Centre for Genomics and Personalised Health, Queensland University of Technology, 60 Musk Avenue, Brisbane, QLD, 4059, Australia.
Centre for Data Science, Queensland University of Technology, 2 George Street, Brisbane, QLD, 4000, Australia.
Clin Epigenetics. 2023 Dec 12;15(1):190. doi: 10.1186/s13148-023-01604-8.
Chronic migraine, a highly disabling migraine subtype, affects nearly 2% of the general population. Understanding migraine chronification is vital for developing better treatment and prevention strategies. An important factor in the chronification of migraine is the overuse of acute headache medication. However, the mechanisms behind the transformation of episodic migraine to chronic migraine and vice versa have not yet been elucidated. We performed a longitudinal epigenome-wide association study to identify DNA methylation (DNAm) changes associated with treatment response in patients with chronic migraine and medication overuse as part of the Chronification and Reversibility of Migraine clinical trial. Blood was taken from patients with chronic migraine (n = 98) at baseline and after a 12-week medication withdrawal period. Treatment responders, patients with ≥ 50% reduction in monthly headache days (MHD), were compared with non-responders to identify DNAm changes associated with treatment response. Similarly, patients with ≥ 50% versus < 50% reduction in monthly migraine days (MMD) were compared.
At the epigenome-wide significant level (p < 9.42 × 10), a longitudinal reduction in DNAm at an intronic CpG site (cg14377273) within the HDAC4 gene was associated with MHD response following the withdrawal of acute medication. HDAC4 is highly expressed in the brain, plays a major role in synaptic plasticity, and modulates the expression and release of several neuroinflammation markers which have been implicated in migraine pathophysiology. Investigating whether baseline DNAm associated with treatment response, we identified lower baseline DNAm at a CpG site (cg15205829) within MARK3 that was significantly associated with MMD response at 12 weeks.
Our findings of a longitudinal reduction in HDAC4 DNAm status associated with treatment response and baseline MARK3 DNAm status as an early biomarker for treatment response, provide support for a role of pathways related to chromatin structure and synaptic plasticity in headache chronification and introduce HDAC4 and MARK3 as novel therapeutic targets.
慢性偏头痛是一种高度致残的偏头痛亚型，影响近 2%的普通人群。了解偏头痛的慢性化对于制定更好的治疗和预防策略至关重要。偏头痛慢性化的一个重要因素是急性头痛药物的过度使用。然而，从阵发性偏头痛到慢性偏头痛的转变以及反之亦然的机制尚未阐明。我们进行了一项纵向全基因组表观遗传关联研究，以确定与慢性偏头痛和药物过度使用患者治疗反应相关的 DNA 甲基化 (DNAm) 变化，作为偏头痛慢性化和逆转临床试验的一部分。从慢性偏头痛患者 (n=98) 中采集基线和 12 周药物戒断期后的血液。将治疗反应者（每月头痛天数 (MHD) 减少≥50%的患者）与无反应者进行比较，以确定与治疗反应相关的 DNAm 变化。同样，比较每月偏头痛天数 (MMD) 减少≥50%与<50%的患者。
在全基因组显著水平 (p<9.42×10)，在 HDAC4 基因内含子中的 CpG 位点 (cg14377273) 处的 DNAm 纵向减少与急性药物戒断后 MHD 反应相关。HDAC4 在大脑中高度表达，在突触可塑性中起主要作用，并调节几种神经炎症标志物的表达和释放，这些标志物与偏头痛病理生理学有关。研究基线 DNAm 是否与治疗反应相关，我们发现 MARK3 中 CpG 位点 (cg15205829) 的基线 DNAm 较低与 12 周时的 MMD 反应显著相关。
我们发现 HDAC4 DNAm 状态的纵向降低与治疗反应相关，以及 MARK3 DNAm 状态作为治疗反应的早期生物标志物，为与染色质结构和突触可塑性相关的途径在头痛慢性化中的作用提供了支持，并将 HDAC4 和 MARK3 作为新的治疗靶点。
