The Genetics of Familial and Non-Familial Hyperthyroid Graves’ Disease

  • Yaron Tomer
  • Terry F. Davies
Part of the Endocrine Updates book series (ENDO, volume 6)


Graves’ disease (GD) is a multifactorial disease that develops as a result of a complex interaction between genetic susceptibility genes and environmental factors (1). Pathologically, the thyroid gland is infiltrated by T cells and B cells reactive with thyroid antigens, including the thyrotropin receptor (TSHR). This infiltration is associated with the production of antibodies which stimulate the thyroid via the TSHR causing hyperthyroidism and diffuse goiter as well as evidence of an ongoing thyroiditis associated with antibodies to thyroglobulin (Tg) and thyroid peroxidase (TPO)(1). Hence, the characterization of GD as autoimmune thyroiditis Type 3 (2). However, the cause of the immune response to thyroid antigens in GD remains unknown. Research into the pathogenesis of GD has focused on the possible precipitating environmental insults (such as infection)(3) and on under-standing the genetic predisposition to the disease. The recent advances in our under-standing of the genetic susceptibility to GD is the focus of this chapter.


Autoimmune Thyroid Disease Yersinia Enterocolitica Thyroid Epithelial Cell Maturity Onset Diabetes Ofthe Young TSHR Gene 
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  1. 1.
    Davies TF. The pathogenesis of Graves’ disease. 1996 In: Braverman LE, Utiger RD, ed. Werner and Ingbar’s The Thyroid: a fundamental and clinical text. Philadelphia: Lippincott-Raven, pp 525–536.Google Scholar
  2. 2.
    Davies TF, Amino N. 1993 A new classification for human autoimmune thyroid disease. Thyroid 3:331–333.PubMedCrossRefGoogle Scholar
  3. 3.
    Tomer Y, Davies TF. 1993 Infection, thyroid disease and autoimmunity. Endocr Rev. 14:107–120.PubMedGoogle Scholar
  4. 4.
    Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F, Young ET. 1995 The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham survey. Clin Endocrinol. 43:55–68.CrossRefGoogle Scholar
  5. 5.
    Jansson R, Safwenberg J, Dahlberg PA. 1985 Influence of HLA DR4 antigen and iodine status on the development of autoimmune thyroiditis. J Clin Endocrinol Metab. 60:168–174.PubMedCrossRefGoogle Scholar
  6. 6.
    Jansson R, Dahlberg PA, Winsa B, Meirik O, Safwenberg J, Karlsson A. 1987 The postpartum period constitutes an important risk for the development of clinical Graves’ disease in young women. Acta Endocrinol. 116:321–325.PubMedGoogle Scholar
  7. 7.
    Tada H, Hidaka Y, Tsuruta E, Kashiwai T, Tamaki H, Iwatani Y, Amino N. 1994 Prevalence of postpartum onset of disease within patients with Graves’ disease of child-bearing age. Endocr J. 41:325–327.PubMedCrossRefGoogle Scholar
  8. 8.
    Sonino N, Girelli M, Boscaro M, Fallo F, Busnardo B, Fava GA. 1993 Life events in the pathogenesis of Graves’ disease. A controlled study. Acta Endocrinol. 128:293–296.PubMedGoogle Scholar
  9. 9.
    Winsa B, Adami H-O, Bergstrom R, Gamstedt A, Dahlberg PA, Adamson U, Jansson R, Karlsson A. 1991 Stressful life events and Graves’ disease. Lancet 338:1475–1479.Google Scholar
  10. 10.
    Davies TF, Martin A, Concepcion ES, Graves P, Cohen L, Ben-Nun A. 1991 Evidence of limited variability of antigen receptors on intrathyoidal T cells in autoimmune thyroid disease. N Engl J Med. 325:238–244.PubMedCrossRefGoogle Scholar
  11. 11.
    Cox SP, Phillips DI, Osmond C. 1989 Does infection initiate Graves disease? A population based 10 year study. Autoimmunity 4:43–49.PubMedCrossRefGoogle Scholar
  12. 12.
    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. 23:283–287.CrossRefGoogle Scholar
  13. 13.
    Valtonen VV, Ruutu P, Varis K, Ranki M, Malkamaki M, Makela PH. 1986 Serological evidence for the role of bacterial infections in the patho-genesis of thyroid diseases. Acta Med Scand. 219:105–111.PubMedCrossRefGoogle Scholar
  14. 14.
    Segal RL, Fiedler R, Jacobs DR, Antrobus J. 1976 Mini-epidemic of thyrotoxicosis occurring in physicians. Am J Med Sci. 271:55–57.PubMedCrossRefGoogle Scholar
  15. 15.
    Lidman K, Eriksson U, Norberg R, Fagraeus A. 1976 Indirect immunofluorescence staining of human thyroid by antibodies occurring in Yersinia enterocolitica infections. Clin Exp Immunol. 23:429–435.PubMedGoogle Scholar
  16. 16.
    Shenkman L, Bottone EJ. 1976 Antibodies to Yersinia enterocolitica in thyroid disease. Ann Int Med. 85:735–739.PubMedGoogle Scholar
  17. 17.
    Wenzel BE, Heesemann J, Wenzel KW, Scriba PC. 1988 Antibodies to plasmid-encoded proteins of enteropathogenic Yersinia in patients with autoimmune thyroid disease (letter). Lancet 1:56PubMedCrossRefGoogle Scholar
  18. 18.
    Weiss M, Ingbar SH, Winblad S, Kasper DL. 1983 Demonstration of a saturable binding site for thyrotropin in Yersinia enterocolitica. Science 219:1331–1333.PubMedCrossRefGoogle Scholar
  19. 19.
    Heyma P, Harrison LC, Robins-Browne R. 1986 Thyrotropin (TSH) binding sites on Yersinia enterocolitica recognized by immunoglobulins from humans with Grave’s disease. Clin Exp Immunol. 64:249–254.PubMedGoogle Scholar
  20. 20.
    Ebner S, Alex S, Klugnam T, Appel M, Heesemann J, Wenzel B. 1991 Immunization with Yersinia enterocolitica purified outer membrane protein induces lymphocytic thyroiditis in the BB/WOR rat (abstract). Thyroid 1 (Suppl):S28.Google Scholar
  21. 21.
    Ciampolillo A, Mirakian R, Schulz T, Vittoria M, Buscema M, Pujol Borrell R, Bottazzo GF. 1989 Retrovirus-like sequences in Graves’ disease: implications for human autoimmunity. Lancet 1:1096–1099.PubMedCrossRefGoogle Scholar
  22. 22.
    Tunbridge WMG, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Evans JG, Young E, Bird T, Smith PA. 1977 The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol. 7:481–493.CrossRefGoogle Scholar
  23. 23.
    Furszyfer J, Kurland LT, McConahey WM, Elveback LR. 1970 Graves’ disease in Olmsted County, Minnesota, 1935 through 1967. Mayo Clin Proc. 45:636–644.PubMedGoogle Scholar
  24. 24.
    Mogensen EF, Green A. 1980 The epidemiology of thyrotoxicosis in Denmark. Incidence and geographical variation in the Funen region 1972–1974. Acta Med Scand. 208:183–186.PubMedCrossRefGoogle Scholar
  25. 25.
    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.PubMedCrossRefGoogle Scholar
  26. 26.
    Volpe R. 1985 Autoimmune thyroid disease. In: Volpe R, ed. Autoimmunity and endocrine disease. New York: Marcel Dekker, pp 109–285.Google Scholar
  27. 27.
    Bartels ED. 1941 Twin Examinations: Heredity in Graves’ disease. Copenhagen: Munksgaad 32–36.Google Scholar
  28. 28.
    Martin L. 1945 The heredity and familial aspects of exophathalmic goitre and nodular goitre. Q J Med. 14:207–29.PubMedGoogle Scholar
  29. 29.
    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 followup study of 69 patients. J Clin Endocrinol Metab. 51:1123–1128.PubMedCrossRefGoogle Scholar
  30. 30.
    Chopra IJ, Solomon DH, Chopra U, Yodhihara E, Tersaki PL, Smith F. 1977 Abnormalities in thyroid function in relatives of patients with Graves’ disease and Hashimoto’s thyroiditis: lack of correlation with inheritance of HLA-B8. J Clin Endocrinol Metab. 45:45–54.PubMedCrossRefGoogle Scholar
  31. 31.
    Tamai H, Kumagai LF, Nagataki S. 1986 Immunogenetics of Graves’ disease. In: McGregor AM, editor. Immunology of endocrine diseases. Lancaster, U.K.: MTP Press pp 123–141.CrossRefGoogle Scholar
  32. 32.
    Burek CL, Hoffman WH, Rose NR. 1982 The presence of thyroid autoanti-bodies in children and adolescents with AITD and in their siblings and parents. Clin Immunol Immunopathol. 25:395–404.PubMedCrossRefGoogle Scholar
  33. 33.
    Hall R, Stanbury JB. 1967 Familial studies of autoimmune thyroiditis. Clin Exp Immunol. 2:719–725.PubMedGoogle Scholar
  34. 34.
    Vyse TJ, Todd JA. 1996 Genetic analysis of autoimmune disease. Cell 85:311–318.PubMedCrossRefGoogle Scholar
  35. 35.
    Haraldsson A, Gudmundsson ST, Larusson G, Sigurdsson G. 1985 Thyrotoxicosis in Iceland 1980–1982. An epidemiological survey. Acta Med Scand. 217:253–258.PubMedCrossRefGoogle Scholar
  36. 36.
    Brix TH, Christensen K, Holm NV, Harvald B, Hegedus L. 1998 A population-based study of Graves’ diseases in Danish twins. Clin Endocrinol. 48:397–400.CrossRefGoogle Scholar
  37. 37.
    Volpe R. 1990 Immunology of human thyroid disease. In: Volpe R, editor. Autoimmunity in endocrine disease. Boca Raton: CRC Press p73.Google Scholar
  38. 38.
    Hall R, Dingle PR, Roberts DF. 1972 Thyroid antibodies: a study of first degree relatives. Clin Genet. 3:319–324.PubMedCrossRefGoogle Scholar
  39. 39.
    Burek CL, Hoffman WH, Rose NR. 1982 The presence of thyroid autoantibodies in children and adolescents with AITD and in their siblings and parents. Clin Immunol Immunopathol. 25:395–404.PubMedCrossRefGoogle Scholar
  40. 40.
    Aho K, Gordin A, Sievers K, Takala J. 1983 Thyroid autoimmunity in siblings: a population study. Acta Endocrinol; Suppl. 251:11–15.Google Scholar
  41. 41.
    Phillips DIW, 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.PubMedCrossRefGoogle Scholar
  42. 42.
    Jaume JC, Guo J, Pauls DL, Zakarija M, McKenzie JM, Egeland JA, Burek CL, Rose NR, Hoffman WH, Rapoport B, McLachlan SM. 1999 Evidence for genetic transmission of thyroid peroxidase autoantibody epitopic “fingerprints”. J Clin Endocrinol Metab. 84:1424–1431.PubMedCrossRefGoogle Scholar
  43. 43.
    Weetman AP. Thyroid-associated ophthalmopathy. 1992 Autoimmunity 12:215–222.PubMedCrossRefGoogle Scholar
  44. 44.
    Koskinen S. Long-term follow-up of health in blood donors with primary selective IgA deficiency. J Clin Immunol. 16:165–170.Google Scholar
  45. 45.
    Liblau RS, Bach JF. 1992 Selective IgA deficiency and autoimmunity. Int Arch Allergy Immunol. 99:16–27.PubMedCrossRefGoogle Scholar
  46. 46.
    Mano T, Kawakubo A, Yamamoto M. 1992 Isolated IgA deficiency accompanied by autoimmune thyroid disease. Int Med. 31:1201–1203.CrossRefGoogle Scholar
  47. 47.
    Michael NL, Chang G, Louie LG, Mascola JR, Dondero D, Birx DL, Sheppard HW. 1997 The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression. Nat Med. 3:338–340.PubMedCrossRefGoogle Scholar
  48. 48.
    Kockum I, Wassmuth R, Holmberg E, et al. 1993 HLA-DQ protection and HLA-DR susceptibility in Type 1 (insulin-dependent) diabetes studied in population-based affected families and controls. Am J Hum Genet. 42:150–167.Google Scholar
  49. 49.
    Lucassen AM, Julier C, Beressi JP, Boitard C, Froguel P, Lathrop M, Bell JI. 1993 Susceptibility to insulin-dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR. Nat Genet. 4:305–310.PubMedCrossRefGoogle Scholar
  50. 50.
    Kennedy GC, German MS, Rutter WJ. 1995 The minisatellite in the diabetes susceptibility locus IDDM2 regulates insulin transcription. Nat Genet. 9:293–298.PubMedCrossRefGoogle Scholar
  51. 51.
    Puglise A, Zeller M, Fernandez Jr. A, Zalcberg LJ, Bartlett RJ, Ricordi C, Pietropaolo M, Eisenbarth GS, Bennett ST, Patel DD. 1997 The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet. 15:293–297.CrossRefGoogle Scholar
  52. 52.
    Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, Wickramasinghe S, Colle E, Polychronakos C. 1997 Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet. 15:289–292.PubMedCrossRefGoogle Scholar
  53. 53.
    Permutt MA, Chiu KC, Tanizawa Y. Glucokinase and NIDDM. 1992 A candidate gene that paid off. Diabetes 41:1367–1372.PubMedCrossRefGoogle Scholar
  54. 54.
    Ott J. 1996 Analysis of human genetic linkage. Baltimore: Johns Hopkins University Press.Google Scholar
  55. 55.
    Lander E, Kruglyak L. 1995 Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 11:241–247.PubMedCrossRefGoogle Scholar
  56. 56.
    Weber JL. 1990 Human DNA polymorphisms based on length variations in simple-sequence tandem repeats. Genome Anal 1:159–181.Google Scholar
  57. 57.
    Nelson JL, Hansen JA. 1990 Autoimmune disease and HLA. CRC Crit Rev Immunol. 10:307–328.Google Scholar
  58. 58.
    Campbell RD, Trowsdale J. 1993 Map of the human MHC. Immunol Today 14:349–352.PubMedCrossRefGoogle Scholar
  59. 59.
    Todd JA. 1995 Genetic analysis of type 1 diabetes using whole genome approaches. Proc Natl Acad Sci USA 92:8560–8565.PubMedCrossRefGoogle Scholar
  60. 60.
    Bech K, Lumholtz B, Nerup J, Thomsen M, Platz P, Ryder LP, Svejgaard A, Siersbaek-Nielsen K, Hansen JM, Larse JH. 1977 HLA antigens in Graves’ disease. Acta Endocrinol. 86:510–516.PubMedGoogle Scholar
  61. 61.
    Farid NR, Sampson L, Noel EP, Barnard JM, Mandeville R, Larsen B, Marshall WH, Carter ND. 1979 A study of human D locus related antigens in Graves’ disease. J Clin Invest. 63:108–113.PubMedCrossRefGoogle Scholar
  62. 62.
    Mangklabruks A, Cox N, DeGroot LJ. 1991 Genetic factors in autoimmune thyroid disease analyzed by restriction fragment length polymorphisms of candidate genes. J Clin Endocrinol Metab. 73:236–244.PubMedCrossRefGoogle Scholar
  63. 63.
    Kawa A, Nakamura S, Nakazawa M, Sakaguch S, Kawabata T, Maeda Y, Kanehisa T. 1977 HLA-BW35 and B5 in Japanese patients with Graves’ disease. Acta Endocrinol. 86:754–757.PubMedGoogle Scholar
  64. 64.
    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.PubMedCrossRefGoogle Scholar
  65. 65.
    Barlow ABT, Wheatcroft N, Watson P, Weetman AP. 1996 Association of HLA-DQA1*0501 with Graves’ disease in English Caucasian men and women. Clin Endocrinol. 44:73–77.CrossRefGoogle Scholar
  66. 66.
    Yanagawa T, Mangklabruks A, Chang YB, Okamoto Y, Fisfalen M-E, 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.PubMedCrossRefGoogle Scholar
  67. 67.
    Hawkins BR, Ma JT, Lam KS, Wang CC, Yeung RT. 1985 Analysis of linkage between HLA haplotype and susceptibility to Graves’ disease in multiple-case Chinese families in Hong Kong. Acta Endocrinol. 1985; 110:66–69.PubMedGoogle Scholar
  68. 68.
    Roman SH, Greenberg DA, Rubinstein P, Wallenstein S, Davies TF. 1992 Genetics of autoimmune thyroid disease: lack of evidence for linkage to HLA within families. J Clin Endocrinol Metab.74:496–503.PubMedCrossRefGoogle Scholar
  69. 69.
    O’Connor G, Neufeld DS, Greenberg DA, Concepcion L, Roman SH, Davies TF. 1993 Lack of disease associated HLA-DQ restriction fragment length polymorphisms in families with autoimmune thyroid disease. Autoimmunity 14:237–241.PubMedCrossRefGoogle Scholar
  70. 70.
    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.PubMedCrossRefGoogle Scholar
  71. 71.
    Payami H, Joe S, Thomson G. 1989 Autoimmune thyroid disease in Type 1 diabetes. Genet Epidem. 6:137–141.CrossRefGoogle Scholar
  72. 72.
    Stenszky V, Kozma L, Balazs C, Rochlitz S, Bear JC, Farid NR. 1985 The genetics of Graves’ disease: HLA and disease susceptibility. J Clin Endocrinol Metab. 61:735–740.PubMedCrossRefGoogle Scholar
  73. 73.
    Schleusener H, Schernthaner G, Mayr WR, Kotulla P, Bogner U, Finke R, Meinhold H, Koppenhagen K, Wenzel KW. 1983 HLA-DR3 and HLA-DR5 associated thyrotoxicosis-two different types of toxic diffuse goiter. J Clin Endocrinol Metab. 56:781–785.PubMedCrossRefGoogle Scholar
  74. 74.
    Farid NR, Stone E, Johnson G. 1980 Graves’ disease and HLA: clinical and epidemiologic associations. Clin Endocrinol. 13:535–544.CrossRefGoogle Scholar
  75. 75.
    Frecker M, Stenszky V, Balazs C, Kozma L, Kraszits E, Farid NR. 1986 Genetic factors in Graves’ ophthalmopathy. Clin Endocrinol. 25:479–485.CrossRefGoogle Scholar
  76. 76.
    Frecker M, Mercer G, Skanes VM, Farid NR. 1988 Major histocompatibility complex (MHC) factors predisposing to and protecting against Graves’ eye disease. Autoimmunity 1:307–315.PubMedCrossRefGoogle Scholar
  77. 77.
    Allannic H, Fauchet R, Lorcy Y, Gueguen M, Le Guerrier AM, Genetet B. 1983 A prospective study of the relationship between relapse of hyperthyroid Graves’ disease after antithyroid drugs and HLA haplotype. J Clin Endocrinol Metab. 57:719–722.PubMedCrossRefGoogle Scholar
  78. 78.
    Kendall-Taylor P, Stephenson A, Stratton A, Papiha SS, Perros P, Roberts DF. 1988 Differentiation of autoimmune ophthalmopathy from Graves’ hyperthyroidism by analysis of genetic markers. Clin Endocrinol 28:601–610.Google Scholar
  79. 79.
    Weetman AP, So AK, Warner CA, Foroni L, Fells P, Shine B. 1988 Immunogenetics of Graves’ ophthalmopathy. Clin Endocrinol 28:619–628.Google Scholar
  80. 80.
    Weetman AP, Ratanachaiyavong S, Middleton GW, Love W, John R, Owen GM, Darke C, Lazarus JH, Hall R, McGregor AM. 1986 Prediction of outcome in Graves’ disease after Carbimazole treatment. Q J Med. 59:409–419.PubMedGoogle Scholar
  81. 81.
    Buus S, Sette A, Grey HM. 1987 The interaction between protein-derived immunogenic peptides and la. Immunol Rev. 98:115–141.PubMedCrossRefGoogle Scholar
  82. 82.
    Nelson JL, Hansen JA. 1990 Autoimmune disease and HLA. CRC Crit Rev Immunol. 10:307–328.Google Scholar
  83. 83.
    Faas S, Trucco M. 1994 The genes influencing the susceptibility to IDDM in humans. J Endocrinol Invest. 17:477–495.PubMedGoogle Scholar
  84. 84.
    Londei M, Lamb JR, Bottazzo GF, Feldmann M. 1984 Epithelial cells expressing aberrant MHC class II determinants can present antigen to cloned human T cells. Nature 312:639–641.PubMedCrossRefGoogle Scholar
  85. 85.
    Hanafusa T, Pujol Borrell R, Chiovato L, Russell RC, Doniach D, Bottazzo GF. 1983 Aberrant expression of HLA-DR antigen on thyrocytes in Graves’ disease: relevance for autoimmunity. Lancet 2:1111–1115.PubMedCrossRefGoogle Scholar
  86. 86.
    Davies TF. 1985 Co-culture of human thyroid monolayer cells and autologous T cells: impact of HLA class II antigen expression. J Clin Endocrinol Metab. 61:418–422.PubMedCrossRefGoogle Scholar
  87. 87.
    Davies TF, Piccinini LA. 1987 Intrathyroidal MHC class II antigen expression and thyroid autoimmunity. Endocrinol Metab Clin North Am. 16:247–268.PubMedGoogle Scholar
  88. 88.
    Neufeld DS, Platzer M, Davies TF. 1989 Reovirus induction of MHC class II antigen in rat thyroid cells. Endocrinology 124:543–545.PubMedCrossRefGoogle Scholar
  89. 89.
    Belfiore A, Mauerhoff T, Pujol Borrell R, Badenhoop K, Buscema M, Mirakian R, Bottazzo GF. 1991 De novo HLA class II and enhanced HLA class I molecule expression in SV40 transfected human thyroid epithelial cells. J Autoimmunity. 4:397–414.CrossRefGoogle Scholar
  90. 90.
    Davies TF, Bermas B, Platzer M, Roman SH. 1985 T-cell sensitization to autologous thyroid cells and normal non- specific suppressor T-cell function in Graves’ disease. Clin Endocrinol. 22:155–167.CrossRefGoogle Scholar
  91. 91.
    Eguchi K, Otsubo T, Kawabe K, Ueki Y, Fukuda T, Mayumi M, Shimomura C, Ishikawa N, Nakao H, Ito K, Morimoto C, Nagataki S. 1987 The remarkable proliferation of helper T cell subset in response to autologous thyrocytes and intrathyroidal T cells from patients with Graves’ disease. Isr J Med Sci 70:403–410.Google Scholar
  92. 92.
    Jackson DG, Capra JD. 1993 TAPI alleles in insulin-dependent diabetes mellitus: a newly defined centromeric boundary of disease susceptibility. Proc Natl Acad Sci USA 90:11079–11083.PubMedCrossRefGoogle Scholar
  93. 93.
    Yanagawa T, Hidaka Y, Guimaraes V, Soliman M, DeGroot LJ. 1995 CTLA-4 gene polymorphism associated with Graves’ disease in a caucasian population. J Clin Endocrinol Metab. 80:41–45.PubMedCrossRefGoogle Scholar
  94. 94.
    Nistico L, Buzzetti R, Pritchard LE, et al. 1996 The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Hum Mol Genet. 5:1075–1080.PubMedCrossRefGoogle Scholar
  95. 95.
    Kotsa K, Watson PF, Weetman AP. 1997 A CTLA-4 gene polymorphism is associated with both Graves’ disease and autoimmune hypothyroidism. Clin Endocrinol. 46:551–554.CrossRefGoogle Scholar
  96. 96.
    Sale MM, Akamizu T, Howard TD, Yokota T, Nakao K, Mori T, Iwasaki H, Rich SS, Jennings-Gee JE, Yamada M, Bowden DW. 1997 Association of autoimmune thyroid disease with a microsatellite marker for the thyrotropin receptor gene and CTLA-4 in a Japanese population. Proc Assoc Am Phys. 109:453–461.PubMedGoogle Scholar
  97. 97.
    Donner H, Rau H, Walfish PG, Braun J, Siegmund T, Finke R, Herwig J, Usadel KH, Badenhoop K. 1997 CTLA4 alanine-17 confers genetic susceptibility to Graves’ disease and to type 1 diabetes mellitus. J Clin Endocrinol Metab. 82:143–146.PubMedCrossRefGoogle Scholar
  98. 98.
    Yanagawa T, Taniyama M, Enomoto S, Gomi K, Maruyama H, Ban Y, Saruta T. 1997 CTLA4 gene polymorphism confers susceptibility to Graves’ disease in Japanese. Thyroid 7:843–846.PubMedCrossRefGoogle Scholar
  99. 99.
    Vaidya B, Imrie H, Perros P, Dickinson J, McCarthy MI, Kendall-Taylor P, Pearce SH. 1999 Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy (letter). Lancet 354:743–744.PubMedCrossRefGoogle Scholar
  100. 100.
    Heward JM, Allahabadia A, Carr-Smith J, Daykin J, Cockram CS, Gordon CBAH, Franklyn JA, Gough SCL. 1998 No evidence for allelic association of human CTLA-4 promoter polymorphism with autoimmune thyroid disease in either population-based case-control or family-based studies. Clin Endocrinol. 49:331–334.CrossRefGoogle Scholar
  101. 101.
    Vaidya B, Imrie H, Perros P, Young ET, Kelly WF, Carr D, Large DM, Toft AD, McCarthy MI, Kendall-Taylor P, Pearce SH. 1999 The cytotoxic T lymphocyte antigen-4 is a major Graves’ disease locus. Hum Mol Genet. 8:1195–1199.PubMedCrossRefGoogle Scholar
  102. 102.
    Reiser H, Stadecker MJ. 1996 Costimulatory B7 molecules in the pathogenesis of infectious and autoimmune diseases. N Engl J Med. 335:1369–1377.PubMedCrossRefGoogle Scholar
  103. 103.
    Lenschow DJ, Ho SC, Sattar H, Rhee L, Gray G, Nabavi N, Herold KC, Bluestone JA. 1995 Differential effects of anti-B7-l and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse. J Exp Med. 181:1145–1155.PubMedCrossRefGoogle Scholar
  104. 104.
    Lenschow DJ, Herold KC, Rhee L, Patel B, Koons A, Qin HY, Fuchs E, Singh B, Thompson CB, Bluestone JA. 1996 CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes. Immunity 5:285–293.PubMedCrossRefGoogle Scholar
  105. 105.
    Abbas AK, Murphy KM, Sher A. 1996 Functional diversity of helper T lymphocytes. Nature 383:787–793.PubMedCrossRefGoogle Scholar
  106. 106.
    Smith TJ, Sciaky D, Phipps RP, Jennings TA. 1999 CD40 expression in human thyroid tissue: evidence for involvement of multiple cell types in autoimmune and neoplastic diseases. Thyroid 9:749–755.PubMedCrossRefGoogle Scholar
  107. 107.
    Metcalfe RA, McIntosh RS, Marelli-Berg F, Lombardi G, Lechler R, Weetman AP. 1998 Detection of CD40 on human thyroid follicular cells: analysis of expression and function. J Clin Endocrinol Metab. 83:1268–1274.PubMedCrossRefGoogle Scholar
  108. 108.
    Faure GC, Bensoussan-Lejzerowicz D, Bene MC, Aubert V, Ledere J. 1997 Coexpression of CD40 and class II antigen HLA-DR in Graves’ disease thyroid epithelial cells. Clin Immunol Immunopathol. 84:212–215.PubMedCrossRefGoogle Scholar
  109. 109.
    Demaine A, Welsh KI, Hawe BS, Farid NR. 1987 Polymorphism of the T cell receptor beta-chain in Graves’ disease. J Clin Endocrinol Metab. 65:643–646.PubMedCrossRefGoogle Scholar
  110. 110.
    Weetman AP, So AK, Roe C, Walport MJ, Foroni L. 1987 T-cell receptor alpha chain V region polymorphism linked to primary autoimmune hypothyroidism but not Graves’ disease. Human Immunol. 20:167–173.CrossRefGoogle Scholar
  111. 111.
    Barbesino G, Tomer Y, Concepcion ES, Davies TF, Greenberg DA. 1998 Linkage analysis of candidate genes in autoimmune thyroid disease: I. Selected immunoregulatory genes. J Clin Endocrinol Metab. 83:1580–1584.PubMedCrossRefGoogle Scholar
  112. 112.
    Nakao Y, Matsumoto H, Miyazaki T, Nishitani H, Takatsuki K, Kasukawa R, Nakayama S, Izumi S, Fujita T, Tsuji K. 1980 IgG heavy chain allotypes (Gm) in atrophic and goitrous thyroiditis. Clin Exp Immunol. 42:20–26.PubMedGoogle Scholar
  113. 113.
    Blakemore AIF, Watson PF, Weetman AP, Duff GW. 1995 Association of Graves’ disease with an allele of the interleukin-1 receptor antagonist gene. J Clin Endocrinol Metab. 80:111–115.PubMedCrossRefGoogle Scholar
  114. 114.
    Cuddihy RM, Bahn RS. 1996 Lack of an association between alleles of interleukin-1 alpha and interleukin-1 receptor antagonsit genes and Graves’ disease in a north American Caucasian population. J Clin Endocrinol Metab. 81:4476–4478.PubMedCrossRefGoogle Scholar
  115. 115.
    Weetman AP, Gunn C, Hall R, McGregor AM. 1985 Thyroid autoantigen-induced lymphocyte proliferation in Graves’ disease and Hashimoto’s thyroiditis. J Clin Lab Immunol. 17:1–6.PubMedGoogle Scholar
  116. 116.
    Weetman AP. 1992 Autoimmune thyroiditis: predisposition and pathogenesis. Clin Endocrinol. 36:307–323.CrossRefGoogle Scholar
  117. 117.
    Rosenbaum D, Davies TF. 1992 The clinical use of thyroid autoantibodies. The Endocrinologist 2:55–62.CrossRefGoogle Scholar
  118. 118.
    Raspe E, Costagliola S, Ruf J, Mariotti S, Dumont JE, Ludgate M. 1995 Identification of the thyroid Na+/I- cotransporter as a potential autoantigen in thyroid autoimmune disease (see comments). Eur J Endocrinol. 132:399–405.PubMedCrossRefGoogle Scholar
  119. 119.
    Bohr URM. 1993 A heritable point mutation in an extracellular domain of the TSHR involved in the interaction with Graves’ disease. Biochem Biophys Acta 1216:504–508.PubMedCrossRefGoogle Scholar
  120. 120.
    Bahn RS, Dutton CM, Heufelder AE, Sarkar G. 1994 A genomic point mutation in the extracellular domain of the TSHR in patients with Graves’ ophthalmopathy. J Clin Endocrinol Metab. 78:256–260.PubMedCrossRefGoogle Scholar
  121. 121.
    Ahmad MF, Stenszky V, Juhazs F, Balzs G, Farid NR. 1994 No mutations in the translated region of exon 1 in the TSHR in Graves’ thyroid glands. Thyroid 4:151–153.PubMedCrossRefGoogle Scholar
  122. 122.
    Watson PF, French A, Pickerill AP, McIntosh RS, Weetman AP. 1995 Lack of association between a polymorphism in the coding region of the thyrotropin receptor gene and Graves’ disease. J Clin Endocrinol Metab. 80:1032–1035.PubMedCrossRefGoogle Scholar
  123. 123.
    De Roux N, Misrahi M, Chatelain N, Gross B, Milgrom E. 1996 Microsatellites and PCR primers for genetic studies and genomic sequencing of the human TSHR gene. Mol Cell Endocrinol. 117:253–256.PubMedCrossRefGoogle Scholar
  124. 124.
    De Roux N, Shields DC, Misrahi M, Ratanachaiyavong S, McGregor AM, Milgrom E. 1996 Analysis of the thyrotropin receptor as a candidate gene in familial Graves’ disease. J Clin Endocrinol Metab. 81:3483–3486.PubMedCrossRefGoogle Scholar
  125. 125.
    Tomer Y, Barbesino G, Greenberg DA, Concepcion ES, Davies TF. 1998 Linkage analysis of candidate genes in autoimmune thyroid disease: 3. Detailed analysis of chromosome 14 localizes GD-1 close to MNG-1. J Clin Endocrinol Metab. 83:4321–4327.PubMedCrossRefGoogle Scholar
  126. 126.
    Pirro MT, De Filippis V, Di Cerbo A, Scillitani A, Liuzzi A, Tassi V. 1995 Thyroperoxidase microsatellite polymorphism in thyroid disease. Thyroid 5:461–464.PubMedCrossRefGoogle Scholar
  127. 127.
    Paavonen T. Hormonal regulation of immune responses. Ann Med 1994; 26:255–258.PubMedCrossRefGoogle Scholar
  128. 128.
    Van Griensven M, Bergijk EC, Baelde JJ, De Heer E, Bruijn JA. 1997 Differential effects of sex hormones on autoantibody production and proteinuria in chronic graft-versus-host disease-induced experimental lupus nephritis. Clin Exp Immunol. 107:254–260.PubMedCrossRefGoogle Scholar
  129. 129.
    Grossman CJ, Roselle GA, Mendenhall CL. 1991 Sex steroid regulation of autoimmunity. J Steroid Biochem Mol Biol. 40:649–659.PubMedCrossRefGoogle Scholar
  130. 130.
    Stewart JJ. 1998 The female X-inactivation mosaic in systemic lupus erythematosus. Immunol Today 19:352–357.PubMedCrossRefGoogle Scholar
  131. 131.
    Barbesino G, Tomer Y, Concepcion ES, Davies TF, Greenberg D. 1998 Linkage analysis of candidate genes in autoimmune thyroid disease: 2. Selected gender-related genes and the X-chromosome. J Clin Endocrinol Metab. 83:3290–3295.PubMedCrossRefGoogle Scholar
  132. 132.
    Villanueva RB, Tomer Y, Tucci S, Greenberg DA, Concepcion ES, Davies TF. 1999 Analysis of the BTK gene on chromosome X as a candidate gene in Graves’ disease. Endocrine Society 81st Annual Meeting; San Diego, CA.Google Scholar
  133. 133.
    Tomer Y, Barbesino G, Greenberg DA, Concepcion ES, Davies TF. 1998 A new Graves disease-susceptibility locus maps to chromosome 20ql 1.2. Am J Hum Genet. 63:1749–1756.PubMedCrossRefGoogle Scholar
  134. 134.
    Tomer Y, Barbesino G, Greenberg DA, Concepcion ES, Davies TF. 1999 Mapping the major susceptibility loci for familial Graves’ and Hashimoto’s diseases: Evidence for genetic heterogeneity and gene interactions. J Clin Endocrinol Metab. In press.Google Scholar
  135. 135.
    Bignell GR, Canzian F, Shayeghi M, et al. 1997 A familial non-toxic multinodular thyroid goiter locus maps to chromosome 14q but does not account for familial nonmedullary thyroid cancer. Am J Hum Genet. 61:1123–1130.PubMedCrossRefGoogle Scholar
  136. 136.
    McKenna R, Kearns M, Sugrue D, Drury MI, McCarthy CF. 1982 HLA and hyperthyroidism in Ireland. Tissue Antigens 19:97–99.PubMedCrossRefGoogle Scholar
  137. 137.
    Dahlberg PA, Holmlund G, Karlsson FA, Safwenberg J. 1981 HLA-A, -B, -C and -DR antigens in patients with Graves’ disease and their correlation with signs and clinical course. Acta Endocrinol. 97:42–47.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Yaron Tomer
  • Terry F. Davies

There are no affiliations available

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