The Genetics of Autoimmune Thyroid Disease

Abstract

Recent studies have confirmed that polymorphisms in several genes confer susceptibility for the development of autoimmune thyroid disease, and that of these HLA-DR alleles, and the genes encoding CTLA-4, PTPN22, FCRL3, and probably the IL-2 receptor all have associations with other autoimmune disorders, indicating that they provide a lowering of the background threshold for the development of autoimmunity. Other factors (the TSHR and possibly Tg genes, HLA-C alleles, and environmental factors) determine that the type of disease which results from this background propensity specifically targets the thyroid. We also now appreciate much better how complex these disorders are in their pathogenesis: multiple genes influencing multiple immunological pathways are involved in pathogenesis, but are not involved in every patient. Any individual patient with thyroid autoimmunity has their own cluster of genetic (and environmental) susceptibility factors, only very partially shared with other patients who have the same diagnostic and clinical label. The interplay of forces that cause autoimmune thyroid disease in an individual patient are more subtle than previously imagined and there is at present no obvious upper limit on the number of genes which may be involved.

Key words

autoimmune thyroiditis - Graves’ disease - Hashimoto's disease - TSH-receptor antibodies

References

• 1 Brix TH, Kyvik KO, Christensen K, Hegedüs L. Evidence for a major role of heterdity in Graves’ disease: A population-based study of two Danish twin cohorts.  J Clin Endocrinol Metab. 2001;  86 930-934
• 2 Ringold DA, Nicoloff JT, Kesler M, Davis H, Hamilton A, Mack T. Further evidence for a strong genetic influence on the development of autoimmune thyroid disease: The California twin study.  Thyroid. 2002;  12 647-653
• 3 Vladutiu AO, Rose NR. Autoimmune murine thyroiditis relation to histocompatibility (H-2) type.  Science. 1971;  174 1137-1139
• 4 Jacobson EM, Huber A, Tomer Y. The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology.  J Autoimmun. 2008;  30 58-62
• 5 Bednarczuk T, Gopinath B, Ploski R, Wall JR. Susceptibility genes in Graves’ ophthalmopathy: searching for a needle in a haystack?.  Clin Endocrinol (Oxf). 2007;  67 3-19
• 6 Zeitlin AA, Simmonds MJ, Gough SC. Genetic developments in autoimmune thyroid disease: an evolutionary process.  Clin Endocrinol (Oxf). 2008;  68 671-682
• 7 Heward JM, Allahabadia A, Daykin J, Carr-Smith J, Daly A, Armitage M, Dodson PM, Sheppard MC, Barnett AH, Franklyn JA, Gough SC. Linkage disequilibrium between the human leukocyte antigen class II region of the major histocompatibility complex and Graves’ disease: replication using a population case control and family-based study.  J Clin Endocrinol Metab. 1998;  83 3394-3397
• 8 Chen PL, Fann CS, Chang CC, Wu IL, Chiu WY, Lin CY, Yang WS, Chang TC. Linkage of Graves’ disease to the human leucocyte antigen region in the Chinese-Han population in Taiwan.  Clin Endocrinol (Oxf). 2007;  66 646-651
• 9 Zeitlin AA, Heward JM, Newby PR, Carr-Smith JD, Franklyn JA, Gough SC, Simmonds MJ. Analysis of HLA class II genes in Hashimoto's thyroiditis reveals differences compared to Graves’ disease.  Genes Immun. 2008;  9 358-363
• 10 Golden B, Levin L, Ban Y, Concepcion E, Greenberg DA, Tomer Y. Genetic analysis of families with autoimmune diabetes and thyroiditis: evidence for common and unique genes.  J Clin Endocrinol Metab. 2005;  90 4904-4911
• 11 Simmonds MJ, Howson JM, Heward JM, Carr-Smith J, Franklyn JA, Todd JA, Gough SC. A novel and major association of HLA-C in Graves’ disease that eclipses the classical HLA-DRB1 effect.  Hum Mol Genet. 2007;  16 2149-2153
• 12 Tomer Y, Davies TF. Searching for the autoimmune thyroid disease susceptibility genes: from gene mapping to gene function.  Endocr Rev. 2003;  24 694-717
• 13 Ban Y, Greenberg DA, Davies TF, Jacobson E, Concepcion E, Tomer Y. Linkage analysis of thyroid antibody production: evidence for shared susceptibility to clinical autoimmune thyroid disease.  J Clin Endocrinol Metab. 2008;  93 3589-3596
• 14 Yanagawa T, Hidaka Y, Guimaraes V, Soliman M, DeGroot LJ. CTLA-4 gene polymorphism associated with Graves’ disease in Caucasian population.  J Clin Endocrinol Metab. 1995;  80 41-45
• 15 Wang PW, Chen IY, Liu RT, Hsieh CJ, Hsi E, Juo SH. Cytotoxic T lymphocyte-associated molecule-4 gene polymorphism and hyperthyroid Graves’ disease relapse after antithyroid drug withdrawal: a follow-up study.  J Clin Endocrinol Metab. 2007;  92 2513-2518
• 16 Han S, Zhang S, Zhang W, Li R, Li Y, Wang Z, Xie Y, Mao Y. CTLA4 polymorphisms and ophthalmopathy in Graves’ disease patients: association study and meta-analysis.  Hum Immunol. 2006;  67 618-626
• 17 Ikegami H, Awata T, Kawasaki E, Kobayashi T, Maruyama T, Nakanishi K, Shimada A, Amemiya S, Kawabata Y, Kurihara S, Tanaka S, Kanazawa Y, Mochizuki M, Ogihara T. The association of CTLA4 polymorphism with type 1 diabetes is concentrated in patients complicated with autoimmune thyroid disease: a multicenter collaborative study in Japan.  J Clin Endocrinol Metab. 2006;  91 1087-1092
• 18 Kavvoura FK, Akamizu T, Awata T, Ban Y, Chistiakov DA, Frydecka I, Ghaderi A, Gough SC, Hiromatsu Y, Ploski R, Wang PW, Ban Y, Bednarczuk T, Chistiakova EI, Chojm M, Heward JM, Hiratani H, Juo SH, Karabon L, Katayama S, Kurihara S, Liu RT, Miyake I, Omrani GH, Pawlak E, Taniyama M, Tozaki T, Ioannidis JP. Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis.  J Clin Endocrinol Metab. 2007;  92 3162-3170
• 19 Velaga MR, Wilson V, Jennings CE, Owen CJ, Herington S, Donaldson PT, Ball SG, James RA, Quinton R, Perros P, Pearce SHS. The codon 620 tryptophan allele of the lymphoid tyrosine phosphates (LYP) gene is a major determinant of Graves’ disease.  J Clin Endocrinol Metab. 2004;  89 5862-5865
• 20 Heward JM, Brand OJ, Barrett JC, Carr-Smith JD, Franklyn JA, Gough SC. Association of PTPN22 haplotypes with Graves’ disease.  J Clin Endocrinol Metab. 2007;  92 685-690
• 21 Syed AA, Simmonds MJ, Brand OJ, Franklyn JA, Gough SC, Heward JM. Preliminary evidence for interaction of PTPN12 polymorphism with TSHR genotype and association with Graves’ ophthalmopathy.  Clin Endocrinol (Oxf). 2007;  67 663-667
• 22 Dechairo BM, Zabaneh D, Collins J, Brand O, Dawson GJ, Green AP, Mackay I, Franklyn JA, Connell JM, Wass JA, Wiersinga WM, Hegedus L, Brix T, Robinson BG, Hunt PJ, Weetman AP, Carey AH, Gough SC. Association of the TSHR gene with Graves’ disease: the first disease specific locus.  Eur J Hum Genet. 2005;  131 223-230
• 23 Wellcome Trust Case Control Consortium, Australo-Anglo-American Spondylitis Consortium (TASC). . Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.  Nat Genet. 2007;  39 1329-1337
• 24 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. A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities.  Nat Genet. 2005;  7 478-485
• 25 Simmonds MJ, Heward JM, Carr-Smith J, Foxall H, Franklyn JA, Gough SC. Contribution of single nucleotide polymorphisms within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves’ disease.  J Clin Endocrinol Metab. 2006;  91 1056-1061
• 26 Owen CJ, Kelly H, Eden JA, Merriman ME, Pearce SH, Merriman TR. Analysis of the Fc receptor-like-3 (FCRL3) locus in Caucasians with autoimmune disorders suggests a complex pattern of disease association.  J Clin Endocrinol Metab. 2007;  92 1106-1111
• 27 Vella A, Cooper JD, Lowe CE, Walker N, Nutland S, Widmer B, Jones R, Ring SM, McArdle W, Pembrey ME, Strachan DP, Dunger DB, Twells RC, Clayton DG, Todd JA. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms.  Am J Hum Genet. 2005;  76 773-779
• 28 Brand OJ, Lowe CE, Heward JM, Franklyn JA, Cooper JD, Todd JA, Gough SC. Association of the interleukin-2 receptor alpha (IL-2R alpha)/CD25 gene region with Graves’ disease using a multilocus test and tag SNPs.  Clin Endocrinol (Oxf). 2007;  66 508-512
• 29 Taylor JC, Gough SC, Hunt PJ, Brix TH, Chatterjee K, Connell JM, Franklyn JA, Hegedus L, Robinson BG, Wiersinga WM, Wass JA, Zabaneh D, Mackay I, Weetman AP. A genome-wide screen in 1119 relative pairs with autoimmune thyroid disease.  J Clin Endocrinol Metab. 2005;  91 646-653
• 30 Collins JE, Heward JM, Howson JM, Foxall H, Carr-Smith J, Franklyn JA, Gough SC. Common allelic variants of exons 10, 12, and 33 of the thyroglobulin gene are not associated with autoimmune thyroid disease in the United Kingdom.  J Clin Endocrinol Metab. 2004;  89 6336-6339
• 31 Hsiao JY, Hsieh MC, Tien KJ, Hsu SC, Shin SJ, Lin SR. Association between a C/T polymorphism in exon 33 of the thyroglobulin gene is associated with relapse of Graves’ hyperthyroidism after antithyroid withdrawal in Taiwanese.  J Clin Endocrinol Metab. 2007;  92 3197-3201
• 32 Kurylowicz A, Kula D, Ploski R, Skorka A, Jurecka-Lubieniecka B, Zebracka J, Steinhof-Radwanska K, Hasse-Lazar K, Hiromatsu Y, Jarzab B, Bednarczuk T. Association of CD40 gene polymorphism (C-1 T) with susceptibility and phenotype of Graves’ disease.  Thyroid. 2005;  15 1119-1124
• 33 Simmonds MJ, Heward JM, Franklyn JA, Gough SC. The CD40 Kozak SNP: a new susceptibility loci for Graves’ disease?.  Clin Endocrinol (Oxf). 2005;  63 232-233
• 34 Jacobson EM, Huber AK, Akeno N, Sivak M, Li CW, Concepcion E, Ho K, Tomer Y. A CD40 Kozak sequence polymorphism and susceptibility to antibody-mediated autoimmune conditions: the role of CD40 tissue-specific expression.  Genes Immun. 2007;  8 205-214
• 35 Tsurumaru M, Kawasaki E, Ida H, Migita K, Moriuchi A, Fukushima K, Fukushima T, Abiru N, Yamasaki H, Noso S, Ikegami H, Awata T, Sasaki H, Eguchi K. Evidence for the role of small ubiquitin-like modifier 4 as a general autoimmunity locus in the Japanese population.  J Clin Endocrinol Metab. 2006;  91 3138-3143
• 36 Newby PR, Roberts-Davies EL, Brand OJ, Heward JM, Franklyn JA, Gough SC, Simmonds MJ. Tag SNP screening of the PDCD1 gene for association with Graves’ disease.  Clin Endocrinol (Oxf). 2007;  67 125-128
• 37 Sutherland A, Davies J, Owen CJ, Vaikkakara S, Walker C, Cheetham TD, James RA, Perros P, Donaldson PT, Cordell HJ, Quinton R, Pearce SH. Genomic polymorphism at the interferon-induced helicase (IFIH1) locus contributes to Graves’ disease susceptibility.  J Clin Endocrinol Metab. 2007;  92 3338-3341
• 38 Huber AK, Jacobson EM, Jazdzewski K, Concepcion ES, Tomer Y. Interleukin (IL)-23 receptor is a major susceptibility gene for Graves’ ophthalmopathy: the IL-23/T-helper 17 axis extends to thyroid autoimmunity.  J Clin Endocrinol Metab. 2008;  93 1077-1081
• 39 Chen HY, Cui B, Wang S, Zhao ZF, Sun H, Zhao YJ, Li XY, Ning G. L-selectin gene polymorphisms in Graves’ disease.  Clin Endocrinol (Oxf). 2007;  67 145-151
• 40 Kisiel B, Bednarczuk T, Kostrzewa G, Kosiñska J, Miœkiewicz P, Płaziñska MT, Bar-Andziak E, Królicki L, Krajewski P, Płoski R. Polymorphism of the oestrogen receptor beta gene (ESR2) is associated with susceptibility to Graves’ disease.  Clin Endocrinol (Oxf). 2008;  68 429-434
• 41 Hafler JP, Maier LM, Cooper JD, Plagnol V, Hinks A, Simmonds MJ, Stevens HE, Walker NM, Healy B, Howson JM, Maisuria M, Duley S, Coleman G, Gough SC, Worthington J, Kuchroo VK, Wicker LS, Todd JA. The International Multiple Sclerosis Genetics Consortium (IMSGC) . CD226 Gly307Ser association with multiple autoimmune diseases.  Genes Immun. 2009;  10 5-10
• 42 Davies TF. Really significant genes for autoimmune thyroid disease do not exist – so how can we predict disease?.  Thyroid. 2007;  17 1027-1029
• 43 Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, Thorne N, Redon R, Bird CP, de Grassi A, Lee C, Tyler-Smith C, Carter N, Scherer SW, Tavaré S, Deloukas P, Hurles ME, Dermitzakis ET. Relative impact of nucleotide and copy number variation on gene expression phenotypes.  Science. 2007;  315 848-853
• 44 Cordell HJ, Clayton DG. Genetic association studies.  Lancet. 2005;  366 1121-1131
• 45 Crow MK. Collaboration, genetic associations, and lupus erythematosus.  N Engl J Med. 2008;  358 956-961
• 46 Ware JH. The limitations of risk factors as prognostic tools.  N Engl J Med. 2006;  355 2615-2617

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