmax）的时间。使用焦磷酸测序法评估 eNOS 基因的血液基因组 DNA 中是否存在表观遗传修饰。没有 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 患儿（11 名 OSAab 和 25 名 OSAn）和 35 名对照组儿童。总体而言，平均年龄为 7.5±2.4 岁，65%为男孩，30%为肥胖；OSA 患儿的平均睡眠呼吸暂停低通气指数为 18±8.6/h。OSAab 组的 Tmax 为 66.7±8.8s，OSAn 组为 30.1±8.3s（P<0.001）。对 eNOS 基因近端启动子区域的焦磷酸测序显示，七个 CpG 位点中有六个没有显著差异。然而，位于转录起始位点前-171 位（相对位置）的一个 CpG 位点，接近重要的转录元件，在 OSAab 组中的甲基化水平明显高于 OSAn 组或对照组（分别为 81.5%±3.5%、74.8%±1.4%和 74.5%±1.7%；P<0.001）。在另一组儿童中评估了 eNOSmRNA 表达水平，与 OSAn 组相比，OSAab 组明显降低。
结论
OSA 患儿存在异常的 eNOS 依赖性血管反应与 eNOS 基因的表观遗传修饰有关。
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