Background

Epigenetic changes are considered the main mechanisms behind the interplay of environment and genetic susceptibility in major depressive disorder (MDD). However, studies focusing on epigenetic dysregulation of the HPA axis stress response in MDD are lacking. Our objective was to simultaneously asses DNA methylation of the glucocorticoid receptor gene (NR3C1) and serotonin transporter gene (SLC6A4) and HPA axis response to stress in MDD.

Methods

We recruited 80 depressed inpatients and 58 gender and age matched healthy controls. All participants underwent the Trier Social Stress Test (TSST) and salivary cortisol was repeatedly measured to assess HPA axis reactivity. DNA methylation of the NR3C1 (exon 1 F) and SLC6A4 CpG islands was quantified from whole blood DNA. In the MDD group, clinical assessment was repeated at 8-week follow-up to test the predictive potential of DNA methylation for symptom improvement.

Results

Depressed patients had blunted cortisol reactivity to TSST compared to healthy controls (p = 0.01). In addition, they presented with increased average SLC6A4 (p = 0.003) and NR3C1 methylation (p = 0.03), as well as methylation of two individual NR3C1 CpG loci overlapping with the NGFI-A-binding sites (CpG12 and CpG20). Methylation of one of these two loci (CpG20) predicted lower symptom improvement at the follow-up (p = 0.007). Both, average NR3C1 and SLC6A4 methylation were associated with lower cortisol reactivity in the MDD group and explained about 16% of variability in cortisol response to TSST.

Conclusions

We provide evidence of the role of NR3C1 and SLC6A4 DNA methylation in HPA axis dysregulation in MDD, which needs to be further explored.

中文翻译：

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NR3C1 和 SLC6A4 甲基化增加与重度抑郁症患者对压力的皮质醇反应减弱有关

背景

表观遗传变化被认为是重度抑郁症（MDD）环境和遗传易感性相互作用背后的主要机制。然而，缺乏关注MDD中HPA轴应激反应的表观遗传失调的研究。我们的目标是同时评估糖皮质激素受体基因 ( NR3C1 ) 和血清素转运蛋白基因 ( SLC6A4 ) 的 DNA 甲基化以及 HPA 轴对 MDD 压力的反应。

方法

我们招募了 80 名抑郁住院患者和 58 名性别和年龄匹配的健康对照。所有参与者都接受了特里尔社会压力测试 (TSST)，并反复测量唾液皮质醇以评估 HPA 轴反应性。从全血 DNA 中定量NR3C1（外显子 1 F）和SLC6A4 CpG 岛的 DNA 甲基化。在 MDD 组中，在 8 周的随访中重复进行临床评估，以测试 DNA 甲基化对症状改善的预测潜力。

结果

与健康对照组相比，抑郁患者对 TSST 的皮质醇反应减弱 ( p  = 0.01)。此外，他们的平均SLC6A4 ( p  = 0.003) 和 NR3C1 甲基化 ( p  = 0.03) 增加，以及与 NGFI-A 结合位点重叠的两个单独的NR3C1 CpG 基因座（CpG12 和 CpG20）的甲基化。这两个基因座之一的甲基化 (CpG20) 预测随访时症状改善较低 ( p  = 0.007)。在 MDD 组中，平均NR3C1和SLC6A4甲基化均与较低的皮质醇反应性相关，并解释了皮质醇对 TSST 反应的约 16% 的变异性。

结论

我们提供了NR3C1和SLC6A4 DNA 甲基化在 MDD 中 HPA 轴失调中作用的证据，这需要进一步探索。