Vrije Universiteit Brussel, Brussels, Belgium, Katholieke Universiteit Leuven, Leuven, Belgium, and Scientific Research Foundation, Flanders, Belgium.
Katholieke Universiteit Leuven, Leuven, Belgium, and Scientific Research Foundation, Flanders, Belgium.
Arthritis Rheumatol. 2020 Nov;72(11):1936-1944. doi: 10.1002/art.41405. Epub 2020 Oct 7.
The epigenetics of neurotrophic factors holds the potential to unravel the mechanisms underlying the pathophysiology of complex conditions such as chronic fatigue syndrome (CFS). This study was undertaken to explore the role of brain-derived neurotrophic factor (BDNF) genetics, epigenetics, and protein expression in patients with both CFS and comorbid fibromyalgia (CFS/FM).
A repeated-measures study was conducted in 54 participants (28 patients with CFS/FM and 26 matched healthy controls). Participants underwent a comprehensive assessment, including questionnaires, sensory testing, and blood withdrawal. Serum BDNF (sBDNF) protein levels were measured using enzyme-linked immunosorbent assay, while polymorphism and DNA methylation were measured in blood using pyrosequencing technology. To assess the temporal stability of the measures, participants underwent the same assessment twice within 4 days.
Repeated-measures mixed linear models were used for between-group analysis, with mean differences and 95% confidence intervals (95% CIs) shown. Compared to controls, serum BNDF was higher in patients with CFS/FM (F = 15.703; mean difference 3.31 ng/ml [95% CI 1.65, 4.96]; P = 0.001), whereas BDNF DNA methylation in exon 9 was lower (F = 7.543; mean difference -2.16% [95% CI -3.93, -0.83]; P = 0.007). BDNF DNA methylation was mediated by the Val66Met (rs6265) polymorphism. Lower methylation in the same region predicted higher sBDNF levels (F = 7.137, β = -0.408 [95% CI -0.711, -0.105]; P = 0.009), which in turn predicted participants' symptoms (F = 14.410, β = 3.747 [95% CI 1.79, 5.71]; P = 0.001) and widespread hyperalgesia (F = 4.147, β = 0.04 [95% CI 0.01, 0.08]; P = 0.044).
Our findings indicate that sBDNF levels are elevated in patients with CFS/FM and that BDNF methylation in exon 9 accounts for the regulation of protein expression. Altered BDNF levels might represent a key mechanism explaining CFS/FM pathophysiology.
神经营养因子的表观遗传学有可能揭示慢性疲劳综合征（CFS）等复杂疾病的病理生理学背后的机制。本研究旨在探讨脑源性神经营养因子（BDNF）的遗传学、表观遗传学和蛋白质表达在 CFS 和共病纤维肌痛（CFS/FM）患者中的作用。
对 54 名参与者（28 名 CFS/FM 患者和 26 名匹配的健康对照者）进行了重复测量研究。参与者接受了全面评估，包括问卷调查、感觉测试和采血。使用酶联免疫吸附试验测量血清 BDNF（sBDNF）蛋白水平，使用焦磷酸测序技术测量血液中的多态性和 DNA 甲基化。为了评估测量的时间稳定性，参与者在 4 天内两次接受相同的评估。
采用重复测量混合线性模型进行组间分析，显示平均值差异和 95%置信区间（95%CI）。与对照组相比，CFS/FM 患者的血清 BNDF 更高（F=15.703；平均差异 3.31ng/ml[95%CI1.65,4.96]；P=0.001），而外显子 9 的 BDNF DNA 甲基化水平较低（F=7.543；平均差异-2.16%[95%CI-3.93,-0.83]；P=0.007）。BDNF DNA 甲基化受 Val66Met（rs6265）多态性的调节。同一区域的低甲基化预测更高的 sBDNF 水平（F=7.137，β=-0.408[95%CI-0.711,-0.105]；P=0.009），进而预测参与者的症状（F=14.410，β=3.747[95%CI1.79,5.71]；P=0.001）和广泛的痛觉过敏（F=4.147，β=0.04[95%CI0.01,0.08]；P=0.044）。
我们的研究结果表明，CFS/FM 患者的 sBDNF 水平升高，外显子 9 的 BDNF 甲基化可调节蛋白质表达。改变的 BDNF 水平可能代表解释 CFS/FM 病理生理学的关键机制。
