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Mechanisms of Disease: genetics of fibromyalgia

Nature Clinical Practice Rheumatology volume 2, pages 671–678 (2006)Cite this article

Abstract

Fibromyalgia is characterized by widespread pain and tenderness, and has a significant familial component. The etiology of fibromyalgia remains unclear, but genetic factors seem to have a significant role, and are influenced by environmental factors. Research over the past two decades has demonstrated that genetic polymorphisms in the serotoninergic, dopaminergic and catecholaminergic systems of pain transmission and processing are involved in the etiology of fibromyalgia, but additional candidates continue to emerge. Fibromyalgia is thought to belong to the group of affective spectrum disorders, which include related psychiatric and medical disorders. As the concept of affective spectrum disorders continues to evolve, progress in the understanding of the genetic basis of related functional disorders, such as irritable bowel syndrome and post-traumatic-stress disorder, is aiding our understanding of the genetic basis of fibromyalgia.

Key Points

  • Familial aggregation is well established in fibromyalgia

  • In the search for a genetic basis for this aggregation, research has focused on polymorphisms in genes related to neurotransmitters involved in pain transmission and processing

  • Serotoninergic and dopaminergic markers, as well as polymorphisms in the genes encoding cathechol-O-methyl transferase and the NK1 receptor, are among the candidates studied, and a number of significant associations have been reported

  • Similar approaches have been used in studying other functional disorders, which, together with fibromyalgia, compromise the affective spectrum disorders

  • Future insight into the genetic basis of fibromyalgia might make classification and diagnosis easier, as well as improving pathophysiologic and therapeutic understanding

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References

  1. Gracely RH et al. (2002) Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum 46: 1333–1343

    Article  PubMed  Google Scholar 

  2. Staud R et al. (2001) Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 91: 165–175

    Article  CAS  PubMed  Google Scholar 

  3. Hudson JI et al. (2004) Family study of fibromyalgia and affective spectrum disorder. Biol Psychiatry 56: 884–891

    Article  PubMed  Google Scholar 

  4. Hudson JI et al. (2003) Family study of affective spectrum disorder. Arch Gen Psychiatry 60: 170–177

    Article  PubMed  Google Scholar 

  5. Arnold LM et al. (2004) Family study of fibromyalgia. Arthritis Rheum 50: 944–952

    Article  PubMed  Google Scholar 

  6. Ablin NJ and Aloush V (2004) Causes of familial aggregation of fibromyalgia: comment on the article by Arnold et al. Arthritis Rheum 50: 3049–3060

    Article  Google Scholar 

  7. Wadhwa PD et al. (2001) The neurobiology of stress in human pregnancy: implications for prematurity and development of the fetal central nervous system. Prog Brain Res 133: 131–142

    Article  CAS  PubMed  Google Scholar 

  8. Couzin J (2002) Quirks of fetal environment felt decades later. Science 296: 2167–2169

    Article  CAS  PubMed  Google Scholar 

  9. Caspi A et al. (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301: 386–389

    Article  CAS  PubMed  Google Scholar 

  10. Burda CD et al. (1986) Histocompatability antigens in the fibrositis (fibromyalgia) syndrome. Clin Exp Rheumatol 4: 355–358

    CAS  PubMed  Google Scholar 

  11. Yunus MB et al. (1999) Genetic linkage analysis of multicase families with fibromyalgia syndrome. J Rheumatol 26: 408–412

    CAS  PubMed  Google Scholar 

  12. Wolfe F et al. (1997) Serotonin levels, pain threshold, and fibromyalgia symptoms in the general population. J Rheumatol 24: 555–559

    CAS  PubMed  Google Scholar 

  13. Russell IJ et al. (1992) Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum 35: 550–556

    Article  CAS  PubMed  Google Scholar 

  14. Yunus MB et al. (1992) Plasma tryptophan and other amino acids in primary fibromyalgia: a controlled study. J Rheumatol 19: 90–94

    CAS  PubMed  Google Scholar 

  15. Offenbaecher M et al. (1999) Possible association of fibromyalgia with a polymorphism in the serotonin transporter gene regulatory region. Arthritis Rheum 42: 2482–2488

    Article  CAS  PubMed  Google Scholar 

  16. Cohen H et al. (2002) Confirmation of an association between fibromyalgia and serotonin transporter promoter region (5- HTTLPR) polymorphism, and relationship to anxiety-related personality traits. Arthritis Rheum 46: 845–847

    Article  PubMed  Google Scholar 

  17. Narita M et al. (2003) Association between serotonin transporter gene polymorphism and chronic fatigue syndrome. Biochem Biophys Res Commun 14: 264–266

    Article  Google Scholar 

  18. Bondy B et al. (1999) The T102C polymorphism of the 5-HT2A-receptor gene in fibromyalgia. Neurobiol Dis 6: 433–439

    Article  CAS  PubMed  Google Scholar 

  19. Frank B et al. (2004) Mutational analysis of serotonin receptor genes: HTR3 A and HTR3B in fibromyalgia patients. Clin Rheumatol 23: 338–344

    Article  PubMed  Google Scholar 

  20. Clauw DJ and Crofford LJ (2003) Chronic widespread pain and fibromyalgia: what we know, and what we need to know. Best Pract Res Clin Rheumatol 17: 685–701

    Article  PubMed  Google Scholar 

  21. Zubieta JK et al. (2003) COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 299: 1240–1243

    Article  CAS  PubMed  Google Scholar 

  22. Gursoy S et al. (2003) Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia syndrome. Rheumatol Int 23: 104–107

    Article  PubMed  Google Scholar 

  23. Malt EA et al. (2003) Altered dopamine D2 receptor function in fibromyalgia patients: a neuroendocrine study with buspirone in women with fibromyalgia compared to female population based controls. J Affect Disord 75: 77–82

    Article  CAS  PubMed  Google Scholar 

  24. Holman AJ and Myers RR (2005) A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis Rheum 52: 2495–2505

    Article  CAS  PubMed  Google Scholar 

  25. Buskila D et al. (2004) An association between fibromyalgia and the dopamine D4 receptor exon III repeat polymorphism and relationship to novelty seeking personality traits. Mol Psychiatry 9: 730–731

    Article  CAS  PubMed  Google Scholar 

  26. Van Tol HH et al. (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 18: 610–614

    Article  Google Scholar 

  27. Vaeroy H et al. (1988) Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis. Pain 32: 21–26

    Article  CAS  PubMed  Google Scholar 

  28. Russell IJ et al. (1994) Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum 37: 1593–1601

    Article  CAS  PubMed  Google Scholar 

  29. Liu Z et al. (1995) Elevated substance P level in cerebrospinal fluid from patients with fibromyalgia is contrasted by a decrease in Met-enkephalin-Arg-Phe. Analgesia 1: 4–6

    Article  Google Scholar 

  30. Evengard B et al. (1998) Chronic fatigue syndrome differs from fibromyalgia. No evidence for elevated substance P levels in cerebrospinal fluid of patients with chronic fatigue syndrome. Pain 78: 153–155

    Article  CAS  PubMed  Google Scholar 

  31. Terman GW (2001) Spinal mechanisms and their modulation. In Bonica's Management of Pain, B, edn 3, 73–152 (Eds Loeser JD and Chapman CR) Philadelphia: Lippincott-Williams & Wilkins

    Google Scholar 

  32. Quartara L and Maggi CA (1998) The tachykinin NK1 receptor. Part II: Distribution and pathophysiological roles. Neuropeptides 32: 1–49

    Article  CAS  PubMed  Google Scholar 

  33. McLean S (2005) Do substance P and the NK1 receptor have a role in depression and anxiety? Curr Pharm Des 11: 1529–1547

    Article  CAS  PubMed  Google Scholar 

  34. Lecci A et al. (2002) Tachykinin receptor antagonists in irritable bowel syndrome. Curr Opin Investig Drugs 3: 589–601

    CAS  PubMed  Google Scholar 

  35. Duffy RA (2004) Potential therapeutic targets for neurokinin-1 receptor antagonists. Expert Opin Emerg Drugs 9: 9–21

    Article  CAS  PubMed  Google Scholar 

  36. Ablin JN et al. (2005) Possible association between fibromyalgia and a novel 1354G>C polymorphism in the TACR1 (substance P receptor) gene in Ashkenazi patients [abstract #656]. Arthritis Rheum 52 (Suppl): S269

    Google Scholar 

  37. Wessely S et al. (1999) Functional somatic syndromes: one or many? Lancet 354: 936–939

    Article  CAS  PubMed  Google Scholar 

  38. Hudson JI and Pope HG Jr (1990) Affective spectrum disorder: does antidepressant response identify a family of disorders with a common pathophysiology? Am J Psychiatry 147: 552–564

    Article  CAS  PubMed  Google Scholar 

  39. Hudson JI et al. (1992) Comorbidity of fibromyalgia with medical and psychiatric disorders. Am J Med 92: 363–367

    Article  CAS  PubMed  Google Scholar 

  40. Buchwald D and Garrity D (1994) Comparison of patients with chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities. Arch Intern Med 154: 2049–2053

    Article  CAS  PubMed  Google Scholar 

  41. Aaron LA et al. (2000) Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med 160: 221–227

    Article  CAS  PubMed  Google Scholar 

  42. Walsh CM et al. (2001) A family history study of chronic fatigue syndrome. Psychiatr Genet 11: 123–128

    Article  CAS  PubMed  Google Scholar 

  43. Camilleri M et al. (2002) Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome. Gastroenterology 123: 425–432

    Article  CAS  PubMed  Google Scholar 

  44. True WR et al. (1993) A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch Gen Psychiatry 50: 257–264

    Article  CAS  PubMed  Google Scholar 

  45. Segman RH et al. (2002) Association between the dopamine transporter gene and posttraumatic stress disorder. Mol Psychiatry 7: 903–907

    Article  CAS  PubMed  Google Scholar 

  46. Lawford BR et al. (2003) D2 dopamine receptor gene polymorphism: paroxetine and social functioning in posttraumatic stress disorder. Eur Neuropsychopharmacol 13: 313–320

    Article  CAS  PubMed  Google Scholar 

  47. Slotkoff AT et al. (1997) The relationship between fibromyalgia and the multiple chemical sensitivity syndrome. Scand J Rheumatol 26: 364–367

    Article  CAS  PubMed  Google Scholar 

  48. Wolfe F et al. (1990) The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 33: 160–172

    Article  CAS  PubMed  Google Scholar 

  49. Gottesman II and Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160: 636–645

    Article  PubMed  Google Scholar 

  50. Epstein SA et al. (1999) Psychiatric disorders in patients with fibromyalgia. A multicenter investigation. Psychosomatics 40: 57–63

    Article  CAS  PubMed  Google Scholar 

  51. Krag NJ et al. (1994) A blinded, controlled evaluation of anxiety and depressive symptoms in patients with fibromyalgia, as measured by standardized psychometric interview scales. Acta Psychiatr Scand 89: 370–375

    Article  CAS  PubMed  Google Scholar 

  52. Aaron LA et al. (1996) Psychiatric diagnoses in patients with fibromyalgia are related to health care-seeking behavior rather than to illness. Arthritis Rheum 39: 436–445

    Article  CAS  PubMed  Google Scholar 

  53. Turk DC et al. (2002) Psychological evaluation of patients diagnosed with fibromyalgia syndrome: a comprehensive approach. Rheum Dis Clin North Am 28: 219–233

    Article  PubMed  Google Scholar 

  54. Ferrari R (2000) The biopsychosocial model—a tool for rheumatologists. Baillieres Best Pract Res Clin Rheumatol 14: 787–795

    Article  CAS  PubMed  Google Scholar 

  55. Williams DA (2003) Psychological and behavioural therapies in fibromyalgia and related syndromes. Best Pract Res Clin Rheumatol 17: 649–665

    Article  PubMed  Google Scholar 

  56. Pellegrino MJ et al. (1989) Familial occurrence of primary fibromyalgia. Arch Phys Med Rehabil 70: 61–63

    CAS  PubMed  Google Scholar 

  57. Buskila D et al. (1996) Familial aggregation in the fibromyalgia syndrome. Semin Arthritis Rheum 26: 605–611

    Article  CAS  PubMed  Google Scholar 

  58. Buskila D and Neumann L (1997) Fibromyalgia syndrome (FM) and nonarticular tenderness in relatives of patients with FM. J Rheumatol 24: 941–944

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. senior physician in the Department of Rheumatology, Tel-Aviv Sourasky Medical Center and at the Sackler Faculty of Medicine, Tel-Aviv University, Israel

    Jacob N Ablin

  2. Ministry of Health in the Anxiety and Stress Research Unit at the Mental Health Center,

    Hagit Cohen & Dan Buskila

  3. Department of Medicine at the Soroka Medical Center, both in Beer Sheba, Israel

    Hagit Cohen & Dan Buskila

Authors
  1. Jacob N Ablin
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  2. Hagit Cohen
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  3. Dan Buskila
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Correspondence to Jacob N Ablin.

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Ablin, J., Cohen, H. & Buskila, D. Mechanisms of Disease: genetics of fibromyalgia. Nat Rev Rheumatol 2, 671–678 (2006). https://doi.org/10.1038/ncprheum0349

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