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

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.

[1]  L. Arendt-Nielsen,et al.  DNA methylation changes in genes involved in inflammation and depression in fibromyalgia: a pilot study , 2020, Scandinavian journal of pain.

[2]  F. González-Salazar,et al.  Immune System Sex Differences May Bridge the Gap Between Sex and Gender in Fibromyalgia , 2020, Frontiers in Neuroscience.

[3]  L. Nathanson,et al.  Activation of Transposable Elements in Immune Cells of Fibromyalgia Patients , 2019, International journal of molecular sciences.

[4]  G. Littlejohn,et al.  Faculty Opinions recommendation of 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. , 2019, Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature.

[5]  Michael B. First,et al.  Chronic pain as a symptom or a disease: the IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11) , 2019, Pain.

[6]  L. Arendt-Nielsen,et al.  Fibromyalgia: Genetics and epigenetics insights may provide the basis for the development of diagnostic biomarkers , 2018, Molecular pain.

[7]  S. Tiosano,et al.  A systematic review of precipitating physical and psychological traumatic events in the development of fibromyalgia. , 2018, Seminars in arthritis and rheumatism.

[8]  M. Fletcher,et al.  Identification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-associated DNA methylation patterns , 2018, PloS one.

[9]  B. McEwen,et al.  Aggression, Social Stress, and the Immune System in Humans and Animal Models , 2018, Front. Behav. Neurosci..

[10]  Ronaldo da Silva Francisco Junior,et al.  Maternal 5mCpG Imprints at the PARD6G-AS1 and GCSAML Differentially Methylated Regions Are Decoupled From Parent-of-Origin Expression Effects in Multiple Human Tissues , 2018, Front. Genet..

[11]  J. Christianson,et al.  Potential Mechanisms Underlying Centralized Pain and Emerging Therapeutic Interventions , 2018, Front. Cell. Neurosci..

[12]  Ping Zhu,et al.  CGmapTools improves the precision of heterozygous SNV calls and supports allele‐specific methylation detection and visualization in bisulfite‐sequencing data , 2018, Bioinform..

[13]  F. Nicoletti,et al.  Analgesia induced by the epigenetic drug, L-acetylcarnitine, outlasts the end of treatment in mouse models of chronic inflammatory and neuropathic pain , 2017, Molecular pain.

[14]  T. Spector,et al.  Genome-wide methylation analysis of a large population sample shows neurological pathways involvement in chronic widespread musculoskeletal pain , 2017, Pain.

[15]  Philip J Mease,et al.  2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. , 2016, Seminars in arthritis and rheumatism.

[16]  K. Noguchi,et al.  Correlation Between DNA Methylation of TRPA1 and Chronic Pain States in Human Whole Blood Cells. , 2016, Pain medicine.

[17]  Karmen K. Yoder,et al.  Differential dopamine function in fibromyalgia , 2015, Brain Imaging and Behavior.

[18]  J Keller,et al.  HPA Axis in Major Depression: Cortisol, Clinical Symptomatology, and Genetic Variation Predict Cognition , 2016, Molecular Psychiatry.

[19]  W. Rief,et al.  Do we need a third mechanistic descriptor for chronic pain states? , 2016, Pain.

[20]  Brian W. Haas,et al.  Epigenetic modification of OXT and human sociability , 2016, Proceedings of the National Academy of Sciences.

[21]  I. Russell,et al.  Neuropeptides CRH, SP, HK-1, and Inflammatory Cytokines IL-6 and TNF Are Increased in Serum of Patients with Fibromyalgia Syndrome, Implicating Mast Cells , 2016, The Journal of Pharmacology and Experimental Therapeutics.

[22]  Jill Waalen,et al.  Genome-wide expression profiling in the peripheral blood of patients with fibromyalgia. , 2016, Clinical and experimental rheumatology.

[23]  Helene Kretzmer,et al.  metilene: fast and sensitive calling of differentially methylated regions from bisulfite sequencing data , 2016, Genome research.

[24]  M. Millecamps,et al.  Overlapping signatures of chronic pain in the DNA methylation landscape of prefrontal cortex and peripheral T cells , 2016, Scientific Reports.

[25]  K. Maggert,et al.  What Do You Mean, “Epigenetic”? , 2015, Genetics.

[26]  M. Millecamps,et al.  An epigenetic hypothesis for the genomic memory of pain , 2015, Front. Cell. Neurosci..

[27]  D. Buskila,et al.  Update on the genetics of the fibromyalgia syndrome. , 2015, Best practice & research. Clinical rheumatology.

[28]  R. Traub,et al.  Epigenetic upregulation of metabotropic glutamate receptor 2 in the spinal cord attenuates oestrogen-induced visceral hypersensitivity , 2014, Gut.

[29]  Patrick O. McGowan,et al.  DNA Methylation Modifications Associated with Chronic Fatigue Syndrome , 2014, PloS one.

[30]  Cui Yin,et al.  Epigenetic Modification of Spinal miR-219 Expression Regulates Chronic Inflammation Pain by Targeting CaMKIIγ , 2014, The Journal of Neuroscience.

[31]  M. Gratacós,et al.  Genome-wide analysis of single nucleotide polymorphisms and copy number variants in fibromyalgia suggest a role for the central nervous system , 2014, PAIN®.

[32]  J. Cavanagh,et al.  Peripheral inflammation is associated with remote global gene expression changes in the brain , 2014, Journal of Neuroinflammation.

[33]  Chrysanthi Ainali,et al.  Differential methylation of the TRPA1 promoter in pain sensitivity , 2014, Nature Communications.

[34]  G. Dammann,et al.  Aberrant Methylation of Gene Associated CpG Sites Occurs in Borderline Personality Disorder , 2013, PloS one.

[35]  Michael Q. Zhang,et al.  BS-Seeker2: a versatile aligning pipeline for bisulfite sequencing data , 2013, BMC Genomics.

[36]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[37]  Paul Jarle Mork,et al.  Fibromyalgia Syndrome is Associated with Hypocortisolism , 2010, International journal of behavioral medicine.

[38]  F. Wolfe,et al.  The American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and Measurement of Symptom Severity , 2010, Arthritis care & research.

[39]  Serge Marchand,et al.  DRD3 Ser9Gly polymorphism is related to thermal pain perception and modulation in chronic widespread pain patients and healthy controls. , 2009, The journal of pain : official journal of the American Pain Society.

[40]  M. Lasaga,et al.  Role of metabotropic glutamate receptors in the control of neuroendocrine function , 2008, Neuropharmacology.

[41]  K. Henriksson,et al.  Pathophysiological mechanisms in chronic musculoskeletal pain (fibromyalgia): the role of central and peripheral sensitization and pain disinhibition. , 2007, Best practice & research. Clinical rheumatology.

[42]  W. Vale,et al.  The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress , 2006, Dialogues in clinical neuroscience.

[43]  C. Kirschbaum,et al.  Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress , 2003, Biological Psychiatry.

[44]  G Lewith,et al.  Identification of novel expressed sequences, up‐regulated in the leucocytes of chronic fatigue syndrome patients , 2003, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[45]  Elizabeth R. Unger,et al.  Utility of the Blood for Gene Expression Profiling and Biomarker Discovery in Chronic Fatigue Syndrome , 2003, Disease markers.

[46]  K. Någren,et al.  Dopamine D2 receptor binding in the human brain is associated with the response to painful stimulation and pain modulatory capacity , 2002, PAIN.

[47]  A. Vercelli,et al.  Defective Dendrite Elongation but Normal Fertility in Mice Lacking the Rho-Like GTPase Activator Dbl , 2002, Molecular and Cellular Biology.

[48]  Jesús Sanz,et al.  Fiabilidad, validez y datos normativosdel inventario para la depresiónde beck , 1998 .

[49]  S. Pillemer,et al.  Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia. , 1994, Arthritis and rheumatism.

[50]  T. Lundeberg,et al.  The antinociceptive effect of non-noxious sensory stimulation is mediated partly through oxytocinergic mechanisms. , 1993, Acta physiologica Scandinavica.

[51]  A. Benelli,et al.  Influence of oxytocin on nociception and morphine antinociception , 1993, Neuropeptides.

[52]  R M Bennett,et al.  The fibromyalgia impact questionnaire: development and validation. , 1991, The Journal of rheumatology.

[53]  M. Jackson.  What do you mean? , 1989, Geriatric nursing.

[54]  Daniel J Buysse,et al.  The Pittsburgh sleep quality index: A new instrument for psychiatric practice and research , 1989, Psychiatry Research.

[55]  S. Sheather,et al.  Clinical applications of visual analogue scales: a critical review , 1988, Psychological Medicine.

[56]  G. Fasano,et al.  A multidimensional version of the Kolmogorov–Smirnov test , 1987 .

[57]  A. Beck,et al.  An inventory for measuring depression. , 1961, Archives of general psychiatry.

[58]  İ. Coşkun Benlidayı.  Role of inflammation in the pathogenesis and treatment of fibromyalgia , 2019, Rheumatology international.

[59]  Chiao-Ling Lo,et al.  Environmental Influence of Epigenetics , 2017 .

[60]  J. Wiley,et al.  Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system. , 2015, Gastroenterology.

[61]  G. Fan,et al.  DNA Methylation and Its Basic Function , 2013, Neuropsychopharmacology.

[62]  M. Blanco,et al.  Propuesta de una versión de consenso del Fibromyalgia Impact Questionnaire (FIQ) para la población española , 2007 .