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Role of genetic and non-genetic factors in the etiology of Graves’ disease

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Abstract

In spite of the advancements in understanding the pathogenic mechanisms of Graves’ disease (GD), its ultimate cause remains elusive. The majority of investigators agree that GD is likely a multifactorial disease, due to a complex interplay of genetic and non-genetic factors that lead to the loss of immune tolerance to thyroid antigens and to the initiation of a sustained autoimmune reaction. Twin and family studies support a role of genetic factors, among which the HLA complex, CD40, CTLA-4, PTPN22, FCRL3, thyroglobulin, and the TSH receptor may be involved. Among non-genetic factors, iodine, infections, psychological stress, gender, smoking, thyroid damage, vitamin D, selenium, immune modulating agents, and periods of immune reconstitution may contribute the development of the diseases. Here we review in detail the respective role of genetic and non-genetic factors in the etiology of GD, taking advantage of the great bulk of data generated especially over the past 30 years.

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References

  1. Menconi F, Marcocci C, Marinò M (2014) Diagnosis and classification of Graves’ disease. Autoimmun Rev 13:398–402

    PubMed  Google Scholar 

  2. Bartalena L, Fatourechi V (2014) Extrathyroidal manifestations of Graves’ disease: a 2014 update. J Endocrinol Invest 37:691–700

    PubMed  Google Scholar 

  3. Piantanida E, Tanda ML, Lai A, Sassi L, Bartalena L (2013) Prevalence and natural history of Graves’ orbitopathy in the XXI century. J Endocrinol Invest 36:444–449

    CAS  PubMed  Google Scholar 

  4. Marinò M, Latrofa F, Menconi F, Chiovato L, Vitti P (2014) An update on the medical treatment of Graves’ hyperthyroidism. J Endocrinol Invest 37:1041–1048

  5. Brix TH, Hegedüs L (2012) Twin studies as a model for exploring the aetiology of autoimmune thyroid disease. Clin Endocrinol (Oxf) 76:457–464

    CAS  Google Scholar 

  6. Brix TH, Kyvik KO, Christensen K, Hegedüs L (2001) Evidence for a major role of heredity in Graves’ disease: a population-based study of two Danish twin cohorts. J Clin Endocrinol Metab 86:930–934

    CAS  PubMed  Google Scholar 

  7. Ringold DA, Nicoloff JT, Kesler M, Davis H, Hamilton A, Mack T (2002) Further evidence for a strong genetic influence on the development of autoimmune thyroid disease: the California twin study. Thyroid 12:647–653

    PubMed  Google Scholar 

  8. Hall R, Stanbury JB (1967) Familial studies of autoimmune thyroiditis. Clin Exp Immunol 2:719–725

    PubMed Central  PubMed  Google Scholar 

  9. Hall RO, Owen SG, Smart GA (1960) Evidence for a genetic predisposition to formation of thyroid autoantibodies. Lancet ii:187–190

    Google Scholar 

  10. Phillips D, McLachlan S, Stephenson A, Roberts D, Moffitt S, McDonald D, Ad’Hiah A, Stratton A, Young E, Clark F, Beever K, Bradbury K, Rees-Smith B (1990) Autosomal dominant transmission of autoantibodies to thyroglobulin and thyroid peroxidase. J Clin Endocrinol Metab 70:742–746

    CAS  PubMed  Google Scholar 

  11. Phillips DI, Prentice L, McLachlan SM, Upadhyaya M, Lunt PW, Rees Smith B (1991) Autosomal dominant inheritance of the tendency to develop thyroid autoantibodies. Exp Clin Endocrinol 97:170–172

    CAS  PubMed  Google Scholar 

  12. Pauls DL, Zakarija M, McKenzie JM, Egeland JA (1993) Complex segregation analysis of antibodies to thyroid peroxidase in Old Order Amish families. Am J Med Genet 47:375–379

    CAS  PubMed  Google Scholar 

  13. Shields DC, Ratanachaiyavong S, McGregor AM, Collins A, Morton NE (1994) Combined segregation and linkage analysis of Graves’ disease with a thyroid autoantibody diathesis. Am J Hum Genet 55:540–554

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Hall R, Dingle PR, Roberts DF (1972) Thyroid antibodies: a study of first degree relatives. Clin Genet 3:319–324

    CAS  PubMed  Google Scholar 

  15. Jacobson EM, Tomer Y (2007) The genetic basis of thyroid autoimmunity. Thyroid 17:949–961

    CAS  PubMed  Google Scholar 

  16. Villanueva R, Greenberg DA, Davies TF, Tomer Y (2003) Sibling recurrence risk in autoimmune thyroid disease. Thyroid 13:761–764

    CAS  PubMed  Google Scholar 

  17. Dittmar M, Libich C, Brenzel T, Kahaly GJ (2011) Increased familial clustering of autoimmune thyroid diseases. Horm Metab Res 43:200–204

    CAS  PubMed  Google Scholar 

  18. Tamai H, Ohsako N, Takeno K, Fukino O, Takahashi H, Kuma K, Kumagai LF, Nagataki S (1980) Changes in thyroid function in euthyroid subjects with family history of Graves’ disease; a follow up study of 69 patients. J Clin Endocrinol Metab 51:1123–1128

    CAS  PubMed  Google Scholar 

  19. Villanueva R, Inzerillo AM, Tomer Y, Barbesino G, Meltzer M, Concepcion ES, Greenberg DA, MacLaren N, Sun ZS, Zhang DM, Tucci S, Davies TF (2000) Limited genetic susceptibility to severe Graves’ ophthalmopathy: no role for CTLA-4 but evidence for an environmental etiology. Thyroid 10:791–798

    CAS  PubMed  Google Scholar 

  20. Hemminki K, Li X, Sundquist J, Sundquist K (2010) The epidemiology of Graves’ disease: evidence of a genetic and an environmental contribution. J Autoimmun 34:J307–J313

    CAS  PubMed  Google Scholar 

  21. Tomer Y (2010) Genetic susceptibility to autoimmune thyroid disease: past, present, and future. Thyroid 20:715–725

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Eschler DC, Hasham A, Tomer Y (2011) Cutting edge: the etiology of autoimmune thyroid diseases. Clin Rev Allergy Immunol 41:190–197

    PubMed Central  CAS  PubMed  Google Scholar 

  23. Davies TF, Latif R, Yin X (2012) New genetic insights from autoimmune thyroid disease. J Thyroid Res 2012:623852. doi:10.1155/2012/623852

  24. Zeitlin AA, Simmonds MJ, Gough SC (2008) Genetic developments in autoimmune thyroid disease: an evolutionary process. Clin Endocrinol (Oxf) 68:671–682

    CAS  Google Scholar 

  25. Brand OJ, Gough SC (2010) Genetics of thyroid autoimmunity and the role of the TSHR. Mol Cell Endocrinol 322:135–143

    CAS  PubMed  Google Scholar 

  26. Effraimidis G, Wiersinga WM (2014) Mechanisms in endocrinology: autoimmune thyroid disease: old and new players. Eur J Endocrinol 170:R241–R252

    CAS  PubMed  Google Scholar 

  27. Jacobson EM, Huber A, Tomer Y (2008) The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology. J Autoimmun 30:58–62

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Farid NR, Barnard JM, Marshall WH (1976) The association of HLA with autoimmune thyroid disease in Newfoundland. The influence of HLA homozygosity in Graves’ disease. Tissue Antigens 8:181–189

    CAS  PubMed  Google Scholar 

  29. Irvine WJ, Gray RS, Morris PJ, Ting A (1977) Correlation of HLA and thyroid antibodies with clinical course of thyrotoxicosis treated with antithyroid drugs. Lancet 2:898–900

    CAS  PubMed  Google Scholar 

  30. Allannic H, Fauchet R, Lorcy Y, Heim J, Gueguen M, Leguerrier AM, Genetet B (1980) HLA and Graves’ disease: an association with HLA-DRw3. J Clin Endocrinol Metab 51:863–867

    CAS  PubMed  Google Scholar 

  31. Yanagawa T, Mangklabruks A, Chang YB, Okamoto Y, Fisfalen ME, Curran PG, DeGroot LJ (1993) Human histocompatibility leukocyte antigen-DQA1*0501 allele associated with genetic susceptibility to Graves’ disease in a Caucasian population. J Clin Endocrinol Metab 76:1569–1574

    CAS  PubMed  Google Scholar 

  32. Ban Y, Davies TF, Greenberg DA, Concepcion ES, Osman R, Oashi T, Tomer Y (2004) Arginine at position 74 of the HLA-DR beta1 chain is associated with Graves’ disease. Genes Immun 5:203–208

    CAS  PubMed  Google Scholar 

  33. Ofosu MH, Dunston G, Henry L, Ware D, Cheatham W, Brembridge A, Brown C, Alarif L (1996) HLA-DQ3 is associated with Graves’ disease in African-Americans. Immunol Invest 25:103–110

    CAS  PubMed  Google Scholar 

  34. Chan SH, Yeo PP, Lui KF, Wee GB, Woo KT, Lim P, Cheah JS (1978) HLA and thyrotoxicosis (Graves’ disease) (in Chinese). Tissue Antigens 12:109–114

    CAS  PubMed  Google Scholar 

  35. Yanagawa T, DeGroot LJ (1996) HLA class II associations in African-American female patients with Graves’ disease. Thyroid 6:37–39

    CAS  PubMed  Google Scholar 

  36. Tomer Y, Barbesino G, Keddache M, Greenberg DA, Davies TF (1997) Mapping of a major susceptibility locus for Graves’ disease (GD-1) to chromosome 14q31. J Clin Endocrinol Metab 82:1645–1648

    CAS  PubMed  Google Scholar 

  37. Chatzigeorgiou A, Lyberi M, Chatzilymperis G, Nezos A, Kamper E (2009) CD40/CD40L signaling and its implication in health and disease. BioFactors 35:474–483

    CAS  PubMed  Google Scholar 

  38. Tomer Y, Concepcion E, Greenberg DA (2002) A C/T single-nucleotide polymorphism in the region of the CD40 gene is associated with Graves’ disease. Thyroid 12:1129–1135

    CAS  PubMed  Google Scholar 

  39. Teft WA, Kirchhof MG, Madrenas J (2006) A molecular perspective of CTLA-4 function. Annu Rev Immunol 24:65–97

    CAS  PubMed  Google Scholar 

  40. Tomer Y (2001) Unraveling the genetic susceptibility to autoimmune thyroid disease: CTLA-4 takes the stage. Thyroid 11:167–169

    CAS  PubMed  Google Scholar 

  41. Kouki T, Gardine CA, Yanagawa T, De Groot LJ (2002) Relation of three polymorphisms of the CTLA-4 gene in patients with Graves’ disease. J Endocrinol Invest 25:208–213

    CAS  PubMed  Google Scholar 

  42. Tomer Y, Greenberg DA, Barbesino G, Conception ES, Davies TF (2001) CTLA-4 and not CD28 is a susceptibility gene for thyroid autoantibody production. J Clin Endocrinol Metab 86:1687–1693

    CAS  PubMed  Google Scholar 

  43. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RC, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, Metzker ML, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Tuomilehto-Wolf E, Tuomilehto J, Bingley P, Gillespie KM, Undlien DE, Rønningen KS, Guja C, Ionescu-Tîrgovişte C, Savage DA, Maxwell AP, Carson DJ, Patterson CC, Franklyn JA, Clayton DG, Peterson LB, Wicker LS, Todd JA, Gough SC (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511

    CAS  PubMed  Google Scholar 

  44. Mayans S, Lackovic K, Nyholm C, Lindgren P, Ruikka K, Eliasson M, Cilio CM, Holmberg D (2007) CT60 genotype does not affect CTLA-4 isoform expression despite association to T1D and AITD in northern Sweden. BMC Med Genet 8:3

    PubMed Central  PubMed  Google Scholar 

  45. Rhee I, Veillette A (2012) Protein tyrosine phosphatases in lymphocyte activation and autoimmunity. Nat Immunol 13:439–447

    CAS  PubMed  Google Scholar 

  46. Velaga MR, Wilson V, Jennings CE, Owen CJ, Herington S, Donaldson PT, Ball SG, James RA, Quinton R, Perros P, Pearce SH (2004) The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J Clin Endocrinol Metab 89:5862–5865

    CAS  PubMed  Google Scholar 

  47. Criswell LA, Pfeiffer KA, Lum RF, Gonzales B, Novitzke J, Kern M, Moser KL, Begovich AB, Carlton VE, Li W, Lee AT, Ortmann W, Behrens TW, Gregersen PK (2005) Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet 76:561–571

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Davis RS (2007) Fc receptor-like molecules. Annu Rev Immunol 25:525–560

    CAS  PubMed  Google Scholar 

  49. Kochi Y, Yamada R, Suzuki A, Harley JB, Shirasawa S, Sawada T, Bae SC, Tokuhiro S, Chang X, Sekine A, Takahashi A, Tsunoda T, Ohnishi Y, Kaufman KM, Kang CP, Kang C, Otsubo S, Yumura W, Mimori A, Koike T, Nakamura Y, Sasazuki T, Yamamoto K (2005) A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet 37:478–485

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Simmonds MJ, Heward JM, Carr-Smith J, Foxall H, Franklyn JA, Gough SC (2006) Contribution of single nucleotide polymorphisms within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves’ disease. J Clin Endocrinol Metab 91:1056–1061

    CAS  PubMed  Google Scholar 

  51. Simmonds MJ, Brand OJ, Barrett JC, Newby PR, Franklyn JA, Gough SC (2010) Association of Fc receptor-like 5 (FCRL5) with Graves’ disease is secondary to the effect of FCRL3. Clin Endocrinol (Oxf) 73:654–660

    CAS  Google Scholar 

  52. Marinò M, Chiovato L, Lisi S, Altea MA, Marcocci C, Pinchera A (2004) Role of thyroglobulin in the pathogenesis of Graves’ ophthalmopathy: the hypothesis of Kriss revisited. J Endocrinol Invest 27:230–236

    PubMed  Google Scholar 

  53. Tomer Y, Greenberg DA, Conception E, Ban Y, Davies TF (2002) Thyroglobulin is a thyroid specific gene for the familial autoimmune diseases. J Clin Endocrinol Metab 87:404–407

    CAS  PubMed  Google Scholar 

  54. Ban Y, Greenberg DA, Concepcion E, Skrabanek L, Villanueva R, Tomer Y (2003) Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease. Proc Natl Acad Sci USA 100:15119–15124

    PubMed Central  CAS  PubMed  Google Scholar 

  55. Stefan M, Jacobson EM, Huber AK, Greenberg DA, Li CW, Skrabanek L, Conception E, Fadlalla M, Ho K, Tomer Y (2011) Novel variant of thyroglobulin promoter triggers thyroid autoimmunity through an epigenetic interferon alpha-modulated mechanism. J Biol Chem 286:31168–31179

    PubMed Central  CAS  PubMed  Google Scholar 

  56. Stefan M, Wei C, Lombardi A, Li CW, Concepcion ES, Inabnet WB 3rd, Owen R, Zhang W, Tomer Y (2014) Genetic-epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity. Proc Natl Acad Sci USA 111:12562–12567

    PubMed Central  CAS  PubMed  Google Scholar 

  57. Durães C, Moreira CS, Alvelos I, Mendes A, Santos LR, Machado JC, Melo M, Esteves C, Neves C, Sobrinho-Simões M, Soares P (2014) Polymorphisms in the TNFA and IL6 genes represent risk factors for autoimmune thyroid disease. PLoS One 9:e105492

    PubMed Central  PubMed  Google Scholar 

  58. Brown RS, Lombardi A, Hasham A, Greenberg DA, Gordon J, Concepcion E, Hammerstad SS, Lotay V, Zhang W, Tomer Y (2014) Genetic analysis in young-age-of-onset Graves’ disease reveals new susceptibility loci. J Clin Endocrinol Metab 99:E1387–E1391

    CAS  PubMed  Google Scholar 

  59. Tomer Y, Hasham A, Davies TF, Stefan M, Concepcion E, Keddache M, Greenberg DA (2013) Fine mapping of loci linked to autoimmune thyroid disease identifies novel susceptibility genes. J Clin Endocrinol Metab 98:E144–E152

    PubMed Central  CAS  PubMed  Google Scholar 

  60. Laurberg P, Pedersen KM, Vestergaard H, Sigurdsson G (1991) High incidence of multinodular toxic goitre in the elderly population in a low iodine intake area vs. high incidence of Graves’ disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland. J Intern Med 229:415–420

    CAS  PubMed  Google Scholar 

  61. Furszyfer J, Kurland LT, McConahey WM, Woolner LB, Elveback LR (1972) Epidemiologic aspects of Hashimoto’s thyroiditis and Graves’ disease in Rochester Minnesota (1935–1967), with special reference to temporal trends. Metabolism 21:197–204

    CAS  PubMed  Google Scholar 

  62. Aghini-Lombardi F, Antonangeli L, Martino E, Vitti P, Maccherini D, Leoli F, Rago T, Grasso L, Valeriano R, Balestrieri A, Pinchera A (1999) The spectrum of thyroid disorders in an iodine-deficient community: the Pescopagano survey. J Clin Endocrinol Metab 84:561–566

    CAS  PubMed  Google Scholar 

  63. Aghini-Lombardi F, Vitti P, Antonangeli L, Fiore E, Piaggi P, Pallara A, Consiglio E, Pinchera A (2013) The size of the community rather than its geographical location better defines the risk of iodine deficiency: results of an extensive survey in Southern Italy. J Endocrinol Invest 36:282–286

    CAS  PubMed  Google Scholar 

  64. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F (1995) The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 43:55–68

    CAS  Google Scholar 

  65. Abraham-Nordling M, Byström K, Törring O, Lantz M, Berg G, Calissendorff J, Nyström HF, Jansson S, Jörneskog G, Karlsson FA, Nyström E, Ohrling H, Orn T, Hallengren B, Wallin G (2011) Incidence of hyperthyroidism in Sweden. Eur J Endocrinol 165:899–905

    CAS  PubMed  Google Scholar 

  66. Nyström HF, Jansson S, Berg G (2013) Incidence rate and clinical features of hyperthyroidism in a long-term iodine sufficient area of Sweden (Gothenburg) 2003–2005. Clin Endocrinol (Oxf) 78:768–776

    Google Scholar 

  67. Jacobson DL, Gange SJ, Rose NR, Graham NM (1997) Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 84:223–243

    CAS  PubMed  Google Scholar 

  68. Connolly RJ, Vidor GI, Stewart JC (1970) Increase in thyrotoxicosis in endemic goitre area after iodination of bread. Lancet 1:500–502

    CAS  PubMed  Google Scholar 

  69. Stanbury JB, Ermans AE, Bourdoux P, Todd C, Oken E, Tonglet R, Vidor G, Braverman LE, Medeiros-Neto G (1998) Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid 8:83–100

    CAS  PubMed  Google Scholar 

  70. Burgi H, Kohler M, Morselli B (1998) Thyrotoxicosis incidence in Switzerland and benefit of improved iodine supply. Lancet 352:1034

    CAS  PubMed  Google Scholar 

  71. Lundgren E, Christensen Borup S (1990) Decreasing incidence of thyrotoxicosis in an endemic goitre inland area of Sweden. Clin Endocrinol (Oxf) 33:133–138

    CAS  Google Scholar 

  72. Brownlie BE, Wells JE (1990) The epidemiology of thyrotoxicosis in New Zealand: incidence and geographical distribution in north Canterbury, 1983–1985. Clin Endocrinol (Oxf) 33:249–259

    CAS  Google Scholar 

  73. Barker DJP, Phillips DIW (1984) Current incidence of thyrotoxicosis and past prevalence of goitre in 12 British towns. Lancet 2:567–570

    CAS  PubMed  Google Scholar 

  74. Laurberg P, Jørgensen T, Perrild H, Ovesen L, Knudsen N, Pedersen IB, Rasmussen LB, Carlé A, Vejbjerg P (2006) The Danish investigation on iodine intake and thyroid disease, DanThyr: status and perspectives. Eur J Endocrinol 155:219–228

    CAS  PubMed  Google Scholar 

  75. Bülow Pedersen I, Laurberg P, Knudsen N, Jørgensen T, Perrild H, Ovesen L, Rasmussen LB (2006) Increase in incidence of hyperthyroidism predominantly occurs in young people after iodine fortification of salt in Denmark. J Clin Endocrinol Metab 91:3830–3834

    PubMed  Google Scholar 

  76. Davies TF (2008) Infection and autoimmune thyroid disease. J Clin Endocrinol Metab 93:674–676

    CAS  PubMed  Google Scholar 

  77. Phillips DI, Barker DJ, Rees Smith B, Didcote S, Morgan D (1985) The geographical distribution of thyrotoxicosis in England according to the presence or absence of TSH-receptor antibodies. Clin Endocrinol (Oxf) 23:283–287

    CAS  Google Scholar 

  78. Cox SP, Phillips DIW, Osmond C (1989) Does infection initiate Graves disease? A population based 10 year study. Autoimmunity 4:43–49

    CAS  PubMed  Google Scholar 

  79. Facciani JM, Kazim M (2000) Absence of seasonal variation in Graves disease. Ophthalmic Plast Reconstr Surg 16:67–71

    CAS  Google Scholar 

  80. Hamilton A, Newby PR, Carr-Smith JD, Disanto G, Allahabadia A, Armitage M, Brix TH, Chatterjee K, Connell JM, Hegedüs L, Hunt PJ, Lazarus JH, Pearce SH, Robinson BG, Taylor JC, Vaidya B, Wass JA, Wiersinga WM, Weetman AP, Ramagopalan SV, Franklyn JA, Gough SC, Simmonds MJ (2014) Impact of month of birth on the development of autoimmune thyroid disease in the United kingdom and europe. J Clin Endocrinol Metab 99:E1459–E1465

    CAS  PubMed  Google Scholar 

  81. Toft AD, Blackwell CC, Saadi AT, Wu P, Lymberi P, Soudjidelli M, Weir DM (1990) Secretor status and infection in patients with Grave’s disease. Autoimmunity 7:279–289

    CAS  PubMed  Google Scholar 

  82. Prabhkar BS, Bhan RS, Smith TJ (2003) Current perspective on the pathogenesis of Graves’ disease and ophthalmopathy. Endocr Rev 24:802–835

    Google Scholar 

  83. Bech K (1990) Yersinia enterocolitica and thyroid autoimmunity. Autoimmunity 7:291–294

    CAS  PubMed  Google Scholar 

  84. Brix TH, Hansen PS, Hegedüs L, Wenzel BE (2008) Too early to dismiss Yersinia enterocolitica infection in the aetiology of Graves’ disease. Evidence from a twin case-control study. Clin Endocrinol 69:491–496

    Google Scholar 

  85. Luo G, Fan JL, Seetharamaiah GS, Desai RK, Dallas JS, Wagle N, Doan R, Niesel DW, Klimpel GR, Prabhakar BS (1993) Immunization of mice with Yersinia enterocolitica leads to the induction of antithyrotropin receptor antibodies. J Immunol 151:922–928

    CAS  PubMed  Google Scholar 

  86. Lindholm H, Visakorpi R (1991) Late complications after a Yersinia enterocolitica epidemic: a follow up study. Ann Rheum Dis 50:694–696

    PubMed Central  CAS  PubMed  Google Scholar 

  87. Larizza D, Calcaterra V, Martinetti M, Negrini R, De Silvestri A, Cisternino M, Iannone AM, Solcia E (2006) Helicobacter pylori infection and autoimmune thyroid disease in young patients: the disadvantage of carrying the human leukocyte antigen-DRB1*0301 allele. J Clin Endocrinol Metab 91:176–179

    CAS  PubMed  Google Scholar 

  88. Bassi V, Marino G, Iengo A, Fattoruso O, Santinelli C (2012) Autoimmune thyroid diseases and Helicobacter pylori: the correlation is present only in Graves’ disease. World J Gastroenterol 18:1093–1097

    PubMed Central  PubMed  Google Scholar 

  89. Ciampolillo A, Marini V, Mirakian R, Buscema M, Schulz T, Pujol-Borrell R, Bottazzo GF (1989) Retrovirus-like sequences in Graves’ disease: implications for human autoimmunity. Lancet 1:1096–1099

    CAS  PubMed  Google Scholar 

  90. Humphrey M, Mosca J, Baker JR Jr, Drabick JJ, Carr FE, Burke DS, Wartofsky L, Djuh YY, Burman KD (1991) Absence of retroviral sequences in Graves’ disease. Lancet 337:17–18

    CAS  PubMed  Google Scholar 

  91. Fierabracci A, Upton CP, Hajibagheri N, Bottazzo GF (2001) Lack of detection of retroviral particles (HIAP-1) in the H9 T cell line co-cultured with thyrocytes of Graves’ disease. J Autoimmun 16:457–462

    CAS  PubMed  Google Scholar 

  92. Wick G, Grubeck-Loebenstein B, Trieb K, Kalischnig G, Aguzzi A (1992) Human foamy virus antigens in thyroid tissue of Graves’ disease patients. Int Arch Allergy Immunol 99:153–156

    CAS  PubMed  Google Scholar 

  93. Schweizer M, Turek R, Reinhardt M, Neumann HD (1994) Absence of foamy virus DNA in Graves’ disease. AIDS Res Hum Retrovir 10:601–605

    CAS  PubMed  Google Scholar 

  94. Schweizer M, Turek R, Hahn H, Schliephake A, Netzer KO, Eder G, Reinhardt M, Rethwilm A, Neumann-Haefelin D (1995) Markers of foamy virus infections in monkeys, apes, and accidentally infected humans: appropriate testing fails to confirm suspected foamy virus prevalence in humans. AIDS Res Hum Retrovir 11:161–170

    CAS  PubMed  Google Scholar 

  95. Burch HB, Nagy EV, Lukes YG, Cai WY, Wartofsky L, Burman KD (1991) Nucleotide and amino acid homology between the human thyrotropin receptor and HIV-1 nef protein: identification and functional analysis. Biochem Biophys Res Commun 181:498–505

    CAS  PubMed  Google Scholar 

  96. Tas M, de Haan-Meulman M, Kabel PJ, Drexhage HA (1991) Defects in monocyte polarization and dendritic cell clustering in patients with Graves’ disease. A putative role for a non-specific immunoregulatory factor related to retroviral p15E. Clin Endocrinol 34:441–448

    CAS  Google Scholar 

  97. Leib-Mösch C, Bachmann M, Brack-Werner R, Werner T, Erfle V, Hehlmann R (1992) Expression and biological significance of human endogenous retroviral sequences. Leukemia 6(suppl):72–75

    Google Scholar 

  98. Jaspan JB, Luo H, Ahmed B, Tenenbaum S, Voss T, Sander DM, Bollinger K, Baquet T, Garry RF (1995) Evidence for a retroviral trigger in Graves’ disease. Autoimmunity 20:135–142

    CAS  PubMed  Google Scholar 

  99. Fierabracci A, Hammond L, Lowdell M, Chiovato L, Goode AW, Bottazzo GF, Mirakian R (1999) The effect of staphylococcal enterotoxin B on thyrocyte HLA molecule expression. J Autoimmun 12:305–314

    CAS  PubMed  Google Scholar 

  100. Kondrashova A, Viskari H, Haapala AM, Seiskari T, Kulmala P, Ilonen J, Knip M, Hyöty H (2008) Serological evidence of thyroid autoimmunity among schoolchildren in two different socioeconomic environments. J Clin Endocrinol Metab 93:729–734

    CAS  PubMed  Google Scholar 

  101. Ziemssen T, Kern S (2007) Psychoneuroimmunology-cross-talk between the immune and nervous systems. J Neurol 254(Suppl 2):II8–II11

    PubMed  Google Scholar 

  102. Russo L, Vitti P, Pinchera A, Marinò M (2010) Exacerbation of autoimmune thyroiditis following bilateral adrenalectomy for Cushing’s syndrome. Thyroid 20:669–670

    PubMed  Google Scholar 

  103. Weetman AP (2010) Immunity, thyroid function and pregnancy: molecular mechanisms. Nat Rev Endocrinol 6:311–318

    CAS  PubMed  Google Scholar 

  104. Parry CH (1825) Collections from the unpublished medical writings of the late Caleb Hillier Parry. Underwood, London

    Google Scholar 

  105. Chiovato L, Pinchera A (1996) Stressful life events and Graves’ disease. Eur J Endocrinol 134:680–682

    CAS  PubMed  Google Scholar 

  106. Bagnasco M, Bossert I, Pesce G (2007) Stress and autoimmune thyroid diseases. Neuroimmunomodulation 13:309–317

    Google Scholar 

  107. Mizokami T, Wu Li A, El-Kaissi S, Wall JR (2004) Stress and thyroid autoimmunity. Thyroid 14:1047–1055

    CAS  PubMed  Google Scholar 

  108. Dayan CM (2001) Stressful life events and Graves’ disease revisited. Clin Endocrinol 55:15–19

    Google Scholar 

  109. Chiovato L, Marinò M, Perugi G, Fiore E, Montanelli L, Lapi P, Cavaliere R, Ciampi M, Patronelli A, Placidi G, Placidi GF, Cassano GB, Pinchera A (1998) Chronic recurrent stress due to panic disorder does not precipitate Graves’ disease. J Endocrinol Invest 21:758–764

    CAS  PubMed  Google Scholar 

  110. Zandman-Goddard G, Peeva E, Shoenfeld Y (2007) Gender and autoimmunity. Autoimmun Rev 6:366–372

    CAS  PubMed  Google Scholar 

  111. Chiovato L, Lapi P, Fiore E, Tonacchera M, Pinchera A (1993) Thyroid autoimmunity and female gender. J Endocrinol Invest 16:384–391

    CAS  PubMed  Google Scholar 

  112. Wong GW, Kwok MY, Ou Y (1995) High incidence of juvenile Graves’ disease in Hong Kong. Clin Endocrinol (Oxf) 43:697–700

    CAS  Google Scholar 

  113. Grossman CJ (1984) Regulation of the immune system by sex steroids. Endocr Rev 5:435

    CAS  PubMed  Google Scholar 

  114. Lutfi RJ, Fridmanis M, Misiunas AL, Pafume O, Gonzalez EA, Villemur JA, Mazzini MA, Niepomniszcze H (1985) Association of melasma with thyroid autoimmunity and other thyroidal abnormalities and their relationship to the origin of the melasma. J Clin Endocrinol Metab 61:28–31

    CAS  PubMed  Google Scholar 

  115. Chiovato L, Larizza D, Bendinelli G, Tonacchera M, Marinó M, Mammoli C, Lorini R, Severi F, Pinchera A (1996) Autoimmune hypothyroidism and hyperthyroidism in patients with Turner’s syndrome. Eur J Endocrinol 134:568–575

    CAS  PubMed  Google Scholar 

  116. Vallotton MB, Forbes AP (1967) Autoimmunity in gonadal dysgenesis and Klinefelter’s syndrome. Lancet 1:648–651

    CAS  PubMed  Google Scholar 

  117. Rotondi M, Pirali B, Lodigiani S et al (2008) The post partum period and the onset of Graves’ disease: an overestimated risk factor. Eur J Endocrinol 159:161–165

    CAS  PubMed  Google Scholar 

  118. Rotondi M, Pirali B, Lodigiani S, Bray S, Leporati P, Chytiris S, Balzano S, Magri F, Chiovato L (2008) The effect of pregnancy on subsequent relapse from Graves’ disease following a successful course of anti-thyroid drug therapy. J Clin Endocrinol Metab 93:3985–3988

    CAS  PubMed  Google Scholar 

  119. Barbesino G, Tomer Y, Concepcion ES, Davies TF, Greenberg DA (1998) Linkage analysis of candidate genes in autoimmune thyroid disease. II. Selected gender-related genes and the X-chromosome. International Consortium for the Genetics of Autoimmune Thyroid Disease. J Clin Endocrinol Metab 83:3290–3295

    CAS  PubMed  Google Scholar 

  120. Yin X, Latif R, Tomer Y, Davies TF (2007) Thyroid epigenetics: X chromosome inactivation in patients with autoimmune thyroid disease. Ann NY Acad Sci 1110:193–200

    CAS  PubMed  Google Scholar 

  121. Simmonds MJ, Kavvoura FK, Brand OJ, Newby PR, Jackson LE, Hargreaves CE, Franklyn JA, Gough SC (2014) Skewed X chromosome inactivation and female preponderance in autoimmune thyroid disease: an association study and meta-analysis. J Clin Endocrinol Metab 99:E127–E131

    PubMed  Google Scholar 

  122. Fugazzola L, Cirello V, Beck-Peccoz P (2012) Microchimerism and endocrine disorders. J Clin Endocrinol Metab 97:1452–1461

    CAS  PubMed  Google Scholar 

  123. Wiersinga WM (2013) Smoking and thyroid. Clin Endocrinol (Oxf) 79:145–151

    CAS  Google Scholar 

  124. Monzani F, Del Guerra P, Caraccio N, Casolaro A, Lippolis PV, Goletti O (1997) Appearance of Graves’ disease after percutaneous ethanol injection for the treatment of hyperfunctioning thyroid adenoma. J Endocrinol Invest 20:294–298

    CAS  PubMed  Google Scholar 

  125. Chiovato L, Santini F, Vitti P, Bendinelli G, Pinchera A (1994) Appearance of thyroid stimulating antibody and Graves’ disease after radioiodine therapy for toxic nodular goitre. Clin Endocrinol (Oxf) 40:803–806

    CAS  Google Scholar 

  126. Werner SC (1979) Graves’ disease following acute (subacute) thyroiditis. Arch Intern Med 139:1313–1315

    CAS  PubMed  Google Scholar 

  127. Yasuda T, Okamoto Y, Hamada N, Miyashita K, Takahara M, Sakamoto F, Miyatsuka T, Kitamura T, Katakami N, Kawamori D, Otsuki M, Matsuoka TA, Kaneto H, Shimomura I (2012) Serum vitamin D levels are decreased and associated with thyroid volume in female patients with newly onset Graves’ disease. Endocrine 42(739–741):2012

    Google Scholar 

  128. Yasuda T, Okamoto Y, Hamada N, Miyashita K, Takahara M, Sakamoto F, Miyatsuka T, Kitamura T, Katakami N, Kawamori D, Otsuki M, Matsuoka TA, Kaneto H, Shimomura I (2013) Serum vitamin D levels are decreased in patients without remission of Graves’ disease. Endocrine 43:230–232

    PubMed Central  CAS  PubMed  Google Scholar 

  129. Rotondi M, Chiovato L (2013) Vitamin D deficiency in patients with Graves’ disease: probably something more than a casual association. Endocrine 43:3–5

    CAS  PubMed  Google Scholar 

  130. Bülow Pedersen I, Knudsen N, Carlé A, Schomburg L, Köhrle J, Jørgensen T, Rasmussen LB, Ovesen L, Laurberg P (2013) Serum selenium is low in newly diagnosed Graves’ disease: a population-based study. Clin Endocrinol (Oxf) 79:584–590

    Google Scholar 

  131. Marcocci C, Kahaly GJ, Krassas GE, Bartalena L, Prummel M, Stahl M, Altea MA, Nardi M, Pitz S, Boboridis K, Sivelli P, von Arx G, Mourits MP, Baldeschi L, Bencivelli W, Wiersinga W (2011) Selenium and the course of mild Graves’ orbitopathy. N Engl J Med 364:1920–1931

    CAS  PubMed  Google Scholar 

  132. Weetman AP (2009) Immune reconstitution syndrome and the thyroid. Best Pract Res Clin Endocrinol Metab 23:693–702

    CAS  PubMed  Google Scholar 

  133. Weetman AP (2014) Graves’ disease following immune reconstitution or immunomodulatory treatment: should we manage it any differently? Clin Endocrinol (Oxf) 80:629–632

    CAS  Google Scholar 

  134. Pfeffer LM, Dinarello CA, Herberman RB, Williams BR, Borden EC, Bordens R, Walter MR, Nagabhushan TL, Trotta PP, Pestka S (1998) Biological properties of recombinant alpha-interferons: 40th anniversary of the discovery of interferons. Cancer Res 58:2489–2499

    CAS  PubMed  Google Scholar 

  135. Tomer Y, Blackard JT, Akeno N (2007) Interferon alpha treatment and thyroid dysfunction. Endocrinol Metab Clin North Am 36:1051–1066

    PubMed Central  CAS  PubMed  Google Scholar 

  136. Daniels GH, Vladic A, Brinar V, Zavalishin I, Valente W, Oyuela P, Palmer J, Margolin DH, Hollenstein J (2014) Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis. J Clin Endocrinol Metab 99:80–89

    CAS  PubMed  Google Scholar 

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The authors declare that they do not have any conflict of interest that could be perceived as prejudicing the impartiality of the manuscript.

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Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, University Of Pisa, Pisa, Italy

    M. Marinò, F. Latrofa, F. Menconi & P. Vitti

  2. Endocrinology Unit, University Hospital of Pisa, Via Paradisa 2, 56124, Pisa, Italy

    M. Marinò, F. Latrofa, F. Menconi & P. Vitti

  3. Unit of Endocrinology, Department of Internal Medicine and Medical Therapy, University of Pavia, Fondazione Salvatore Maugeri IRCCS, Pavia, Italy

    L. Chiovato

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  1. M. Marinò
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  2. F. Latrofa
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Correspondence to M. Marinò.

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Marinò, M., Latrofa, F., Menconi, F. et al. Role of genetic and non-genetic factors in the etiology of Graves’ disease. J Endocrinol Invest 38, 283–294 (2015). https://doi.org/10.1007/s40618-014-0214-2

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