Cancer & Disease Epigenetics, Murdoch Children's Research Institute, Royal Children's Hospital & Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
INSERM, U1061, Neuropsychiatrie, Recherche Clinique et Epidémiologique, Univ. Montpellier, Montpellier, France.
Psychoneuroendocrinology. 2018 Feb;88:1-8. doi: 10.1016/j.psyneuen.2017.11.003. Epub 2017 Nov 8.
Depression is one of the most prevalent psychiatric disorders, and in older persons is associated with high levels of comorbidity and under-treatment. Dysfunction of the hypothalamic-pituitary-adrenal (HPA) stress axis is consistently observed in the older population as well as depressed patients, with the angiotensin converting enzyme (ACE) a key regulator of the stress response. Epigenetic regulation of ACE may play an important role in HPA axis (dys)regulation.
To investigate ACE promoter methylation as a biomarker of late-life depression, and its association with genetic variation and cortisol secretion.
The longitudinal general population ESPRIT study is aimed at investigating psychiatric disorders in older persons (n=1863, average age=73). Depression was assessed using the Mini International Neuropsychiatric Interview according to DSM-IV criteria and the Centre for Epidemiologic Studies Depression Scale (CES-D). Genotype information for seven polymorphisms across the ACE gene was also available. Blood and saliva samples collected at baseline and used to extract DNA and measure cortisol, respectively. Sequenom MassARRAY was used to measure promoter DNA methylation of the ACE gene (n=552).
There was no evidence of an association between ACE promoter methylation and depression. However, there was evidence that ACE genetic variants influenced methylation, and modified the association between depression and methylation (Δ at various sites; -2.05% to 1.74%; p=0.019 to 0.039). Multivariate analyses were adjusted for participants' lifestyle, health and medical history. Independent of depression status, ACE methylation was inversely correlated with cortisol levels (r=-0.336, p=0.042).
This study provides evidence that associations between ACE methylation and depression are genotype-dependent, suggesting that the development of reliable depression biomarkers may need to consider methylation levels in combination with underlying genetic variation. ACE methylation may also be a suitable biomarker of cortisol and/or HPA axis activity.
抑郁症是最常见的精神疾病之一，在老年人中常伴有较高的合并症发生率和治疗不足。在老年人和抑郁症患者中，下丘脑-垂体-肾上腺（HPA）应激轴的功能障碍是一致观察到的，血管紧张素转换酶（ACE）是应激反应的关键调节剂。ACE 的表观遗传调控可能在 HPA 轴（失调）调节中发挥重要作用。
研究 ACE 启动子甲基化为老年抑郁症的生物标志物，及其与遗传变异和皮质醇分泌的关系。
纵向一般人群 ESPRIT 研究旨在调查老年人中的精神障碍（n=1863，平均年龄=73）。使用 Mini 国际神经精神访谈根据 DSM-IV 标准和流行病学研究抑郁量表（CES-D）评估抑郁症。ACE 基因中七个多态性的基因型信息也可用。基线时采集血液和唾液样本，分别用于提取 DNA 和测量皮质醇。使用 Sequenom MassARRAY 测量 ACE 基因启动子 DNA 甲基化（n=552）。
ACE 启动子甲基化与抑郁症之间没有关联的证据。然而，有证据表明 ACE 遗传变异影响甲基化，并改变了抑郁与甲基化之间的关联（在不同的部位；-2.05%至 1.74%；p=0.019 至 0.039）。多变量分析调整了参与者的生活方式、健康和病史。独立于抑郁状态，ACE 甲基化与皮质醇水平呈负相关（r=-0.336，p=0.042）。
本研究提供了证据表明 ACE 甲基化与抑郁之间的关联是依赖于基因型的，这表明开发可靠的抑郁症生物标志物可能需要考虑与潜在遗传变异相结合的甲基化水平。ACE 甲基化也可能是皮质醇和/或 HPA 轴活性的合适生物标志物。
