Abstract
Previously, we and others have demonstrated the association of a C/T single nucleotide polymorphism (SNP), in the Kozak sequence of CD40, with Graves' disease (GD). Here, using an expanded data set of patients, we confirm the association of the CD40 SNP with GD (n=210, P=0.002, odds ratio (OR)=1.8). Subset analysis of patients with persistently elevated thyroid peroxidase (TPO) and/or thyroglobulin (Tg) antibodies (Abs), (TPO/Tg Abs), after treatment (n=126), revealed a significantly stronger association of the SNP with disease (P=5.2 × 10−5, OR=2.5) than in GD patients who were thyroid antibody-negative. However, the CD40 SNP was not associated with TPO/Tg Abs in healthy individuals. Next, we tested the CD40 SNP for association with Myasthenia Gravis (MG), which, like GD is an antibody-mediated autoimmune condition. Analysis of 81 MG patients found no association of the SNP with disease. Functional studies revealed significant expression of CD40 mRNA and protein in the thyroid (target tissue in GD) but not in skeletal muscle (target tissue in MG). Combined, our genetic and tissue expression data suggest that the CD40 Kozak SNP is specific for thyroid antibody production involved in the etiology of GD. Increased thyroidal expression of CD40 driven by the SNP may contribute to this disease specificity.
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References
Jacobson DL, Gange SJ, Rose NR, Graham NM . Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997; 84: 223–243.
McIver B, Morris JC . The pathogenesis of Graves' disease. Endocrinol Metab Clin North Am 1998; 27: 73–89.
Weetman AP, McGregor AM . Autoimmune thyroid disease: further developments in our understanding. Endocr Rev 1994; 15: 788–830.
Ai J, Leonhardt JM, Heymann WR . Autoimmune thyroid diseases: etiology, pathogenesis, and dermatologic manifestations. J Am Acad Dermatol 2003; 48: 641–659; quiz 660–662.
Ban Y, Tomer Y . Susceptibility genes in thyroid autoimmunity. Clin Dev Immunol 2005; 12: 47–58.
Tomer Y, Davies TF . Infection, thyroid disease, and autoimmunity. Endocr Rev 1993; 14: 107–120.
Weetman AP . Autoimmune thyroid disease: propagation and progression. Eur J Endocrinol 2003; 148: 1–9.
Prummel MF, Strieder T, Wiersinga WM . The environment and autoimmune thyroid diseases. Eur J Endocrinol 2004; 150: 605–618.
Tomer Y, Davies TF . Searching for the autoimmune thyroid disease susceptibility genes: from gene mapping to gene function. Endocr Rev 2003; 24: 694–717.
Simmonds MJ, Gough SC . Unravelling the genetic complexity of autoimmune thyroid disease: HLA, CTLA-4 and beyond. Clin Exp Immunol 2004; 136: 1–10.
Tomer Y, Barbesino G, Greenberg DA, Concepcion E, Davies TF . A new Graves' disease-susceptibility locus maps to chromosome 20q11.2. International Consortium for the Genetics of Autoimmune Thyroid Disease. Am J Hum Genet 1998; 63: 1749–1756.
Tomer Y, Concepcion E, Greenberg DA . A C/T single-nucleotide polymorphism in the region of the CD40 gene is associated with Graves' disease. Thyroid 2002; 12: 1129–1135.
Pearce SH, Vaidya B, Imrie H, Perros P, Kelly WF, Toft AD et al. Further evidence for a susceptibility locus on chromosome 20q13.11 in families with dominant transmission of Graves' disease. Am J Hum Genet 1999; 65: 1462–1465.
Houston FA, Wilson V, Jennings CE, Owen CJ, Donaldson P, Perros P et al. Role of the CD40 locus in Graves' disease. Thyroid 2004; 14: 506–509.
Kurylowicz A, Kula D, Ploski R, Skorka A, Jurecka-Lubieniecka B, Zebracka J et al. Association of CD40 gene polymorphism (C-1T) with susceptibility and phenotype of Graves' disease. Thyroid 2005; 15: 1119–1124.
Kim TY, Park YJ, Hwang JK, Song JY, Park KS, Cho BY et al. A C/T polymorphism in the 5′-untranslated region of the CD40 gene is associated with Graves' disease in Koreans. Thyroid 2003; 13: 919–925.
Ban Y, Tozaki T, Taniyama M, Tomita M, Ban Y . Association of a C/T single-nucleotide polymorphism in the 5′ untranslated region of the CD40 gene with Graves' disease in Japanese. Thyroid 2006; 16: 443–446.
Mukai T, Hiromatsu Y, Fukutani T, Ichimura M, Kaku H, Miyake I et al. A C/T polymorphism in the 5′ untranslated region of the CD40 gene is associated with later onset of Graves' disease in Japanese. Endocr J 2005; 52: 471–477.
Heward JM, Simmonds MJ, Carr-Smith J, Foxall H, Franklyn JA, Gough SC . A single nucleotide polymorphism in the CD40 gene on chromosome 20q (GD-2) provides no evidence for susceptibility to Graves' disease in UK Caucasians. Clin Endocrinol (Oxford) 2004; 61: 269–272.
Tomer Y, Davies TF, Greenberg DA . What is the contribution of a kozak snp in the CD40 gene to Graves' disease? Clin Endocrinol (Oxford) 2005; 62: 258.
Jacobson EM, Concepcion E, Oashi T, Tomer Y . A Graves' disease-associated Kozak sequence single-nucleotide polymorphism enhances the efficiency of CD40 gene translation: a case for translational pathophysiology. Endocrinology 2005; 146: 2684–2691.
Johnson D, Lanahan A, Buck CR, Sehgal A, Morgan C, Mercer E et al. Expression and structure of the human NGF receptor. Cell 1986; 47: 545–554.
Clark LB, Foy TM, Noelle RJ . CD40 and its ligand. Adv Immunol 1996; 63: 43–78.
Lougaris V, Badolato R, Ferrari S, Plebani A . Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features. Immunol Rev 2005; 203: 48–66.
Im SH, Barchan D, Maiti PK, Fuchs S, Souroujon MC . Blockade of CD40 ligand suppresses chronic experimental myasthenia gravis by down-regulation of Th1 differentiation and up-regulation of CTLA-4. J Immunol 2001; 166: 6893–6898.
Resetkova E, Kawai K, Enomoto T, Arreaza G, Togun R, Foy TM et al. Antibody to gp39, the ligand for CD40 significantly inhibits the humoral response from Graves' thyroid tissues xenografted into severe combined immunodeficient (SCID) mice. Thyroid 1996; 6: 267–273.
Chen CR, Aliesky HA, Guo J, Rapoport B, McLachlan SM . Blockade of costimulation between T cells and antigen-presenting cells: an approach to suppress murine Graves' disease induced using thyrotropin receptor-expressing adenovirus. Thyroid 2006; 16: 427–434.
Drachman DB . Myasthenia gravis. N Engl J Med 1994; 330: 1797–1810.
Conti-Fine BM, Milani M, Kaminski HJ . Myasthenia gravis: past, present, and future. J Clin Invest 2006; 116: 2843–2854.
Mariotti S, Caturegli P, Piccolo P, Barbesino G, Pinchera A . Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab 1990; 71: 661–669.
Nadler LM, Anderson KC, Marti G, Bates M, Park E, Daley JF et al. B4, a human B lymphocyte-associated antigen expressed on normal, mitogen-activated, and malignant B lymphocytes. J Immunol 1983; 131: 244–250.
Valentine MA, Meier KE, Rossie S, Clark EA . Phosphorylation of the CD20 phosphoprotein in resting B lymphocytes. Regulation by protein kinase C. J Biol Chem 1989; 264: 11282–11287.
Tedder TF, Tuscano J, Sato S, Kehrl JH . CD22, a B lymphocyte-specific adhesion molecule that regulates antigen receptor signaling. Annu Rev Immunol 1997; 15: 481–504.
Banchereau J, Bazan F, Blanchard D, Briere F, Galizzi JP, van Kooten C et al. The CD40 antigen and its ligand. Annu Rev Immunol 1994; 12: 881–922.
Braesch-Andersen S, Paulie S, Koho H, Nika H, Aspenstrom P, Perlmann P . Biochemical characteristics and partial amino acid sequence of the receptor-like human B cell and carcinoma antigen CDw40. J Immunol 1989; 142: 562–567.
Vaidya B, Imrie H, Perros P, Dickinson J, McCarthy MI, Kendall-Taylor P et al. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy. Lancet 1999; 354: 743–744.
Dechairo BM, Zabaneh D, Collins J, Brand O, Dawson GJ, Green AP et al. Association of the TSHR gene with Graves' disease: the first disease specific locus. Eur J Hum Genet 2005; 13: 1223–1230.
Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988–1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002; 87: 489–499.
Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxford) 1995; 43: 55–68.
Huang D, Liu L, Noren K, Xia SQ, Trifunovic J, Pirskanen R et al. Genetic association of Ctla-4 to myasthenia gravis with thymoma. J Neuroimmunol 1998; 88: 192–198.
Vandiedonck C, Giraud M, Garchon HJ . Genetics of autoimmune myasthenia gravis: the multifaceted contribution of the HLA complex. J Autoimmun 2005; 25 (Suppl): 6–11.
Sugiura T, Kawaguchi Y, Harigai M, Takagi K, Ohta S, Fukasawa C et al. Increased CD40 expression on muscle cells of polymyositis and dermatomyositis: role of CD40-CD40 ligand interaction in IL-6, IL-8, IL-15, and monocyte chemoattractant protein-1 production. J Immunol 2000; 164: 6593–6600.
Metcalfe RA, McIntosh RS, Marelli-Berg F, Lombardi G, Lechler R, Weetman AP . Detection of CD40 on human thyroid follicular cells: analysis of expression and function. J Clin Endocrinol Metab 1998; 83: 1268–1274.
Smith TJ, Sciaky D, Phipps RP, Jennings TA . CD40 expression in human thyroid tissue: evidence for involvement of multiple cell types in autoimmune and neoplastic diseases. Thyroid 1999; 9: 749–755.
Faure GC, Bensoussan-Lejzerowicz D, Bene MC, Aubert V, Leclere J . Coexpression of CD40 and class II antigen HLA-DR in Graves' disease thyroid epithelial cells. Clin Immunol Immunopathol 1997; 84: 212–215.
Davies TF, Bermas B, Platzer M, Roman SH . T-cell sensitization to autologous thyroid cells and normal non-specific suppressor T-cell function in Graves' disease. Clin Endocrinol (Oxford) 1985; 22: 155–167.
Hanafusa T, Pujol-Borrell R, Chiovato L, Russell RC, Doniach D, Bottazzo GF . Aberrant expression of HLA-DR antigen on thyrocytes in Graves' disease: relevance for autoimmunity. Lancet 1983; 2: 1111–1115.
Bottazzo GF, Pujol-Borrell R, Hanafusa T, Feldmann M . Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet 1983; 2: 1115–1119.
Bravo SB, Pampin S, Cameselle-Teijeiro J, Carneiro C, Dominguez F, Barreiro F et al. TGF-beta-induced apoptosis in human thyrocytes is mediated by p27kip1 reduction and is overridden in neoplastic thyrocytes by NF-kappaB activation. Oncogene 2003; 22: 7819–7830.
Francis DA, Karras JG, Ke XY, Sen R, Rothstein TL . Induction of the transcription factors NF-kappa B, AP-1 and NF-AT during B cell stimulation through the CD40 receptor. Int Immunol 1995; 7: 151–161.
Berberich I, Shu GL, Clark EA . Cross-linking CD40 on B cells rapidly activates nuclear factor-kappa B. J Immunol 1994; 153: 4357–4366.
Yanagawa Y, Onoe K . Distinct regulation of CD40-mediated interleukin-6 and interleukin-12 productions via mitogen-activated protein kinase and nuclear factor kappaB-inducing kinase in mature dendritic cells. Immunology 2006; 117: 526–535.
Mukundan L, Bishop GA, Head KZ, Zhang L, Wahl LM, Suttles J . TNF receptor-associated factor 6 is an essential mediator of CD40-activated proinflammatory pathways in monocytes and macrophages. J Immunol 2005; 174: 1081–1090.
Manning E, Pullen SS, Souza DJ, Kehry M, Noelle RJ . Cellular responses to murine CD40 in a mouse B cell line may be TRAF dependent or independent. Eur J Immunol 2002; 32: 39–49.
Bravo SB, Pampin S, Cameselle-Teijeiro J, Carneiro C, Dominguez F, Barreiro F et al. TGF-beta-induced apoptosis in human thyrocytes is mediated by p27kip1 reduction and is overridden in neoplastic thyrocytes by NF-kappaB activation. Oncogene 2003; 22: 7819–7830.
Bonif M, Meuwis MA, Close P, Benoit V, Heyninck K, Chapelle JP et al. TNFalpha- and IKKbeta-mediated TANK/I-TRAF phosphorylation: implications for interaction with NEMO/IKKgamma and NF-kappaB activation. Biochem J 2006; 394 (Part 3): 593–603.
He L, Grammer AC, Wu X, Lipsky PE . TRAF3 forms heterotrimers with TRAF2 and modulates its ability to mediate NF-{kappa}B activation. J Biol Chem 2004; 279: 55855–55865.
Morrison MD, Reiley W, Zhang M, Sun SC . An atypical tumor necrosis factor (TNF) receptor-associated factor-binding motif of B cell-activating factor belonging to the TNF family (BAFF) receptor mediates induction of the noncanonical NF-kappaB signaling pathway. J Biol Chem 2005; 280: 10018–10024.
Chan H, Reed JC . TRAF-dependent association of protein kinase Tpl2/COT1 (MAP3K8) with CD40. Biochem Biophys Res Commun 2005; 328: 198–205.
Ahmed-Choudhury J, Russell CL, Randhawa S, Young LS, Adams DH, Afford SC . Differential induction of nuclear factor-kappaB and activator protein-1 activity after CD40 ligation is associated with primary human hepatocyte apoptosis or intrahepatic endothelial cell proliferation. Mol Biol Cell 2003; 14: 1334–1345.
Buck D, Kroner A, Rieckmann P, Maurer M, Wiendl H . Analysis of the C/T(-1) single nucleotide polymorphism in the CD40 gene in multiple sclerosis. Tissue Antigens 2006; 68: 335–338.
Gaffney PM, Langefeld CD, Graham RR, Ortmann WA, Williams AH, Rodine PR et al. Fine-mapping chromosome 20 in 230 systemic lupus erythematosus sib pair and multiplex families: evidence for genetic epistasis with chromosome 16q12. Am J Hum Genet 2006; 78: 747–758.
Robertson NP, Deans J, Compston DA . Myasthenia gravis: a population based epidemiological study in Cambridgeshire, England. J Neurol Neurosurg Psychiatry 1998; 65: 492–496.
Sahay BM, Blendis LM, Reene R . Relation between myasthenia gravis and thyroid disease. Br Med J 1965; 5437: 762–765.
Kiessling WR, Finke R, Kotulla P, Schleusener H . Circulating TSH-binding inhibiting immunoglobulins in myasthenia gravis. Acta Endocrinol (Copenhagen) 1982; 101: 41–46.
Muller PY, Janovjak H, Miserez AR, Dobbie Z . Processing of gene expression data generated by quantitative real-time RT-PCR. BioTechniques 2002; 32: 1372–1374, 1376, 1378, 1379.
Ferrari S, Giliani S, Insalaco A, Al-Ghonaium A, Soresina AR, Loubser M et al. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci USA 2001; 98: 12614–12619.
Woolf B . On estimating the relation between blood group and disease. Ann Hum Genet 1955; 19: 251–253.
Acknowledgements
We thank all the study subjects who graciously agreed to participate in the study. We also thank Dr David Greenberg for his continued advice, and NDRI for providing us with human skeletal muscle tissue. We thank the investigators who helped enroll subjects for our studies: Drs Luca Chiovato, Roberto Rocchi and Aldo Pinchera (Pisa, Italy), Sandra McLachlan (Los Angeles, USA), Bernard Rees Smith (Cardiff, Wales, UK), Fred Clark and Eric Young (Newcastle upon Tyne, UK), Meir Berezin (Tel-Hashomer, Israel), George Carayanniotis (Newfoundland, Canada), Rhoda Cobin (New York, NY). This work was supported in part by DK61659, DK067555, and DK073681 from NIDDKD (to YT), and by a research grant from the American Thyroid Association (EMJ).
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Jacobson, E., Huber, A., Akeno, N. et al. A CD40 Kozak sequence polymorphism and susceptibility to antibody-mediated autoimmune conditions: the role of CD40 tissue-specific expression. Genes Immun 8, 205–214 (2007). https://doi.org/10.1038/sj.gene.6364375
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DOI: https://doi.org/10.1038/sj.gene.6364375
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