Dan Buskila1, Piercarlo Sarzi-Puttini2
1Soroka Medical Center, Israel
2Rheumatology Unit, ASST Fatebenefratelli-Sacco, University of Milan, Italy
Fibromyalgia (FM) is a common chronic widespread pain disorder persisting for more than 3 months that presents diagnostic challenges for clinicians (1,2). FM is commonly accompanied by additional symptoms, such as fatigue, sleep disturbance, cognitive dysfunction, and depression.
Previous studies have clearly demonstrated a strong familial aggregation of chronic pain, leading researchers to conclude that up to 50% of the development of chronic pain may be explained by heritability(3,4). Pellegrino et al. (5) found that 26 (52%) of the enrolled parents and siblings exhibited clinical evidence of FM, and an additional 11 (22%), without apparent symptoms of FM, exhibited abnormal muscle consistency on palpation. Similar observations in terms of familial aggregation among FM patients were also reported in two studies by Buskila et al. (6-8)
Psychological factors such as depression and personality traits also demonstrate familial aggregation among FM patients.
Glazer et al. (9) searching for shared personality traits in FM patients and first-degree relatives, reached the conclusion that hereditary factor determining personality traits may play a role in FM development as well.
Genome-wide association studies (GWAS)
Genome-wide association studies (GWAS) investigated genes potentially involved in fibromyalgia pathogenesis (3). Feng et al. (10) performed whole-exome sequencing and subsequent directed mutation analysis to discover possible candidate genes for FM. Two nonsense mutations associated with high levels of specific cytokines were identified. The W32X mutation in C11orf40 and the Q100X mutation in in ZNF77 (zinc finger protein 77) correlated with high plasma MCP-1 (monocyte chemoattractant protein 1) and IP-10 (interferon γ-induced protein 10) levels, and with high plasma IL-12 (interleukin 12) levels, respectively (11).
Other potential candidate genes found associated to fibromyalgia are SLC64A4, TRPV2, MYT1L, and NRXN3. Furthermore, a gene-environmental interaction has been proposed as triggering mechanism, through epigenetic alterations: In particular, fibromyalgia appears to be characterized by a hypomethylated DNA pattern, in genes implicated in stress response, DNA repair, autonomic system response, and subcortical neuronal abnormalities (12,13).
Associations between FM and certain genetic polymorphisms affecting the serotonergic, dopaminergic, and catecholaminergic pathways have been found via candidate gene analyses (4).
A variety of studies found that FM was associated with disturbances in serum and cerebrospinal fluid (CSF) serotonin metabolism and neurotransmission; the levels of 5-HT and metabolites thereof were significantly lower in the serum and CSF of FM patients(14-16).
Catechol-O-methyl transferase is one of the major enzymes responsible for metabolizing and inactivating catecholamine neurotransmitters including dopamine, norepinephrine and epinephrine, as well as catechol-containing drugs. COMT in the CNS affects catecholamine neurotransmission in the prefrontal cortex (17). SNPs of the COMT gene may contribute to FM susceptibility and symptom severity.
Disruption of dopaminergic response to painful stimulation has been demonstrated among FM patients and there is some clinical indication of a role played by Dopamine in FM pathophysiology (3). Smith et al. (18) performed a large-scale candidate gene analysis using a dedicated gene-array chip which assays variants of over 350 genes known to be involved in biological pathways.. After replication analysis using an independent cohort, the authors suggested that the trace amine-associated receptor 1 (TAAR1), regulator of G protein signaling 4 (RGS4), cannabinoid receptor 1 (CNR1), and glutamate ionotropic receptor AMPA type subunit 4 provided (GRIA4) genes were potentially associated with the development of FM.
In FM, Vargas-Alarcon et al.(19) found that patients with polymorphisms in the sodium channel SCN9A gene, expressed in the dorsal root ganglia, had higher FIQ scores. Furthermore, Vargas-Alarcon et al.(20) found an association between adrenergic receptor (AR) gene polymorphisms and FM.
Bjersing et al. (21) conducted the first microRNA study, identifying nine microRNAs that were significantly lower in the CSF of FM patients than controls. In another study, Bjersing et al. (22) identified eight serum-circulating microRNAs that were differentially expressed between FM patients and healthy female controls.
In view of this it appears likely that novel genetic approaches are poised to expand our understanding of the genetic underpinnings of FM in the future.
Similar to other complex CNS disorders, FM is considered to result from an interaction between genetic factors and environmental factors (3,4). Thus, genetics per se appear to explain only part of pathogenetic puzzle of FM.
The genetic studies conducted over the past two decades have not completely explained the molecular mechanisms of FM. Moreover, the effects of genetic factors on FM disease progression, therapeutic response, and outcomes have not yet been defined (5). Additionally, pharmacogenetic research is likely to have an impact on the pharmacological management of FM in the future. Hence, the genetics of FM remains a project under construction.
1. Arnold LM, Bennett RM, Crofford LJ, Dean LE, Clauw DJ, Goldenberg DL, Fitzcharles MA, Paiva ES, Staud R, Sarzi-Puttini P, Buskila D, Macfarlane GJ. AAPT Diagnostic Criteria for Fibromyalgia. J Pain. 2018 Nov 16. pii: S1526-5900(18)30832-0.
2. Jones GT, Atzeni F, Beasley M, FluB E, Sarzi-Puttini P, Macfarlane GJ. The prevalence of fibromyalgia in the general population: a comparison of the American College of Rheumatology 1990, 2010, and modified 2010 classification criteria. Arthritis Rheumatol. 2015;67:568–575.
3. Park DJ, Lee SS. New insights into the genetics of fibromyalgia. Korean J Intern Med. 2017 Nov;32(6):984-995.
4. Ablin JN, Buskila D. Update on the genetics of the fibromyalgia syndrome. Best Pract Res Clin Rheumatol. 2015 Feb;29(1):20-8.
5. Buskila D, Sarzi-Puttini P. Biology and therapy of fibromyalgia. Genetic aspects of fibromyalgia syndrome. Arthritis Res Ther. 2006;8:218.
6. Pellegrino MJ, Waylonis GW, Sommer A. Familial occurrence of primary fibromyalgia. Arch Phys Med Rehabil. 1989;70:61–63.
7. Buskila D, Neumann L, Hazanov I, Carmi R. Familial aggregation in the fibromyalgia syndrome. Semin Arthritis Rheum. 1996;26:605–611.
8. Buskila D, Neumann L. Fibromyalgia syndrome (FM) and nonarticular tenderness in relatives of patients with FM. J Rheumatol. 1997;24:941–944.
9. Glazer Y, Buskila D, Cohen H, Ebstein RP, Neumann L. Differences in the personality profile of fibromyalgia patients and their relatives with and without fibromyalgia. Clin Exp Rheumatol. 2010;28(6 Suppl 63):S27–S32
10. Feng J, Zhang Z, Wu X, et al. Discovery of potential new gene variants and inflammatory cytokine associations with fibromyalgia syndrome by whole exome sequencing. PLoS One. 2013;8:e65033
11. D'Agnelli S, Arendt-Nielsen L, Gerra MC, Zatorri K, Boggiani L, Baciarello M, Bignami E. Fibromyalgia: Genetics and epigenetics insights may provide the basis for the development of diagnostic biomarkers. Mol Pain. 2019 Jan-Dec;15:174480691881994
12. Menzies V, Lyon DE, Archer KJ, Zhou Q, Brumelle J, Jones KH, Gao G, York TP, and Jackson-Cook C. Epigenetic alterations and an increased frequency of micronuclei in women with fibromyalgia. Nurs Res Pract 2013; 2013: 795784.
13. Ciampi de Andrade D, Maschietto M, Galhardoni R, Gouveia G, Chile T, Victorino Krepischi AC, Dale CS, Brunoni AR, Parravano DC, Cueva Moscoso AS, Raicher I, Kaziyama HHS, Teixeira MJ, and Brentani HP. Epigenetics insights into chronic pain: DNA hypo-methylation in fibromyalgia-a controlled pilot-study. Pain 2017; 158: 1473–1480.
14. Russell IJ, Michalek JE, Vipraio GA, Fletcher EM, Javors MA, Bowden CA. Platelet 3H-imipramine uptake receptor density and serum serotonin levels in patients with fibromyalgia/fibrositis syndrome. J Rheumatol. 1992;19:104–109.
15. Russell IJ, Vaeroy H, Javors M, Nyberg F. Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum. 1992;35:550–556.
16. Wolfe F, Russell IJ, Vipraio G, Ross K, Anderson J. Serotonin levels, pain threshold, and fibromyalgia symptoms in the general population. J Rheumatol. 1997;24:555–559.
17. Cohen H, Neumann L, Glazer Y, Ebstein RP, Buskila D. The relationship between a common catechol-Omethyltransferase (COMT) polymorphism val(158) met and fibromyalgia. Clin Exp Rheumatol. 2009;27(5 Suppl 56):S51–S56
18. Smith SB, Maixner DW, Fillingim RB, et al. Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia. Arthritis Rheum. 2012;64:584–593
19. Vargas-Alarcon G, Alvarez-Leon E, Fragoso JM, et al. A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia. BMC Musculoskelet Disord. 2012;13:23.
20. Vargas-Alarcon G, Fragoso JM, Cruz-Robles D, et al. Association of adrenergic receptor gene polymorphisms with different fibromyalgia syndrome domains. Arthritis Rheum. 2009;60:2169–2173.
21. Bjersing JL, Lundborg C, Bokarewa MI, Mannerkorpi K. Profile of cerebrospinal microRNAs in fibromyalgia. PLoS One. 2013;8:e78762
22. Bjersing JL, Bokarewa MI, Mannerkorpi K. Profile of circulating microRNAs in fibromyalgia and their relation to symptom severity: an exploratory study. Rheumatol Int. 2015;35:635–642.