Candidate gene studies of fibromyalgia: a systematic review and meta-analysis

Abstract

The aim of this study was to explore whether the candidate gene polymorphisms contribute to fibromyalgia susceptibility. The authors conducted a meta-analysis on associations between serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) S/L allele, catechol-O-methltransferase (COMT) val158Met, and serotonin 2A (5-HT2A) receptor 102T/C polymorphisms and fibromyalgia susceptibility as determined using the following: (1) allele contrast, (2) recessive, (3) dominant models, and (4) contrast of homozygotes. We also performed a systematic review with available data of the candidate genes. A total of 21 separate comparisons were considered in this systematic review and meta-analysis. Seventeen candidate genes and over 35 different polymorphisms were identified in studies on fibromyalgia susceptibility. Meta-analysis of the 5-HTTLPR S/L allele and COMT val158Met failed to reveal any association with fibromyalgia. However, meta-analysis of the C allele, CC + CT genotype, and CC versus TT genotype of the 5-HT2A receptor 102T/C polymorphism showed significant association with fibromyalgia. The overall OR of the association between the C allele and fibromyalgia was 1.333 (95% CI = 1.053–1.688, P = 0.017). The ORs for the CC + CT genotype, and CC versus TT genotype showed the same pattern as that observed for the C allele (OR = 1.541, 95% CI = 1.032–2.303, P = 0.035; OR = 1.838, 95% CI = 1.151–2.936, P = 0.011). This meta-analysis demonstrates that the 5-HT2A receptor 102T/C polymorphism confers susceptibility to fibromyalgia. In contrast, no association was found between the 5-HTTLPR S/L allele, COMT val158Met, and susceptibility to fibromyalgia.

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References

  1. 1.

    Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, Fam AG, Farber SJ, Fiechtner JJ, Franklin CM, Gatter RA, Hamaty D, Lessard J, Lichtbroun AS, Masi AT, Mccain GA, Reynolds WJ, Romano TJ, Russell IJ, Sheon RP (1990) The American college of rheumatology 1990 criteria for the classification of fibromyalgia. Report of the multicenter criteria committee. Arthritis Rheum 33:160–172

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Neumann L, Buskila D (2003) Epidemiology of fibromyalgia. Curr Pain Headache Rep 7:362–368

    PubMed  Article  Google Scholar 

  3. 3.

    Wallace DJ, Linker-Israeli M, Hallegua D, Silverman S, Silver D, Weisman MH (2001) Cytokines play an aetiopathogenetic role in fibromyalgia: a hypothesis and pilot study. Rheumatology (Oxford) 40:743–749

    Article  CAS  Google Scholar 

  4. 4.

    Buskila D, Sarzi-Puttini P (2006) Biology and therapy of fibromyalgia. Genetic aspects of fibromyalgia syndrome. Arthritis Res Ther 8:218

    PubMed  Article  Google Scholar 

  5. 5.

    Ablin JN, Cohen H, Buskila D (2006) Mechanisms of disease: genetics of fibromyalgia. Nat Clin Pract Rheumatol 2:671–678

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Potvin S, Larouche A, Normand E, Souza JB, Gaumond I, Marchand S, Grignon S (2010) No relationship between the ins del polymorphism of the serotonin transporter promoter and pain perception in fibromyalgia patients and healthy controls. Eur J Pain published on 15 Jan 2010. doi:10.1016/j.ejpain.2009.12.004

  7. 7.

    Vargas-Alarcon G, Fragoso JM, Cruz-Robles D, Vargas A, Martinez A, Lao-Villadoniga JI, Garcia-Fructuoso F, Vallejo M, Martinez-Lavin M (2009) Association of adrenergic receptor gene polymorphisms with different fibromyalgia syndrome domains. Arthritis Rheum 60:2169–2173

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Potvin S, Larouche A, Normand E, de Souza JB, Gaumond I, Grignon S, Marchand S (2009) DRD3 Ser9Gly polymorphism is related to thermal pain perception and modulation in chronic widespread pain patients and healthy controls. J Pain 10:969–975

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Cohen H, Neumann L, Glazer Y, Ebstein RP, Buskila D (2009) The relationship between a common catechol-O-methyltransferase (COMT) polymorphism val (158) met and fibromyalgia. Clin Exp Rheumatol 27:S51–S56

    PubMed  CAS  Google Scholar 

  10. 10.

    Ablin JN, Bar-Shira A, Yaron M, Orr-Urtreger A (2009) Candidate-gene approach in fibromyalgia syndrome: association analysis of the genes encoding substance P receptor, dopamine transporter and alpha1-antitrypsin. Clin Exp Rheumatol 27:S33–S38

    PubMed  CAS  Google Scholar 

  11. 11.

    Tander B, Gunes S, Boke O, Alayli G, Kara N, Bagci H, Canturk F (2008) Polymorphisms of the serotonin-2A receptor and catechol-O-methyltransferase genes: a study on fibromyalgia susceptibility. Rheumatol Int 28:685–691

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Vargas-Alarcon G, Fragoso JM, Cruz-Robles D, Vargas A, Lao-Villadoniga JI, Garcia-Fructuoso F, Ramos-Kuri M, Hernandez F, Springall R, Bojalil R, Vallejo M, Martinez-Lavin M (2007) Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia. Arthritis Res Ther 9:R110

    PubMed  Article  Google Scholar 

  13. 13.

    Gursoy S, Erdal E, Sezgin M, Barlas IO, Aydeniz A, Alasehirli B, Sahin G (2008) Which genotype of MAO gene that the patients have are likely to be most susceptible to the symptoms of fibromyalgia? Rheumatol Int 28:307–311

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Alasehirli B, Demiryurek S, Arica E, Gursoy S, Demiryurek AT (2007) No evidence for an association between the Glu298Asp polymorphism of the endothelial nitric oxide synthase gene and fibromyalgia syndrome. Rheumatol Int 27:275–280

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Su SY, Chen JJ, Lai CC, Chen CM, Tsai FJ (2007) The association between fibromyalgia and polymorphism of monoamine oxidase A and interleukin-4. Clin Rheumatol 26:12–16

    PubMed  Article  Google Scholar 

  16. 16.

    Frank B, Niesler B, Bondy B, Spath M, Pongratz DE, Ackenheil M, Fischer C, Rappold G (2004) Mutational analysis of serotonin receptor genes: HTR3A and HTR3B in fibromyalgia patients. Clin Rheumatol 23:338–344

    PubMed  Article  Google Scholar 

  17. 17.

    Buskila D, Cohen H, Neumann L, Ebstein RP (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

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Gursoy S, Erdal E, Herken H, Madenci E, Alasehirli B, Erdal N (2003) Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia syndrome. Rheumatol Int 23:104–107

    PubMed  Google Scholar 

  19. 19.

    Gursoy S (2002) Absence of association of the serotonin transporter gene polymorphism with the mentally healthy subset of fibromyalgia patients. Clin Rheumatol 21:194–197

    PubMed  Article  Google Scholar 

  20. 20.

    Cohen H, Buskila D, Neumann L, Ebstein RP (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

    PubMed  Article  Google Scholar 

  21. 21.

    Gursoy S, Erdal E, Herken H, Madenci E, Alasehirli B (2001) Association of T102C polymorphism of the 5-HT2A receptor gene with psychiatric status in fibromyalgia syndrome. Rheumatol Int 21:58–61

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Offenbaecher M, Bondy B, de Jonge S, Glatzeder K, Kruger M, Schoeps P, Ackenheil M (1999) Possible association of fibromyalgia with a polymorphism in the serotonin transporter gene regulatory region. Arthritis Rheum 42:2482–2488

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Bondy B, Spaeth M, Offenbaecher M, Glatzeder K, Stratz T, Schwarz M, de Jonge S, Kruger M, Engel RR, Farber L, Pongratz DE, Ackenheil M (1999) The T102C polymorphism of the 5-HT2A-receptor gene in fibromyalgia. Neurobiol Dis 6:433–439

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Graeff FG (1997) Serotonergic systems. Psychiatr Clin North Am 20:723–739

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, Lesch KP (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66:2621–2624

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Collier DA, Stober G, Li T, Heils A, Catalano M, Di Bella D, Arranz MJ, Murray RM, Vallada HP, Bengel D, Muller CR, Roberts GW, Smeraldi E, Kirov G, Sham P, Lesch KP (1996) A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1:453–460

    PubMed  CAS  Google Scholar 

  28. 28.

    Tokunaga A, Saika M, Senba E (1998) 5-HT2A receptor subtype is involved in the thermal hyperalgesic mechanism of serotonin in the periphery. Pain 76:349–355

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Williams J, Spurlock G, McGuffin P, Mallet J, Nothen MM, Gill M, Aschauer H, Nylander PO, Macciardi F, Owen MJ (1996) Association between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2a-receptor gene. European Multicentre Association Study of Schizophrenia (EMASS) Group. Lancet 347:1294–1296

    PubMed  CAS  Google Scholar 

  30. 30.

    Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W (2005) Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 14:135–143

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM (1996) Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6:243–250

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Egger M, Smith GD, Phillips AN (1997) Meta-analysis: principles and procedures. BMJ 315:1533–1537

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    PubMed  Article  Google Scholar 

  35. 35.

    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Buskila D, Sarzi-Puttini P, Ablin JN (2007) The genetics of fibromyalgia syndrome. Pharmacogenomics 8:67–74

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Ablin J, Neumann L, Buskila D (2008) Pathogenesis of fibromyalgia—a review. Joint Bone Spine 75:273–279

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Hagen K, Pettersen E, Stovner LJ, Skorpen F, Zwart JA (2006) No association between chronic musculoskeletal complaints and Val158Met polymorphism in the Catechol-O-methyltransferase gene. The HUNT study. BMC Musculoskelet Disord 7:40

    PubMed  Article  Google Scholar 

  39. 39.

    Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306–309

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Wolfe F, Russell IJ, Vipraio G, Ross K, Anderson J (1997) Serotonin levels, pain threshold, and fibromyalgia symptoms in the general population. J Rheumatol 24:555–559

    PubMed  CAS  Google Scholar 

  41. 41.

    Yunus MB, Dailey JW, Aldag JC, Masi AT, Jobe PC (1992) Plasma tryptophan and other amino acids in primary fibromyalgia: a controlled study. J Rheumatol 19:90–94

    PubMed  CAS  Google Scholar 

  42. 42.

    Polesskaya OO, Sokolov BP (2002) Differential expression of the “C” and “T” alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics. J Neurosci Res 67:812–822

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

This study was supported by a Korea University Grant.

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We have no financial and non-financial conflicts of interest.

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Correspondence to Young Ho Lee.

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Lee, Y.H., Choi, S.J., Ji, J.D. et al. Candidate gene studies of fibromyalgia: a systematic review and meta-analysis. Rheumatol Int 32, 417–426 (2012). https://doi.org/10.1007/s00296-010-1678-9

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Keywords

  • Candidate gene
  • Polymorphism
  • Fibromyalgia
  • Meta-analysis