DNA Methylation and Brain‐Derived Neurotrophic Factor Expression Account for Symptoms and Widespread Hyperalgesia in Patients With Chronic Fatigue Syndrome and Comorbid Fibromyalgia

Abstract

Objective 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). Methods 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. Results 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). Conclusion 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.

High‐dose spironolactone lacks effectiveness in treatment of fibromyalgia (RCT)

“…Actual concepts of FMS suggest a multifactorial pathology including disruption of inhibitory pain modulation (Uygur‐Kucukseymen et al., 2020), altered BDNF expression (Polli et al., 2020), central sensitization (Vecchio et al., 2020), peripheral neuropathies (Leinder et al., 2016), post‐traumatic stress disorder and corresponding behavioural features (Conversona et al., 2019) as well a variety of psychological and social stress factors and chronic fatigue (Haeuser, 2016).…”

Fatores genéticos associados à fibromialgia: uma revisão narrativa

“…Alguns estudos (em grande parte estudos piloto ou com pequeno número amostral) foram conduzidos com pacientes com FM e evidências sugerem uma prevalência da influência de padrões (hipo ou hiper) de metilação do DNA nesse grupo, em genes implicados em vias reparo de DNA, processos relacionados ao sistema imunológico, metabolismo relacionado a lipídios, transporte de membrana, sensibilização central, depressão, diferenciação neuronal, desenvolvimento do sistema esquelético e compactação da cromatina (Menzies et al, 2013;Ciampi de Andrade et al, 2017;Gerra et al, 2020;Gerra et al, 2021). Em um estudo com um pequeno grupo misto, composto por pacientes com FM e síndrome da fadiga crônica, resultados preliminares demonstraram que nesse grupo a metilação do DNA do BDNF foi menor em comparação aos indivíduos do grupo controle e que essa metilação é mediada pelo polimorfismo BDNF Val66Met, sugerindo que sua influência na expressão do BDNF possa se dar através desse mecanismo epigenético (Polli et al, 2020). RNAs não codificantes também foram encontrados em pacientes com FM, associados a processos relacionados ao sistema imunológico (Dolcino et al, 2020).…”

Fibromyalgia: Recent Advances in Diagnosis, Classification, Pharmacotherapy and Alternative Remedies

“…With regards FM pathophysiology, serum brain-derived neurotrophic factors (BDNF) were found at higher levels in FM patients while BDNF methylation in exon 9 accounted for the regulation of protein expression. These data suggest that altered BDNF levels might represent a key mechanism explaining FM pathophysiology [ 75 ].…”