DNA Methylation Changes in Fibromyalgia Suggest the Role of the Immune-Inflammatory Response and Central Sensitization

Abstract

Fibromyalgia (FM) has been explained as a result of gene-environment interactions. The present study aims to verify DNA methylation differences in eleven candidate genome regions previously associated to FM, evaluating DNA methylation patterns as potential disease biomarkers. DNA methylation was analyzed through bisulfite sequencing, comparing 42 FM women and their 42 healthy sisters. The associations between the level of methylation in these regions were further explored through a network analysis. Lastly, a logistic regression model investigated the regions potentially associated with FM, when controlling for sociodemographic variables and depressive symptoms. The analysis highlighted significant differences in the GCSAML region methylation between patients and controls. Moreover, seventeen single CpGs, belonging to other genes, were significantly different, however, only one cytosine related to GCSAML survived the correction for multiple comparisons. The network structure of methylation sites was different for each group; GRM2 methylation represented a central node only for FM patients. Logistic regression revealed that depressive symptoms and DNA methylation in the GRM2 region were significantly associated with FM risk. Our study encourages better exploration of GCSAML and GRM2 functions and their possible role in FM affecting immune, inflammatory response, and central sensitization of pain.

DNA Methylation Signatures of Functional Somatic Syndromes: Systematic Review

“…Of these, the study investigating 112 regions within 100 genes (including NR3C1 ) found no group differences in methylation (46). The larger follow-up study by the same group, which included all pilot cases, investigated 12 regions within 11 genes (including NR3C1 ) and found one site within GCSAML , the gene encoding the germinal center–associated signaling and motility-like protein, to be hypomethylated in women with fibromyalgia compared with controls (47).…”

Mechanisms of transcranial direct current stimulation (tDCS) for pain in patients with fibromyalgia syndrome

“…Neuroplastic changes, including long-term potentiation (LTP) and long-term depression (LTD) ( Kourosh-Arami et al, 2021 ), refer to the ability of the brain to reshape itself by generating new neural connections. Because of this adaptability, FMS causes an overactive brain pain processing system and generalized widespread pain ( Gerra et al, 2021 ; Jayakar et al, 2021 ; Mezhov et al, 2021 ). Neuroplastic changes are associated with brain-derived neurotrophic factor (BDNF), which affects neuronal growth and synaptic connectivity.…”

Fatores genéticos associados à fibromialgia: uma revisão narrativa

“…Estes, por sua vez, podem modular a função do genoma e o fenótipo por meio de modificações covalentes de histonas, metilação do DNA ou RNAs não codificadores, sem que a sequência do DNA seja alterada (Low & Schweinhardt, 2012;Szyf & Bick 2013). 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).…”